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Wenzhen Ge,1 Ning Wu,1 Chieh-I Chen,1 Timothy J Inocencio,1 Patrick R LaFontaine,2 Frank Seebach,3 Matthew Fury,4 James Harnett,1 Emily S Ruiz5 1Department of Health Economics and Outcomes Research, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 2Department of Global Health Economics & Outcomes Research, Sanofi, Cambridge, MA, USA; 3Department of Regulatory Affairs, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 4Department of Clinical Sciences, Oncology, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 5Department of Dermatology, Dana-Farber Cancer Institute, Boston, MA, USACorrespondence: Wenzhen Ge, Regeneron Pharmaceuticals, Inc, 1 Rockwood Road, Sleepy Hollow, NY, 10591, Tel +1 914-847-7000, Email wenzhen.ge@regeneron.comBackground: Prior to the Food and Drug Administration approval of cemiplimab in 2018, the median overall survival (OS) for adult patients with advanced CSCC receiving systemic therapy was approximately 8 to 15 months. Limited real-world data are available on cemiplimab for this indication in the US.Patients and Methods: This retrospective cohort study included US patients with advanced CSCC initiating cemiplimab monotherapy in a real-world database (2018– 2021). A clinical trial–like sub-cohort was identified using select criteria. Time to treatment discontinuation (TTD), time to next treatment (TTNT), and OS were estimated using Kaplan–Meier methods. Cox proportional hazard models were used to examine prognostic factors associated with OS in the main cohort.Results: The main cohort included 622 patients (n = 240 in the trial-like cohort). In the main cohort, the median age was 78 years, 77.8% were male, 21.4% were immunocompromised/immunosuppressed, and 63.8% had metastatic CSCC. Median (95% CI) TTD and TTNT were 8.0 (6.6– 9.0) months and 16.4 (13.3– 21.0) months, respectively, in the main cohort. Median (95% CI) OS was 24.8 (21.8– 29.1) months in the main cohort (not reached in the trial-like cohort). In multivariable analyses, age < 60 years (hazard ratio [HR], 0.37), Eastern Cooperative Oncology Group performance status < 3– 4 (HR range, 0.13– 0.57), and primary CSCC location in the head and neck only versus extremities only (HR, 0.59) were associated with better OS. Similar OS was observed between patients who had immunosuppressing/immunocompromising conditions and those without.Conclusion: These findings confirm the effectiveness of cemiplimab among a heterogenous, real-world advanced CSCC patient population and substantiate the efficacy of cemiplimab observed in clinical trials.Keywords: cutaneous squamous cell carcinoma, cemiplimab, immune checkpoint inhibitor, real-world study, skin cancer

Neha Gupta, Emily S Ruiz Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Jamaica Plain, MA, USACorrespondence: Emily S RuizDepartment of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, 1153 Centre Street, Suite 4J, Jamaica Plain, MA, 02130, USATel +1 617-983-4626Fax +1 617-983-4504Email esruiz@bwh.harvard.eduAbstract: Basal cell carcinoma (BCC) is the most common cancer in Caucasians, and its incidence continues to rise. Generally, BCCs have good outcomes when diagnosed and treated early. However, 1– 10% of patients will develop advanced disease due to either delays in accessing treatment or aggressive tumors that may be refractory to treatment. Locally advanced basal cell carcinomas (laBCCs) are large, aggressive, or recurrent tumors that have the potential to invade surrounding tissues including bone, cartilage, nerve, and muscle. Treatment requires a multi-disciplinary approach where different modalities including surgery, radiation therapy, Hedgehog Pathway Inhibitors, and immunotherapy can be considered.Keywords: hedgehog pathway inhibitors, surgery, radiotherapy, immunotherapy, skin cancer

Chagas disease constitutes a relatively prevalent condition in Latin America and is increasing worldwide, with a wide spectrum of clinical subsets. Imaging modalities are critical for adequate diagnosis, staging and prognosis of this entity. Currently Echocardiography and Cardiac Magnetic Resonance are the most valuable techniques for this purpose. Evidence for both modalities has increased in the last years, as the role of advanced techniques such as Speckle Tracking Echocardiography has been explored. We aim to review the evidence of advanced imaging in the spectrum of patients with Chagas Heart Disease.

The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.

Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART). Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event. Results: Random sampling of matched patient pairs ( n  = 52 ART-treated; 371 no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1. Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).

Background: Mental health problems represent a large and growing public health concern. Primary care handles most of the patients with mental health problems, but there are many barriers to detection and treatment in this setting, causing under-recognition and under-treatment of patients. The service delivery model Primary Care Behavioral Health (PCBH) shows promise to manage mental health problems in primary care, but more research is needed regarding its effects on multiple levels., Methods: This project investigates the effectiveness and implementation of a large-scale implementation of PCBH in Region Östergötland, Sweden. The aim is to generate new knowledge concerning the impact of a real-world implementation and use of PCBH in routine primary care. A Pragmatic Stepped-Wedge Cluster Trial will be used: 24 PCBH primary care centres in one region will be compared with 48 standard care centres in three other regions. The model will be implemented sequentially at the PCBH centres according to a staggered timetable. Results will be investigated at patient, staff and organization levels and various forms of data will be collected: (1) local and national registry data; (2) questionnaire data; (3) interview data; and (4) document data., Discussion: This project investigates the effectiveness and implementation of PCBH in routine primary care. The project could result in improved mental health care for the included patients and contribute to the general good for a wider population who have mental health problems. The project's study design will make it possible to assess many important effects of the PCBH service delivery model at different levels, providing evidence of the effectiveness (or not) of the PCBH model under routine conditions in primary care. The project has the potential to generate clinically meaningful results that can provide a basis for decisions concerning further implementation and use of the model and thus for future development of mental health care provision in primary care., Trial Registration: NCT05633940, date of registration: 2021-04-21., (© 2024. The Author(s).)

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.

