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Summary: Background: Merkel cell carcinoma (MCC) is an aggressive, high‐grade, cutaneous neuroendocrine tumour (NET). Agents blocking programmed death 1/programmed death ligand 1 have efficacy in metastatic MCC (mMCC), but half of patients do not derive durable benefit. Somatostatin analogues (SSAs) are commonly used to treat low‐ and moderate‐grade NETs that express somatostatin receptors (SSTRs). Objectives: To assess SSTR expression and the efficacy of SSAs in mMCC, a high‐grade NET. Methods In this retrospective study of 40 patients with mMCC, SSTR expression was assessed radiologically by somatostatin receptor scintigraphy (SRS; n = 39) and/or immunohistochemically when feasible (n = 9). Nineteen patients (18 had SRS uptake in MCC tumours) were treated with SSA. Disease control was defined as progression‐free survival (PFS) of ≥ 120 days after initiation of SSA. Results: Thirty‐three of 39 patients (85%) had some degree (low 52%, moderate 23%, high 10%) of SRS uptake. Of 19 patients treated with SSA, seven had a response‐evaluable target lesion; three of these seven patients (43%) experienced disease control, with a median PFS of 237 days (range 152–358). Twelve of 19 patients did not have a response‐evaluable lesion due to antecedent radiation; five of these 12 (42%) experienced disease control (median PFS of 429 days, range 143–1757). The degree of SSTR expression (determined by SRS and/or immunohistochemistry) did not correlate significantly with the efficacy endpoints. Conclusions: In contrast to other high‐grade NETs, mMCC tumours appear frequently to express SSTRs. SSAs can lead to clinically meaningful disease control with minimal side‐effects. Targeting of SSTRs using SSA or other novel approaches should be explored further for mMCC. What is already known about this topic? Merkel cell carcinoma (MCC) is an aggressive, high‐grade neuroendocrine tumour (NET) of the skin.Blockade of programmed death 1/programmed death ligand 1 is associated with high response rates in metastatic MCC, but approximately half of patients do not respond and need alternative therapeutic options.Somatostatin analogues (SSAs) are frequently used for treatment in low‐ and medium‐grade NETs but are typically not considered for high‐grade NETs due to presumably low expression of somatostatin receptors (SSTRs). What does this study add? A high proportion (85%) of metastatic MCC tumours express SSTR by somatostatin receptor scintigraphy (SRS), in striking contrast to other high‐grade NETs.SSAs can lead to clinically meaningful disease control with minimal side‐effects in some patients with metastatic MCC who are not candidates for or did not benefit from immunotherapy. What are the clinical implications of this work? The high frequency of SSTR expression by SRS in metastatic MCC, a high‐grade NET, offers a strong rationale for therapeutic SSTR targeting, using either SSAs or other emerging approaches.SSTR targeting may be especially relevant for those patients with metastatic MCC who are not eligible for or do not respond to immunotherapy. Linked Comment: Samimi and Becker. Br J Dermatol 2021; 184:195–197. Plain language summary available online [ABSTRACT FROM AUTHOR]

Background: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis., Purpose: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone., Methods: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors., Results: In this multivariable model, the most impactful recurrence risk factors were: American Joint Committee on Cancer stage (P < .001), immunosuppression (hazard ratio 2.05; P < .001), male sex (1.59; P = .003) and unknown primary (0.65; P = .064). Compared to stage alone, the model improved prognostic accuracy (concordance index for 2-year risk, 0.66 vs 0.70; P < .001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs 78% for high-risk IIIA over 5 years)., Limitations: Lack of an external data set for model validation., Conclusion/relevance: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at merkelcell.org/recur) integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients., Competing Interests: Conflicts of interest Paul Nghiem reports personal fees from Rain Therapeutics, EMD Serono, Pfizer, and Merck; grants from EMD Serono and Bristol-Myers Squibb to his institution outside the submitted work; and a patent for Merkel cell polyomavirus T antigen–specific T-cell receptors and uses thereof pending (University of Washington), as well as a patent for novel epitopes as T-cell targets in Merkel cell carcinoma pending (University of Denmark and University of Washington). No other disclosures were reported., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown., Purpose: We assessed if delays in ttPORT were associated with inferior outcomes., Methods: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks., Results: The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs ≤ 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016)., Limitations: The relatively low number of LRRs limited the extent of our multivariable analyses., Conclusions: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival., Competing Interests: Conflict of interest None disclosed., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer. Of the patients who develop MCC annually, only 4% are younger than 50 years., Objective: To identify genetic risk factors for early-onset MCC via genomic sequencing., Design, Setting, and Participants: The study represents a multicenter collaboration between the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Institute of Allergy and Infectious Diseases (NIAID), and the University of Washington. Participants with early-onset and later-onset MCC were prospectively enrolled in an institutional review board-approved study at the University of Washington between January 2003 and May 2019. Unrelated controls were enrolled in the NIAID Centralized Sequencing Program (CSP) between September 2017 and September 2021. Analysis was performed from September 2021 and March 2023. Early-onset MCC was defined as disease occurrence in individuals younger than 50 years. Later-onset MCC was defined as disease occurrence at age 50 years or older. Unrelated controls were evaluated by the NIAID CSP for reasons other than familial cancer syndromes, including immunological, neurological, and psychiatric disorders., Results: This case-control analysis included 1012 participants: 37 with early-onset MCC, 45 with later-onset MCC, and 930 unrelated controls. Among 37 patients with early-onset MCC, 7 (19%) had well-described variants in genes associated with cancer predisposition. Six patients had variants associated with hereditary cancer syndromes (ATM = 2, BRCA1 = 2, BRCA2 = 1, and TP53 = 1) and 1 patient had a variant associated with immunodeficiency and lymphoma (MAGT1). Compared with 930 unrelated controls, the early-onset MCC cohort was significantly enriched for cancer-predisposing pathogenic or likely pathogenic variants in these 5 genes (odds ratio, 30.35; 95% CI, 8.89-106.30; P < .001). No germline disease variants in these genes were identified in 45 patients with later-onset MCC. Additional variants in DNA repair genes were also identified among patients with MCC., Conclusions and Relevance: Because variants in certain DNA repair and cancer predisposition genes are associated with early-onset MCC, genetic counseling and testing should be considered for patients presenting at younger than 50 years.