Competing Interests: Conflicts of interest Dr Ruiz serves is a consultant for Regeneron, Checkpoint Therapeutic, Feldan Pharmaceuticals. She serves as a Principal Investigator/Co-Investigator for the following companies: Regeneron (PI/Co-I), Merck (Co-I), Castle Biosciences (Co-I) and is the Executive Officer of Skin Cancer Outcomes Consortium (SCOUT) Skin Cancer Champions. Dr Carr is an investigator for Regeneron (no direct funds). Dr Cañueto has the following disclosures: grants to institution: Sanofi/Regeneron, Castle Biosciences; Lectures honoraria: Sanofi, Almirall, AbbVie, Regeneron, Sun Pharma; Payment for expert testimony: Sanofi, Regeneron, Almirall; Support for attending meetings: Pfizer, Almirall, Lilly, Castle Biosciences; Advisory board: Almirall, Sanofi, Regeneron, Kyowa, Roche, InflaRx; Funding: support by the Gerencia Regional de Salud de Castilla y León (GRS2549/A/22) and by the Instituto de Salud Carlos III (PI21/01207), co-financed by European Union. Dr Mangold has patent Methods and Materials for assessing and treating cutaneous squamous cell carcinoma (provisional 63-423254) and Regeneron Consulting with payments to the institution. He has consulted for Kyowa, Eli Lilly, Momenta, UCB, and Regeneron in the past, greater than 24 months ago. He has consulted for PHELEC in the past, great than 12 months. He has consulted for Incyte, Soligenix, Clarivate, and Bristol Myers Squibb in the past, less than 12 months ago. He consults for Nuvig, Argenyx, Boehringer, Janssen, and Ingelheim currently. He consults for Pfizer currently with payments to the institution. He has grant support from Kyowa, Miragen, Regeneron, Corbus, Pfizer, Incyte, Eli Lilly, Aregenx, Palbella, AbbVie, Priovant, Merck in the last 24 months. Beyond 24 months, grant support has come from Sun Pharma, Elorac, Novartis, and Janssen. His current patents include the use of oral JAKi in Lichen Planus (provisional 63/453,065), and Topical Ruxolitinib in Lichen Planus (WO2022072814A1). Dr Carucci receives funding for investigator initiated basic science research from Regeneron and is a PI for a clinical trial sponsored by Regeneron. Dr Koyfman has the following disclosures: Advisory board (paid): Merck, BMS, Regeneron, Galera therapeutics; Advisory board (unpaid): Castle Biosciences; Research support: Castle biosciences, merck, BMS, Regeneron; Honoraria: UpToDate. Dr Vidimos has the following dicslosures: Research Support – Castle; Advisory Board - Inhibitor Therapeutics; Honoraria - Up to Date. Dr Wysong has received an institutional research grant from Castle Biosciences. Drs Granger, Ran, Groover, Shahwan, Hirotsu, Carter, Girardi, Brodland, Sruvastava, Zitelli, and Willenbrink have no conflicts of interest to declare.

Background: Risk stratification can identify individuals in primary care settings who are at increased risk of developing melanoma., Objective: Converting and implementing a validated risk stratification tool as a patient self-administered tablet-based survey., Methods: Mackie risk stratification tool was transformed into a patient questionnaire. The questionnaire was completed in academic dermatologist practices by patients and dermatologists and revised to optimize sensitivity and specificity using physician assessment as gold standard. The optimized survey was administered before routine primary care visits during 2019 to 2021. High-risk patients were referred to dermatology. The number needed to screen (NNS), sensitivity, specificity, positive predictive value, and negative predictive value to identify a melanoma were calculated., Results: Of the 7,893 respondents, 5,842 (74%) and 2,051 (26%) patients were categorized as low-risk and high-risk population, respectively. The NNS to identify 1 melanoma was 64 in the high-risk population., Conclusion: Incorporating self-administered patient-risk stratification tools in primary care settings can identify high-risk individuals for targeted melanoma screening. Further studies are needed to optimize specificity and sensitivity in more targeted populations., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Importance: In clinical trials, preoperative immune checkpoint inhibitors (ICIs) have shown clinical activity in advanced cutaneous squamous cell carcinoma (cSCC). However, these studies excluded patients with relevant comorbidities., Objective: To evaluate radiologic and pathologic response rates to neoadjuvant-intent programed cell death protein 1 (PD-1) ICIs in a clinical population., Design, Setting, and Participants: This cohort study of patients who were treated with neoadjuvant cemiplimab or pembrolizumab for advanced cSCC from January 2018 to January 2023 was conducted at 2 academic institutions in Boston, Massachusetts. Median follow-up was 9.5 months (range, 1.2-40.5)., Exposures: Cemiplimab or pembrolizumab., Main Outcomes and Measures: Primary outcomes were radiologic and pathologic response rates. Secondary outcomes were 1-year recurrence-free survival, progression-free survival, disease-specific survival, and overall survival., Results: This cohort study included 27 patients (including 9 patients [33.3%] with a history of lymphoma). Most patients were male (18 of 27 [66.7%]), with a median age of 72 years (range, 53-87 years). Most primary tumors were located on the head/neck (21 of 27 [77.8%]). There were no unexpected delays in surgery. The median number of doses before surgery was 3.5 (range, 1.0-10.0). Five patients (18.5%) ultimately declined to undergo planned surgery due to clinical responses or stability, and 1 (3.7%) did not undergo surgery due to progressive disease. The overall pathologic response rate (pathological complete response [pCR] or major pathological response) was 47.4% (9 of 19), and the overall radiologic response rate (radiologic complete response or partial response) was 50.0% (8 of 16). The pCR rate (7 of 19 [36.8%]) was higher than the radiologic complete response rate (2 of 16 [12.5%]). The pCR rate among patients with cSCC and concomitant lymphoma was 25.0%. The 1-year recurrence-free survival rate was 90.9% (95% CI, 50.8%-98.7%), progression-free survival was 83.3% (95% CI, 27.3%-97.5%), disease-specific survival was 91.7% (95% CI, 53.9%-98.8%), and overall survival was 84.6% (95% CI, 51.2%-95.9%)., Conclusions and Relevance: The results of this cohort study support the reproducibility of neoadjuvant-intent immunotherapy for cSCC in the clinical setting, including for patients with a history of lymphoma. Outside of clinical trials, it is not infrequent for patients to opt out of surgery for regressing tumors. The inclusion of higher-risk patients and preference for nonsurgical treatment are 2 factors that might explain the numerically lower pathologic response rate in this institutional experience.

Background: Immunosuppression is a known risk factor for the development of cutaneous squamous cell carcinoma (CSCC), especially in solid organ transplant recipients and chronic lymphocytic leukemia. However, this risk is less well defined in autoimmune and inflammatory conditions., Objective: Assess the impact that disease-type, duration of immunosuppression, and systemic medications have on CSCC accrual rates, defined as the number of CSCCs a patient develops per year, in autoimmune and inflammatory conditions., Methods: Retrospective review of 94 immunosuppressed (rheumatoid arthritis: 31[33.0%], inflammatory bowel disease: 17[18.1%], psoriasis: 11[11.7%], autoimmune other (AO): 24[25.5%], inflammatory other: 21[22.3%]) and 188 immunocompetent controls to identify all primary, invasive CSCCs diagnosed from 2010 to 2020., Results: Immunosuppressed patients had higher CSCC accrual rates than immunocompetent controls (0.44 ± 0.36): total cohort (0.82 ± 0.95, P < .01), rheumatoid arthritis (0.88 ± 1.10, P < .01), inflammatory bowel disease (0.94 ± 0.88, P < .01), psoriasis (1.06 ± 1.58, P < .01), AO (0.72 ± 0.56, P < .01), and inflammatory other (0.72 ± 0.61, P < .01). There was an association between increased tumor accrual rates and exposure to systemic medications including, immunomodulators, tumor necrosis factor-alpha inhibitors, non-tumor necrosis factor inhibitor biologics, and corticosteroids, but not with number of systemic medication class exposures or duration of immunosuppression., Limitations: Retrospective, singlecenter study., Conclusion: Patients with autoimmune and inflammatory conditions accrue CSCCs at higher rates than immunocompetent patients., Competing Interests: Conflicts of interest Dr Emily Ruiz has served as a consultant for Regeneron, Genentech, and Checkpoint Therapeutics. Dr Chrysalyne Schmults serves as a consultant for the following companies: Regeneron and Sanofi, and Castle Biosciences. She has research support from Castle Biosciences, and Merck and Regeneron. She serves on the Board of Directors for American Society of Dermatologic Surgery as well as Secretary/Treasurer of the International Society of Dermatologic Surgery. She is also the Non-Melanoma Skin Cancer Panel Chair for the National Comprehensive Cancer Network. She currently serves as the Founder/ President of Skin Cancer Outcomes (SCOUT). Emily Granger, BS has no relevant conflicts of interest. Morgan Groover, BS has no relevant conflicts of interest. Emily Karn, MS has no relevant conflicts of interest. Dr Fadi Murad has no relevant conflicts of interest. Dr Catherine Harwood MA PhD FRCP has no relevant conflicts of interest. Dr Charlotte M. Proby MA MRCP has no relevant conflicts of interest., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: Since use of major cutaneous surgeries/reconstructions among patients with cutaneous squamous cell carcinoma (CSCC) is not well described, we sought to quantify major cutaneous surgeries/reconstructions among patients with CSCC who were newly diagnosed and for those treated with systemic therapy, stratified by immune status. Methods: We used the Optum ® Clinformatics ® Data Mart database (2013-2020) and Kaplan-Meier estimators to assess risk of surgeries/reconstructions. Results: 450,803 patients were identified with an incident CSCC diagnosis, including 4111 patients with CSCC who initiated systemic therapy. The respective 7-year risks of major cutaneous surgeries/reconstructions were 10.9% (95% CI: 10.7-11.0) and 21.8% (95% CI: 17.6-25.8). Overall risk of major cutaneous surgeries/reconstructions was higher in patients who were immunocompromised than those who were immunocompetent. Conclusion: Approximately one in nine patients with CSCC will undergo ≥1 major cutaneous surgeries/reconstructions within 7 years of diagnosis; the risk increases in patients who initiate systemic therapy and among those who are immunocompromised.

Purpose: Cemiplimab is approved for treating locally advanced or metastatic cutaneous squamous cell carcinoma (CSCC). Solid organ transplant recipients have been excluded from immunotherapy trials, given concern for allograft rejection despite their increased risk of skin cancers. Chronic immunosuppression is necessary to prevent organ rejection but may attenuate antitumor response with PD-1 inhibitors., Methods: We report a phase I study of cemiplimab for kidney transplant recipients (KTRs) with advanced CSCC. After cross-taper to a mammalian target of rapamycin (mTOR) inhibitor and pulsed dose corticosteroids (prednisone 40 mg once daily, the day before and on days 1-3 of each cycle, followed by 20 mg once daily on days 4-6, then 10 mg once daily until the day before each subsequent cycle), patients received cemiplimab 350 mg intravenously once every 3 weeks for up to 2 years and were assessed for response every 8 weeks. The primary end point was the rate of kidney rejection, with key secondary end points including rate and duration of response, and survival., Results: Twelve patients were treated. No kidney rejection or loss was observed. A response to cemiplimab was observed in five of 11 evaluable patients (46%; 90% CI, 22 to 73), including two with durable responses beyond a year. Median follow-up was 6.8 months (range, 0.7-29.8). Treatment-related grade 3 or greater adverse events occurred in five patients (42%), including diarrhea, infection, and metabolic disturbances. One patient died of angioedema and anaphylaxis attributed to mTOR inhibitor cross-taper., Conclusion: mTOR inhibitor and corticosteroids represent a favorable immunosuppressive regimen for KTRs with advanced CSCC receiving immunotherapy. This combination resulted in durable antitumor responses with no kidney rejection events (funded by Regeneron Pharmaceuticals [ClinicalTrials.gov identifier: NCT04339062]).

Background: Metastatic basal cell carcinoma (mBCC) is rare and there are limited data regarding patient and tumor risk factors, optimal treatments, and disease prognosis., Objective: To assess patient and tumor characteristics, therapeutics, and outcomes of mBCC stratified by location of metastasis., Methods: Retrospective cohort study of 53 patients with mBCC treated at 4 large academic centers in Boston, Massachusetts; Philadelphia, Pennsylvania; and Cleveland, Ohio between January 1, 2005 and December 31, 2021., Results: A total of 53 patients with mBCC were identified across 4 centers, 22 (42%) of whom had mBCC with spread limited to lymph nodes and 31 (58%) patients with distant organ spread (with or without lymph node involvement). Overall, half (n = 11) of patients with nodal metastasis achieved complete remission of disease, compared with just 1 (3%) patient with distant metastasis. The 5-year survival for nodal and distant metastatic patients was 89.3% and 61.0%, respectively., Limitations: Small sample size due to disease rarity., Conclusions and Relevance: Patients with nodal disease are more likely to have disease remission whereas patients with distant metastasis are more likely to have persistent disease and die from their disease. However, 5-year survival rates exceed 50%, even for stage IV disease., Competing Interests: Conflicts of interest Dr Ruiz has received research support from Regeneron and Pellepharm, and has consulted for Regeneron, Checkpoint Therapeutics, and Feldan Therapeutics. Dr Silk has received research support from Biohaven Pharmaceuticals, Replimune, Morphogenesis, Shattuck Laboratories, Regeneron, and Merck, is a member of the Regeneron Ad Board as of July 2023, and is on the Board of Directors of the Society for Immunotherapy of Cancer. Dr Schoenfeld has received research support from Merck, BMS, Regeneron, Debiopharm, and EMD Serono, has consulting, scientific advisory board, and travel fee relationships with Castle Biosciences, Genentech, Immunitas, Debiopharm, BMS, Tilos, ACI Clinical, Astellas, Stimit, Merck KGA, SIRPant, and EMD Serono, has received expert witness fees from Pearson Doyle Mohre & Pastis, is a member of the Data Safety Monitoring or Advisory Board at ACI Clinical, EMD Serono, and Merck KGA, has stock options in Immunitas, and has equity in Doximity. Dr Koyfman has received research support from Merck, BMS, Castle Biosciences, and Regeneron, has consulted for Merck, Regeneron, and Galera, writes for Up To Date, and is a member of the advisory board for Alpha Part. The other authors have no conflicts of interest to declare., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Conflicts of interest Dr Silk reports receiving Grants/Research Support (to the Institution) from Biohaven Pharmaceuticals, Replimune, Morphogenesis, Shattuck Laboratories, advisory board fees from InStil Bio, Signatera, and Merck, and royalties from UpToDate. The other authors have no conflict of interest to declare.

Background: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636)., Patients and Methods: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability., Results: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths., Conclusions: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Dr Ruiz has served as a consultant for Regeneron, Genetech, and Checkpoint Therapeutics. Author Johnson, Author Groover, Author Granger, Dr Murad, and Author Karn have no conflicts of interest to declare.