Approximately 50% of Merkel cell carcinoma (MCC) patients facing this highly aggressive skin cancer initially respond positively to PD-1-based immunotherapy. Nevertheless, the recurrence of MCC post-immunotherapy emphasizes the pressing need for more effective treatments. Recent research has highlighted Cyclin-dependent kinases 4 and 6 (CDK4/6) as pivotal cell cycle regulators gaining prominence in cancer studies. This study reveals that the CDK4/6 inhibitor, palbociclib can enhance PD-L1 gene transcription and surface expression in MCC cells by activating HIF2α. Inhibiting HIF2α with TC-S7009 effectively counteracts palbociclib-induced PD-L1 transcription and significantly intensifies cell death in MCC. Simultaneously, co-targeting CDK4/6 and HIF2α boosts ROS levels while suppressing SLC7A11, a key regulator of cellular redox balance, promoting ferroptosis- a form of immunogenic cell death linked to iron. Considering the rising importance of immunogenic cell death in immunotherapy, this strategy holds promise for improving future MCC treatments, markedly increasing immunogenic cell death various across various MCC cell lines, thus advancing cancer immunotherapy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jung Hyun Lee reports financial support and writing assistance were provided by 10.13039/100001287Elsa U. Pardee Foundation., (© 2023 The Authors. Published by Elsevier Ltd.)

Purpose: The role of postoperative radiation therapy (PORT) in early stage Merkel cell carcinoma (MCC) is controversial. We analyzed the role of PORT in preventing local recurrences (LR) among patients with low-risk, pathologic stage I MCC based on the location of the primary tumors: head/neck (HN) versus non-HN sites., Methods and Materials: One hundred forty-seven patients with MCC were identified that had "low risk" disease (pathologic T1 primary tumor, negative microscopic margins, negative pathologic node status, no immunosuppression or prior systemic therapy). LR was defined as tumor recurrence within 2 cm of the primary surgical bed, and its frequency was estimated with the cumulative incidence method., Results: Seventy-nine patients received PORT (30 HN, 49 non-HN) with a median dose of 50 Gy (range, 8-64 Gy) and 68 patients were treated with surgery alone (30 HN, 38 non-HN). Overall, PORT was associated with a decreased risk of LR (5-year rate: 0% vs 9.5%; P  = .004) with 6 LRs observed in the surgery alone group. Although the addition of PORT significantly reduced LR rates among patients with HN MCC (0% vs. 21%; P  = .034), no LRs were observed in patients with non-HN MCC managed with surgery alone. There was no significant difference in MCC-specific survival comparing HN versus non-HN groups, with or without PORT., Conclusions: For low-risk, pathologic stage I MCC of the extremities and trunk, excellent local control rates were achieved with surgery, and PORT is not indicated. However, PORT was associated with a significant reduction in LRs among low-risk MCC of the HN., Competing Interests: Peter H. Goff reports research funding from Gilead Sciences, Inc, the Conquer Cancer Foundation of the American Society of Clinical Oncology, and the RSNA R&E Foundation not directly related to this work. Daniel S. Hippe reports research grants from GE Health care, Philips Health care, Canon Medical Systems USA, and Siemens Healthineers. Paul Nghiem reports research funding and personal fees from EMD-Serono and Merck & Co. All research funding and personal fees are unrelated to the submitted work., (© 2023 The Authors.)

Restricted, repetitive behaviors and interests (RRBIs) occur commonly in young children in the course of typical development, but too frequent or persistent RRBIs have been linked to a variety of psychosocial and neurodevelopmental disorders. Unfortunately, a lack of psychometrically sound, feasible instruments stymies RRBI study and intervention in early childhood. Therefore, this study validated an extant RRBI measure (i.e., Repetitive Behavior Scale for Early Childhood; RBS-EC) for predominately neurotypical community children ages 2-7 years via an MTurk survey of 300 caregivers. Confirmatory factor analyses best supported a 4-factor model for the RBS-EC (i.e., repetitive motor, rituals and routines, restricted interests, self-directed behaviors). RBS-EC scores varied significantly with age and gender; namely, RRBIs were typically (1) less frequent but more problematic with older versus younger children and (2) more frequent and problematic with boys versus girls. Findings extend the RBS-EC's utility in RRBI assessment and treatment during early childhood., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)