Background: According to the curriculum guidelines of the Accreditation Council of Graduate Medical Education and the American Board of Dermatology, Mohs micrographic surgery & dermatologic oncology (MSDO) fellows must demonstrate competency in the use of oral skin cancer chemoprophylaxis. The current level of education in this area is unknown., Objective: To characterize oral skin cancer chemoprophylaxis education for acitretin and nicotinamide among current MSDO fellows and to compare the clinical indications felt most appropriate for prescribing to a previously published expert consensus., Methods: An electronic survey was distributed to all active MSDO fellows by the American College of Mohs Surgery., Results: Responses were received from 63 (69.2%) MSDO fellows. Twenty (31.7%) and 37 (58.7%) fellows reported receiving fellowship training on acitretin and nicotinamide, respectively. Fifty-seven (90.5%) intend to prescribe chemoprophylaxis after training. Sixteen (28.1%) and 43 (75.4%) report feeling very comfortable prescribing acitretin and nicotinamide, respectively. Fellow concordance with a previously published expert consensus opinion on appropriate prescribing indications is variable. Forty-one (65.1%) indicated that additional education would increase the likelihood to prescribe after training., Conclusion: Although most MSDO fellows intend to prescribe oral skin cancer chemoprophylaxis, a standardized curriculum may promote increased use and concordance with expert consensus recommendations., (Copyright © 2023 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Importance: Perineural invasion (PNI) is an adverse risk feature in cutaneous squamous cell carcinoma (CSCC) that affects patient prognosis and disease management. However, research comparing different PNI patterns on patient outcomes is limited., Objective: To compare 4 assessments of PNI in CSCC, their associations with poor outcomes, and implications for their inclusion in the Brigham and Women's Hospital (BWH) staging system., Design, Setting, and Participants: This retrospective cohort study was performed at a single tertiary care institution and compared 4 PNI assessments: nerve caliber, number of involved nerves per section, PNI maximal depth, and PNI location with respect to tumor. Patients with primary, localized, invasive CSCC with PNI diagnosed between January 1, 2000, and December 31, 2017, were identified via an electronic in-house database. Available pathology slides were secondarily reviewed by study authors. Relevant patient and tumor characteristics and outcomes were abstracted from the medical record. Data analysis was performed between September 6 and October 20, 2022., Main Outcomes and Measures: Risks of recurrence, disease-specific death, and a composite end point (any poor outcome) were calculated via multivariable stepwise Fine and Gray competing-risks regression. Considered revisions to the BWH staging system were assessed via receiver operating characteristic curves and test characteristics., Results: This study included 140 patients with CSCC, with a mean (SD) age of 75.1 (11.2) years. More than half of the patients were men (93 [66.4%]), and most identified as White (132 [94.3%]). Of the 4 PNI assessments studied, only involvement of multiple nerves was associated with poor outcomes. Perineural invasion of 5 or more distinct nerves (extensive PNI [ePNI]) was independently associated with local recurrence (subhazard ratio [SHR], 13.83 [95% CI, 3.50-54.62]; P < .001), disease-specific death (SHR, 6.20 [95% CI, 1.59-24.21]; P = .009), and any poor outcome (SHR, 10.21 [95% CI, 2.88-36.15]; P < .001). A revised BWH staging system with substitution of ePNI for large-caliber PNI resulted in improved area under the curve and test characteristics compared with current BWH staging criteria that use nerve caliber as the measure of PNI., Conclusions and Relevance: The findings of this cohort study suggest that ePNI is the best prognostic measure of PNI. Because ePNI obviated the need for a micrometer and had superior prognostic capacity to nerve caliber in this cohort, ePNI should be considered for inclusion in CSCC tumor staging. Inclusion of ePNI as a high-risk factor in CSCC staging systems may optimize patient selection for primary treatment and adjuvant interventions.

Sentinel lymph node biopsy (SLNB) is an important staging and prognostic tool for cutaneous melanoma (CM). However, there exists a knowledge gap regarding whether sociodemographic characteristics are associated with receipt of SLNB for T1b CMs, for which there are no definitive recommendations for SLNB per current National Comprehensive Cancer Network guidelines. We performed a retrospective analysis of the 2012-2018 National Cancer Database, identifying patients with American Joint Committee on Cancer staging manual 8th edition stage T1b CM, and used multivariable logistic regression to analyze associations between sociodemographic characteristics and receipt of SLNB. Among 40,458 patients with T1b CM, 23,813 (58.9%) received SLNB. Median age was 62 years, and most patients were male (57%) and non-Hispanic White (95%). In multivariable analyses, patients of Hispanic (aOR 0.67, 95%CI 0.48-0.94) and other (aOR 0.78, 95%CI 0.63-0.97) race/ethnicity, and patients aged > 75 (aOR 0.33, 95%CI 0.29-0.38), were less likely to receive SLNB. Conversely, patients in the highest of seven socioeconomic status levels (aOR 1.37, 95%CI 1.13-1.65) and those treated at higher-volume facilities (aOR 1.29, 95%CI 1.14-1.46) were more likely to receive SLNB. Understanding the underlying drivers of these associations may yield important insights for the management of patients with melanoma., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival., Methods: This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing., Findings: Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths., Interpretation: For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need., Funding: Regeneron Pharmaceuticals and Sanofi., Competing Interests: Declaration of interests NDG reports institutional research funding from Regeneron Pharmaceuticals; speaker honoraria from AiCME; and advisory board and consulting fees from PDS Biotechnology, Replimmune, Regeneron Pharmaceuticals, and Merck. DMM reports honoraria for advisory or consultant roles from Castle Biosciences, EMD Serono, Merck KGaA, Merck Sharpe & Dome, Pfizer, Regeneron Pharmaceuticals, Incyte, Sanofi Genzyme, and Bristol Myers Squibb; equity options from Checkpoint Therapeutics and Avstera Therapeutics Corp; and research funding from Kartos Therapeutics, NeoImmune Tech, and Regeneron Pharmaceuticals. NIK reports grants and advisory board fees from Regeneron Pharmaceuticals, Bristol Myers Squibb, Merck, Replimmune, and Novartis; advisory board fees from Iovance, Instil Bio, Castle Biosciences, Nektar, Incyte (data safety monitoring committee), AstraZeneca (data safety monitoring committee), and Jounce Therapeutics; grants from GlaxoSmithKline, HUYA, and Celgene; honoraria from Genzyme, National Comprehensive Cancer Network (paid by Pfizer), Nektar (study steering committee), Regeneron Pharmaceuticals (study steering committee), Bristol Myers Squibb (study steering committee). and Replimmune (study steering committee); grant from Modulation Therapeutics; travel support from Regeneron Pharmaceuticals; and common stock ownership of Bellicum Pharmaceuticals, Amarin, and Asensus Surgical (formerly Transenetrix). VD reports institutional research funding from Genentech, and advisory board fees from Regeneron Pharmaceuticals. ESR reports advisory board and consulting fees from Genentech, Feldan Therapeutics, Regeneron Pharmaceuticals, and Sanofi, and serves on the board of directors for Checkpoint Therapeutics. EJL reports institutional research funding from Regeneron Pharmaceuticals and Sanofi; institutional grants from Bristol Myers Squibb and Merck; advisory board fees from Bristol Myers Squibb, Eisai, Genentech, Instil Bio, Merck, Natera, Nektar Therapeutics, Odonate Therapeutics, Pfizer, Rain Therapeutics, Regeneron Pharmaceuticals, Replimmune, and Sanofi; payment for speaker's fee from Bristol Myers Squibb; and consulting fees from Bristol Myers Squibb, Macrogenics, OncoSec, Merck, Novartis, CareDX, and Pfizer. FM reports travel support, speaker's fees or advisor's honoraria from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Sanofi; and research funding from Novartis and Roche. PLS reports institutional research grants from Ascentage Pharma and Pfizer, and advisory board roles for Elevar Therapeutics, Prelude Therapeutics, and Regeneron Pharmaceuticals. JA reports payment or honoraria for speakers bureaus and presentations from Bristol Myers Squibb and Regeneron Pharmaceuticals; advisory board and consulting fees from Bristol Myers Squibb, Castle Biosciences, Pfizer, Regeneron Pharmaceuticals, and Sanofi. JLG reports institutional research funding from Alkermes, EMD Serono, Merck, Regeneron Pharmaceuticals, and Roche/Genentech; and advisory board or consultant fees from Astellas, Exelixis, EMD Serono, Merck, and Regeneron Pharmaceuticals. AH reports grants and personal fees from Amgen, Bristol Myers Squibb, Merck-Pfizer, MSD/Merck, Philogen, Pierre Fabre, Regeneron Pharmaceuticals, Roche, Sanofi-Genzyme, Novartis Pharma, Eisai, Replimmune, NeraCare; consulting fees from Seagen, IO Biotech, Dermagnostix, Incyte, Highlight Therapeutics, and Iovance; speaker's honoraria from Kyowa Kirin; advisory board fees from Immunocore; and institutional grants from Huya Biosciences outside the submitted work. JHC reports consulting or advisory roles for Exelixis, Coherus Biosciences, Merck Sharp & Dohme, Eisai, and Regeneron Pharmaceuticals, and institutional research funding from Arcus Biosciences and Genmab. BGMH reports consulting or advisory roles at AstraZeneca, Bristol Myers Squibb, Eisai, Merck Sharp & Dohme, Pfizer, and Roche, and institutional research funding from Amgen. DS reports honoraria from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Immunocore, Merck Serono, Array BioPharma, Pfizer, Pierre Fabre, Philogen, Regeneron Pharmaceuticals, 4SC, Sanofi, Regeneron Pharmaceuticals, NeraCare GmbH, Sun Pharma, InflarxGmbH, Ultimovacs, and Sandoz; consulting fees from Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; speaker fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Merck; advisory board fees from AstraZeneca, Daiichi-Sankyo, Roche/Genentech, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, 4SC, Pierre Fabre, Sanofi, Regeneron Pharmaceuticals, and Nektar; institutional research funding from Bristol Myers Squibb, Novartis, Roche, MSD Oncology, and Array BioPharma/Pfizer; unpaid leadership or fiduciary roles with Dermatologic Cooperative Oncology Group, European Organisation for Research and Treatment of Cancer-Melanoma Group, Hiege-Stiftung, and Nationale Versorgungskonferenz Hautkrebs; and travel and accommodation expenses from Roche/Genentech, Bristol Myers Squibb, Merck Serono, Novartis, Merck Sharp & Dohme, Pierre Fabre, Sanofi, and Regeneron Pharmaceuticals. VAP reports honoraria for advisory or consulting roles from Sun Pharma, Almirall, Biofrontera, PhD Biosciences, Regeneron Pharmaceuticals, and Sanofi Genzyme; speakers bureau fees from Regeneron Pharmaceuticals, and Sanofi Genzyme, equity in Avstera Therapeutics and Science 37; and research funding from Regeneron Pharmaceuticals. JMT reports honoraria for advisory or consultant roles for Bristol Myers Squibb, Merck & Co, AstraZeneca, Genentech/Roche, Regeneron Pharmaceuticals, Compugen, Lunaphore, and Akoya Biosciences; stock options in Akoya Biosciences; equipment loan and reagent provision from Akoya Biosciences; and research funding from Bristol Myers Squibb and Akoya Biosciences. AML reports uncompensated consultancy for Eisai, research funding support from Sanofi/Regeneron Pharmaceuticals, and support from a Peter MacCallum Cancer Centre Discovery Partner Fellowship. RF reports grants or investigator-initiated trial support from Merck, Pfizer, Gilead, and Ayala; royalties from UpToDate for a chapter on olfactory neuroblastoma; payment for expert testimony from Guidepoint; and advisory board participation with Regeneron Pharmaceuticals, Prelude Therapeutics, Elevar Therapeutics, Eisai, Remix Therapeutics, and Coherus BioSciences. S-YY, HH, FS, and IL are employees and shareholders of Regeneron Pharmaceuticals. MM and MGF report receipt of support for attending meetings or travel, and are also employees, patent holders, and shareholders of Regeneron Pharmaceuticals. DR reports institutional research grant and funding from Regeneron Pharmaceuticals, Genentech, Sanofi, Kura Oncology, Roche, Merck Sharp & Dohme, Decibel Therapeutics, Bristol Myers Squibb, GlaxoSmithKline, and ALX Oncology; and uncompensated scientific committee and advisory board roles for Merck Sharp & Dohme, Regeneron Pharmaceuticals, Sanofi, and Eisai. YBS and JH declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Competing Interests: Dr Schoenfeld reported receiving research support paid to the institution from Merck, BMS, Regeneron, Debiopharm, EMD Serono; Consulting/Scientific Advisory Board/Travel fees from Castle Biosciences, Genentech, Immunitas, Debiopharm, ACI Clinical, Astellas, Stimit, Merck KGA, SIRPant, EMD Serono; stock options from Immunitas, and equity from Doximity. No other disclosures were reported.

Background: The preferred treatment for clinically node-negative Merkel cell carcinoma (MCC) is surgical excision in conjunction with sentinel lymph node biopsy. There is limited large-scale research on survival outcomes by surgical approach for management of the primary tumor., Objective: To compare overall and MCC-specific survival outcomes in clinically and pathologically, node-negative MCC patients treated with wide-local excision (WLE) and Mohs micrographic surgery (MMS) in a nationally representative sample., Methods: Overall and MCC-specific survival outcomes for primary MCC tumors contained in the SEER (Surveillance, Epidemiology, and End Results)-18 database from 1989 to 2015 were stratified by surgical modality and analyzed via competing risk analysis., Results: A total of 2359 US adults with MCC were included in the analysis. For overall and MCC-specific survival, there was no significant difference in survival outcomes between WLE and MMS on multivariable analysis (hazard ratio, 1.04 [95% CI, 0.88-1.22]; subdistribution hazard ratio, 0.76 [95% CI, 0.53-1.09]). Sentinel lymph node biopsy was associated with improved overall survival and MCC-specific survival., Limitations: Retrospective design of SEER and the lack of covariates such as comorbidities and immunostaining., Conclusion: There is no survival disadvantage for MMS compared to WLE as the surgical modality for primary cutaneous MCC. Sentinel lymph node biopsy should be coordinated prior to MMS., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: The 2022 National Comprehensive Cancer Network (NCCN) reclassified cutaneous squamous cell carcinoma (CSCC) into low-, high-, and very high-risk groups to better risk stratify tumors. Mohs micrographic surgery (Mohs) or peripheral and deep en face margin assessment (PDEMA) became preferred surgical modalities for high- and very high-risk tumors. This new risk stratification and the recommendation for Mohs or PDEMA in high- and very high-risk groups have not been validated., Objective: To compare outcomes in very high-, high-, and low-risk NCCN groups of CSCCs and in CSCCs treated with Mohs or PDEMA compared with wide local excision (WLE)., Design, Setting, and Participants: This retrospective cohort study of CSCCs was performed in 2 tertiary care academic medical centers. Patients 18 years or older and diagnosed between January 1, 1996, and December 31, 2019, at Brigham and Women's Hospital and Cleveland Clinic Foundation were included. Data were analyzed from October 20, 2021, to March 29, 2023., Exposures: NCCN risk group, Mohs or PDEMA, and WLE., Main Outcomes and Measures: Local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD)., Results: A total of 10 196 tumors from 8727 patients were stratified by NCCN guidelines into low-, high-, and very high-risk groups (6003 [59.0%] men; mean [SD] age, 72.4 [11.8] years). Compared with the low-risk group, the high- and very high-risk groups demonstrated a greater risk of LR (high-risk subhazard ratio [SHR], 1.99 [95% CI, 1.21-3.27; P = .007]; very high-risk SHR, 12.66 [95% CI, 7.86-20.39; P < .001]), NM (high-risk SHR, 4.26 [95% CI, 1.28-14.23; P = .02]; very high-risk SHR, 62.98 [95% CI, 19.24-206.17; P < .001]), DM (high-risk SHR, 2.2 × 107 [95% CI, 4.7 × 103-1.1 × 1011; P < .001]; very high-risk SHR, 6.3 × 108 [95% CI, 1.4 × 105-2.9 × 1012; P < .001]), and DSD (high-risk SHR, 4.02 [95% CI, 1.18-13.71; P = .03]; very high-risk SHR, 93.87 [95% CI, 29.19-301.85; P < .001]). Adjusted 5-year cumulative incidence was significantly higher in very high- vs high- and low-risk groups for LR (9.4% [95% CI, 9.2%-14.0%] vs 1.5% [95% CI, 1.4%-2.1%] and 0.8% [95% CI, 0.5%-1.2%], respectively), NM (7.3% [95% CI, 6.8%-10.9%] vs 0.5% [95% CI, 0.4%-0.8%] and 0.1% [95% CI, 0.03%-0.3%], respectively), DM (3.9% [95% CI, 2.6%-5.6%] vs 0.1% [95% CI, 0.04%-0.2%] and 0.01% [95% CI, not applicable], respectively), and DSD (10.5% [95% CI, 10.3%-15.4%] vs 0.5% [95% CI, 0.4%-0.8%] and 0.1% [95% CI, 0.04%-0.3%], respectively). Compared with CSCCs treated with WLE, those treated with Mohs or PDEMA had lower risk of LR (SHR, 0.65 [95% CI, 0.46-0.90]; P = .009), DM (SHR, 0.38 [95% CI, 0.18-0.83]; P = .02), and DSD (SHR, 0.55 [95% CI, 0.36-0.84]; P = .006)., Conclusions and Relevance: The findings of this cohort study suggest that the NCCN high- and very high-risk groups identify CSCCs at greatest risk for developing poor outcomes. Further, Mohs or PDEMA resulted in lower LR, DM, and DSD compared with WLE.

Competing Interests: Conflicts of interest Dr Ruiz is a consultant for Regeneron and Sanofi, is on the advisory board for Checkpoint Therapeutics, and is the recipient of honoraria from UpToDate. Dr Schmults has served as a consultant for Castle Biosciences, Regeneron, and Sanofi; is a board member of the American Society of Dermatologic Surgery and the International Society of Dermatologic Surgery; and is the non-melanoma skin cancer panel chair for the National Comprehensive Cancer Network. Drs Gibson and Murad and Granger have no conflicts of interest to declare.

Background: Microcystic adnexal carcinoma (MAC) is a locally aggressive and deeply infiltrative cutaneous tumor primarily treated with excision; however, there are limited data comparing outcomes by surgical approach., Objective: To compare surgical outcomes of MAC treated with Mohs micrographic surgery (MMS) and wide local excision (WLE)., Methods: A 27-year retrospective cohort study of primary MAC was performed. Surgical (i.e. margin status after resection) and recurrence outcomes (including local recurrence [LR], nodal metastases [NM], and distance metastases [DM]) were analyzed by type of surgical approach (MMS and WLE)., Results: Sixty-nine MACs were included, of which 34 (49.3%) were treated with MMS and 35 (50.7%) with WLE. All MMS-treated tumors had negative margins after the first surgery attempt. Twenty-one (60.0%) tumors treated with WLE had positive margins after the first surgical attempt and required additional procedures. More tumors treated with WLE developed LR, NM, or DM, although this did not meet statistical significance., Limitations: Retrospective single institution study., Conclusion: Greater than half of MAC tumors treated with WLE had positive margins after the initial surgery and required multiple procedures for complete removal. Real-time complete margin assessment is important for this locally aggressive and infiltrative tumor., (Copyright © 2023 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

The rising incidence of cutaneous squamous cell carcinoma (cSCC) represents a public health crisis. Although most cases of cSCC are cured with surgical excision alone, high-risk disease requires a coordinated strategy involving accurate staging, possible multimodal therapy, and clinical and radiologic surveillance. In the following review, we present an evidence-based update on the current paradigm of diagnosis and management of cSCC and discuss the most relevant areas of active research related to prognostic staging as well as the appropriate use of radiologic imaging and adjuvant therapy., Competing Interests: Disclosure None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Background: Although immunocompromised patients have a higher risk of developing cutaneous squamous cell carcinomas, it is unknown whether immune status is an independent risk factor for poor outcomes., Objective: To compare cutaneous squamous cell carcinoma outcomes in immunocompromised and immunocompetent patients when controlling for T-stage., Methods: We performed a retrospective cohort study at 2 tertiary care centers, examining 989 primary tumors from 814 immunocompromised patients (solid organ transplant: 259 [31.7%], chronic lymphocytic leukemia: 113 [13.9%]) and 6608 tumors from 4198 immunocompetent patients. Our primary outcome was the composite of disease-specific death or tumor metastasis ("poor outcomes")., Results: Immunocompromised patients had 50% more high T-stage tumors (ie, Brigham and Women's Hospital stage T2b and T3), than immunocompetent patients (3.3% vs 4.9%, respectively; P < .001). Significant predictors of poor outcomes included tumor stage (sub hazards ratio [SHR], 14.8 for high T-stage tumors; 95% confidence interval [CI], 8.0-27.6; P < .001) and male sex (SHR, 2.3; 95% CI, 1.4-3.8; P = .002). Immune status was not a significant predictor (SHR, 1.04; 95% CI, 0.69-1.6; P = .85)., Limitations: This study is retrospective., Conclusion: Although immunocompromised patients had 50% more high T-stage tumors than immunocompetent patients, immunocompromised patients had a similar chance of metastasis and disease-specific death when adjusting for T-stage in our cohort of primary tumors., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings., Methods: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events., Results: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%)., Conclusions: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)., (Copyright © 2022 Massachusetts Medical Society.)

Competing Interests: Conflict of interest None disclosed.

Background: Although adjuvant radiation (ART) following clear margin surgery is recommended for select high-risk cutaneous squamous cell carcinomas, efficacy data are limited., Objective: To evaluate the impact of ART on outcomes following clear margin surgery for high T-stage cutaneous squamous cell carcinomas., Methods: A 20-year retrospective cohort study at 2 academic centers of high T-stage cutaneous squamous cell carcinomas (Brigham and Women's Hospital T2b or T3) with negative histologic margins post resection. Local recurrence (LR) and locoregional recurrence (LRR) were compared by whether tumors received ART or observation., Results: A total of 508 tumors were included, of which 96 underwent ART (ART + ). ART + had a lower 5-year cumulative incidence of LR (ART + , 3.6% [95% CI, 1.6%-7.7%] vs ART - , 8.7% [95% CI, 6.3%-12.0%]) and LRR (ART + , 7.5% [95% CI, 4.4%-11.9%] vs ART - , 15.3% [95% CI, 11.9%-22.1%]). Recurrent tumors ≥6 cm or Brigham and Women's Hospital T3 tumors were classified as high-risk due to a higher 5-year cumulative incidence of LRR (High-risk, 26.3% [95% CI, 19.0%-35.7%]). High-risk tumors treated with ART had a lower 5-year cumulative incidence of LRR (ART + , 17.2% [95% CI, 11.9%-26.4%] vs ART - , 31.0% [95% CI, 26.1%-40.8%])., Limitations: Retrospective design, heterogeneous population, variations in radiation protocols., Conclusion: ART following clear margin surgery for high T-stage cutaneous squamous cell carcinomas resulted in half the risk of LR and LRR., Competing Interests: Conflicts of interest Dr Ruiz is a consultant for Regeneron and Sanofi, is on the advisory board for Checkpoint Therapeutics, and is the recipient of honoraria from UpToDate. Dr Schoenfeld has received research funds paid to the institution from Merck, BMS, Regeneron, and Debiopharm, has served as a consultant for Genentech, Debiopharm, BMS, Nanobiotix, Tilos, AstraZeneca, LEK, Catenion, ACI Clinical, Astellas, Merck KGA and Stimit, serves on the advisory board, and has equity in Immunitas and in Doximity, and has received expert witness fees. Dr Schmults has received research funding from Castle Biosciences, Merck, and Regeneron, has served as a consultant for Castle Biosciences, Regeneron, and Sanofi, is a board member of the American Society of Dermatologic Surgery and the International Society of Dermatologic Surgery, and is the nonmelanoma skin cancer panel chair for the National Comprehensive Cancer Network. Dr Koyfman has received research funds from Merck and BMS, is a consultant for Merck and Regeneron, serves on the advisory board of Castle Biosciences, and is the recipient of honoraria from UpToDate. Author Kus and Drs Smile, Murad, Zhou, Ilori, Margalit, Tishler, and Vidimos have no conflicts of interest to disclose., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs., Competing Interests: Competing interests: CAB: consulting fees: Regeneron; contracted research: Alpha Tau Medical, Merck, Amgen, Elekta, and EMD Serono. SB: consulting fees: Genentech, Bristol Myers Squibb, EMD Serono, Sanofi Genzyme, and Exicure; contracted research: Bristol Myers Squibb, EMD Serono, Immune Design, Merck, Novartis, Oncosec, Nantkwest, Exicure, and Nektar. KBB: consulting fees: Iovance Biotherapeutics and Nektar Therapeutics. SC: consulting fees: Bristol Myers Squibb, Regeneron, Sanofi Genzyme, Novartis, EMD Serono, Exicure, and Pfizer; contracted research: Bristol Myers Squibb, Merck, Regeneron, Sanofi Genzyme, Novartis, EMD Serono, Exicure, and Pfizer. ZE: consulting fees: Regeneron, Genentech, Novartis, Natera, Pfizer, and OncoSec (advisory boards); research funding (to institution): Pfizer and Novartis. BRG: consulting fees: Quest Imaging (consultant/advisor) and Castle Biosciences (speaker); contracted research: NIT and Alkermes (research grant). KLK: contracted research: Merck, Bristol Myers Squibb, Karyopharm, Novartis, GlaxoSmithKline, Immunocore, and Iovance. HK: consulting fees: Nektar, Roche-Genentech, Pfizer, Iovance, Immunocore, Celldex, Array Biopharma, Merck, Elevate Bio, Instil Bio, and Bristol Myers Squibb; contracted research: Merck, Bristol Myers Squibb, and Apexigen (institutional research grants (to institution)). EJL: consulting fees: Array BioPharma, Bristol Myers Squibb, Eisai, EMD Serono, Genentech, MacroGenics, Novartis, Merck, Odonate Therapeutics, OncoSec, Regeneron, and Sanofi Genzyme; contracted research: Bristol Myers Squibb, Merck, and Regeneron. KM: consulting fees: Pfizer (advisory board). DMM: consulting fees: Sanofi, Regeneron, Intellisphere LLC, OncLive, and Checkpoint Therapeutics; ownership interest: Checkpoint Therapeutics. PN: consulting fees: EMD Serono, Pfizer, 4SC, Wolters Kluwer Health, Merck, Sanofi Genzyme, and Regeneron; contracted research: EMD Serono and Bristol Myers Squibb; other: secretary–treasurer for Society of Investigative Dermatology; partner consulting fees: Pfizer and Kadmon; partner contracted research: Millenium Pharmaceuticals, Amgen, Novartis, Kadmon, Pfizer, Syndax Pharmaceuticals, and Incyte; partner other: President of American Society of Hematology. ACP: consulting fees: Regeneron, Bristol Myers Squibb, and Merck; fees for non-CE services: Bristol Myers Squibb; contracted research: Merck, Bristol Myers Squibb, Iovance, Regeneron, Takeda, Ideaya, and Replimune (all payments to institution). IP: consulting fees: Merck, Amgen, Nouscom, Nektar, and Iovance; other: Bristol Myers Squibb (medical writing/article processing charges); ownership interest: Celldex. GR: consulting fees: Sanofi Genzyme, Regeneron, EMD Serono, Pfizer, Castle, and Merck; ownership interest: Regeneron and Syros Pharmaceuticals. ESR: consulting fees: Sanofi, Leo Pharma, Checkpoint Therapeutics, Pellepharm, and Jounce. AWS: consulting fees: Bristol Myers Squibb, Merck, and EMD Serono. VKS: consulting fees: Merck, Regeneron, and Eisai; other: Bristol Myers Squibb and Polynoma (data safety monitoring boards). MTT: consulting fees: Nanostring LLC, Bristol Myers Squibb, Merck, Myriad Genetics, and Seattle Genetics. EAT: nothing to disclose. IB: Nothing to disclose. Society for Immunotherapy of Cancer (SITC) staff: SMW - shares owned: Pacific Biosciences of California Inc and Editas Medicine Inc; ME, CG, EG, and AK - nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Although most of the poor outcomes with cutaneous squamous cell carcinoma (CSCC) occur in high-stage tumors, 26% of nodal metastases and 8% of disease-specific deaths develop in Brigham and Women's Hospital (BWH) T2a tumors., Objective: To determine risk factors associated with poor outcomes (nodal metastasis, distant metastases, and disease-specific deaths) in BWH T2a CSCC., Methods: A 17-year retrospective multi-institutional cohort study of primary CSCC BWH T2a tumors. A predictive model based on tumor characteristics was developed to identify those at higher risk of poor outcomes., Results: Presence of 1 major criterion (primary tumor diameter ≥40 mm, invasion depth beyond subcutaneous fat, poor differentiation, or large-caliber perineural invasion) and ≥ 1 minor criterion (invasion depth in subcutaneous fat, moderate differentiation, small-caliber perineural invasion, or lymphovascular invasion) was most predictive of developing poor outcomes (area under the curve, 0.53; C-statistic, 0.60). This model has a sensitivity of 7.7%, specificity of 97.4%, and a positive and negative predictive value of 33.3% and 86.1%, respectively. The 5-year cumulative incidence of poor outcomes in these tumors is 8.0% (95% CI, 5.1-13.7) compared to 2.8% (95% CI, 1.9-4.1) in other T2a tumors (sub-hazard ratio, 3.0; 95% CI, 1.5-5.8)., Limitations: Multi-institutional cohort study was not externally validated., Conclusions: BWH T2a-high CSCCs have an 8% chance of developing poor outcomes., Competing Interests: Conflicts of interest Dr Koyfman has received research funds from Merck and BMS, is a consultant for Merk and Regeneron, serves on the advisory board of Castle Biosciences, and is the recipient of honoraria from UpToDate. Authors Gupta, Weitzman, Chang, and Maher and Drs Murad, Smile, Schmults, Vidimos and Ruiz have no conflicts of interest to declare., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Lymphovascular invasion (LVI) is an aggressive histologic finding but is excluded from current staging systems due to its lack of demonstrated independent prognostic significance., Objective: To evaluate the impact of LVI on cutaneous squamous cell carcinoma tumor outcomes., Methods: In total, 10,707 cutaneous squamous cell carcinoma tumors from a 20-year, retrospective, multicenter cohort were stratified by the presence (LVI + ) or absence (LVI - ) of LVI. Outcomes (local recurrence, in-transit metastasis, nodal metastasis, disease-specific death) were compared based on low (Brigham and Women's Hospital [BWH] stage T1/T2a) and high (BWH T2b/T3) tumor stages., Results: Of the 10,707 tumors, 78 had LVI. The analysis of low-stage BWH tumors showed the LVI + group had a significantly higher 5-year cumulative incidence of local recurrence (LVI + : 12.3%; LVI - : 1.1%; P < .01), metastasis (LVI + : 4.2%; LVI - : 0.4%; P < .01), and disease-specific death (LVI + : 16.2%; LVI - : 0.4%; P < .01). The analysis of BWH high-stage tumors showed the LVI + group maintained a higher 5-year cumulative incidence of metastasis (LVI + : 28.5%; LVI - : 16.8%; P = .06) and disease-specific death (LVI + : 25.3%; LVI - : 13.9%; P = .03), however, there was no difference in local recurrence (LVI + : 16.3%; LVI - : 15.8%; P = .11)., Limitations: Retrospective study design., Conclusion: LVI +  cutaneous squamous cell carcinomas have higher rates of metastasis and death at 5 years. Future staging systems should consider incorporating LVI., Competing Interests: Conflicts of interest Dr Koyfman has received research funds from Merck and BMS, is a consultant for Merck and Regeneron, serves on the advisory board of Castle Biosciences, and is the recipient of honoraria from UpToDate. Authors Kus, Murad, Smile, Chang, Ashrafzadeh, Zhou, Ilori, Vidimos, Schmults, and Ruiz have no conflicts of interest to declare., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Unlike Merkel cell carcinoma and melanoma, satellitosis or in-transit metastasis (S-ITM) is not incorporated into the current cutaneous squamous cell carcinoma (CSCC) staging systems. It is important to determine if the clinical outcomes of S-ITM are relevant to prognosis for patients with CSCC., Objectives: To evaluate the association of S-ITM with clinical outcomes in patients with CSCC and to determine its prognostic implications., Design, Settings, and Participants: A dual-institution (Cleveland Clinic and Brigham and Women's Hospital) database was queried for patients who were treated for CSCC in 2010 to 2020. Patients who were node-negative and had S-ITM-the presence of dermal lesions between the primary tumor and first-echelon lymphatic nodal basins at any point in the disease course-were identified. Subcohorts of patients with T3N0 tumors, T4N0 tumors (bone invasive), N1 to 3, and M1 disease were identified for comparison. The American Joint Committee on Cancer staging system was used to define cancer stages. Data were analyzed from January 15 to March 31, 2021., Main Outcomes and Measures: Pairwise comparison of CSCC recurrence and disease-specific survival in patients with and without S-ITM was performed using Cox proportional hazard modeling. Kaplan-Meier and Fine-Gray competing risk methods were used to estimate disease-specific survival and CSCC recurrence, respectively., Results: In a total of 518 patients with CSCC, S-ITM was present in 72 (13.9 %) patients (median age [range], 73.9 [31.6-95.8] years; 59 [82%] men; 69 [96%] White non-Hispanic individuals; 25 [35%] patients with immunosuppression) who were node-negative. The subcohorts were composed of 341 patients with T3N0 cancer, 36 with T4N0, 70 with N1 to 3, and 19 with M1 disease. Pairwise comparisons between disease levels using Cox proportional hazard model demonstrated lower cumulative incidence of CSCC recurrence rates in the T3N0 (HR, 0.21; 95% CI, 0.14-0.30; P < .001) and T4N0 (HR, 0.36; 95% CI, 0.19-0.68; P = .001) cohorts compared with the S-ITM cohort. No significant difference was observed between patients who were node-positive and those with S-ITM (HR, 0.74; 95% CI, 0.48-1.14; P = .16). The 5-year disease-specific survival rates were 76% for T3N0, 64% for T4N0, 41% for S-ITM, and 39% for N1 to 3. Compared with the S-ITM cohort, DSS was significantly higher in the T3N0 (HR, 0.23; 95% CI, 0.15-0.35; P < .0001) and T4N0 (HR, 0.37; 95% CI, 0.19-0.76; P = .01) cohorts, and not significantly different in the node-positive (HR, 0.77; 95% CI, 0.84-3.93; P = .30) and metastatic cohorts (HR, 1.81; 95% CI, 0.84-3.93; P = .13)., Conclusions and Relevance: This multi-institutional cohort study found that patients with CSCC and S-ITM appear to have clinical outcomes comparable to those of patients who are node-positive, and an increased risk of recurrence and worse survival compared with patients who have T3 and T4 disease. These outcomes are similar to those observed for Merkel cell carcinoma and melanoma. Given that S-ITM may be a powerful prognostic factor, it should be incorporated into clinical staging systems.