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Importance There is no consensus on staging and surveillance imaging for cutaneous squamous cell carcinoma (CSCC). Although imaging has been shown to affect management, broad recommendations from the National Comprehensive Cancer Network have led to variability in clinical practice. Objective To develop multidisciplinary consensus recommendations on the use of staging and surveillance imaging of localized CSCC. Evidence Review A multidisciplinary expert panel across academic and clinical practice settings convened a Delphi consensus, with 3 iterative survey rounds from January to June 2025. Data were analyzed from February 2025 to January 2026. Eligibility defined by at least 1 to 2 CSCC publications during the previous 5 years, involvement in a relevant clinical trial, experience treating at least 3 patients monthly with CSCC, and/or 5 years or longer of clinical practice. Fifty-four experts were invited and 45 (83%) completed all 3 rounds and were included in the final analysis. Structured Delphi surveys evaluated clinical scenarios, imaging modalities, and surveillance strategies for CSCC. Consensus and near-consensus recommendations were generated, defined as 80% or greater and 70% to 79% agreement, respectively. Findings The 45 participants (21 female individuals [47%] and 24 male individuals [53%]; 14 Asian individuals [31%], 1 multiracial individual [2%], and 30 White individuals [67%]) consisted of dermatology (15 [33%]), medical oncology (7 [16%]), radiation oncology (9 [20%]), radiology (9 [20%]), surgery (3 [7%]), and otolaryngology specialists (2 [4%]). The Delphi panel recommended staging and surveillance for CSCCs with at least a 15% risk of metastasis. Consensus or near consensus was reached to recommend staging and surveillance imaging for tumors with a concern for metastasis, bone invasion, invasion beyond subcutaneous fat, large-caliber nerve invasion, or a diameter of 4 cm or larger or the combination of tumors with poorly differentiated histology and any of the following: diameter of 2 cm or larger, lymphovascular invasion and subcutaneous fat invasion, or lymphovascular invasion and small-caliber perineural invasion. Computed tomography imaging was the preferred modality for nodal staging (38 [84%]) and surveillance (35 [78%]). For surveillance duration, consensus was reached to provide imaging for at least 2 years, and near consensus was reached for at least 3 years. Conclusions and Relevance This study provides an expert consensus–based framework to standardize imaging in localized CSCC that may inform future guidelines.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses, as well as occult primary cancer, salivary gland cancer, and mucosal melanoma (MM). The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of nasopharynx cancer and ongoing research in this area.

Abstract Purpose: NFE2L2/KEAP1/CUL3 mutations have been validated for radioresistance in cell-based assays and animal models. However, clinical validation of these biomarkers has been challenging because of multimodality treatment regimens. This study aims to investigate the association between NFE2L2/KEAP1/CUL3 mutations and patient outcomes, including local failure, locoregional failure, disease-free survival (DFS), and overall survival, using samples from a phase III trial in which patients were treated with radiation monotherapy at two controlled doses. Patients and Methods: We investigated NFE2L2/KEAP1/CUL3 mutations in 250 randomized patients with T2N0 glottic squamous cell carcinoma receiving definitive radiotherapy in the NRG/RTOG 9512 trial. A total of 119 patients had available biospecimens that were subjected to amplicon-based next-generation sequencing to assess for the presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. Mutations in NFE2L2/KEAP1/CUL3 were assessed blinded to clinical outcomes. Cox models (two-sided α = 0.05) were used to evaluate the association with clinical outcomes, performed by an independent statistical team. Results: Nineteen of 119 patients (16.0%) had NFE2L2/KEAP1/CUL3 mutations. Patient, treatment, and tumor characteristics were similar between those with and without mutations. Patients with mutation compared with those without had significantly more local failure [HR = 3.50; 95% confidence interval (CI), 1.56–7.89; P = 0.0025] and locoregional failure (HR = 3.80; 95% CI, 1.80–8.03; P = 0.0005). DFS was significantly worse for the mutated compared with the nonmutated group in the first 2 years (HR = 2.88; 95% CI, 1.46–5.66; P = 0.0022). The median DFS was shorter in the mutation group (10.3 months) versus those with intact NFE2L2/KEAP1/CUL3 (4.2 years). Conclusions: NFE2L2/KEAP1/CUL3 mutations may predict radiation treatment failure in T2N0 glottic cancer. See related commentary by Rao, p. 1563

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

Abstract Background Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. Methods We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results Change in H3.3K27M VAF over time (“VAF delta”) correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF “spikes” (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. Conclusion Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

560 Background: Level I evidence exists demonstrating the efficacy of the mTOR inhibitor everolimus (EVE) in decreasing tumor volume of syndromic angiomyolipomas (AMLs) among patients with Tuberous Sclerosis. No prospective data are available regarding the effect of mTOR inhibition on growth kinetics in patients with sporadic AMLs. Methods: We conducted a multi-institutional, prospective, phase 2 trial with an optimal two-stage Simon design in patients presenting with > 3cm sporadic AMLs who were candidates for surgical or percutaneous intervention. Response was defined as ≥25% volumetric reduction of the AML. Planned enrollment was 43 patients to test the null hypothesis at a 5% level of significance with 80% power. Baseline, 4- and 6-month volumetric analysis was performed by dynamic contrast-enhanced MRI (DCE-MRI). Patients received EVE 10mg for four 28-day cycles, at which point EVE was discontinued in those with < 25% volumetric reduction. Those with ≥ 25% volumetric reduction received two additional cycles of EVE. Dose reductions and interruptions were allowed to 5 mg QOD. Conservative stopping rules were established for toxicity, given the benign nature of AMLs. Results: The early stopping rules for both efficacy and toxicity were invoked. We enrolled 20 patients (median age = 68) from 5 centers with 21 sporadic AMLs. 11/20 (55%) patients completed 4 cycles of EVE, while 7/20 (35%) completed 6 cycles. Median days on treatment was 88 (2 cycles). 4/20 (20%) patients were withdrawn due to toxicity, while 8/20 (40%) withdrew due to personal preference. Dose reductions were required in 6/20 (30%) patients, and 5/20 (25%) patients had grade 3 toxicities which resolved upon discontinuation or dose reduction of EVE. At 4-month MRI, 10/16 (62.5%) patients had a ≥25% reduction in volume (mean = 54.1% decrease). At 6-month MRI, 8/12 (66.6%) patients had a ≥25% reduction in volume (mean = 51.5% decrease). Conclusions: EVE was effective in reducing tumor volume in patients with sporadic AMLs but was associated with a high rate of treatment termination due to patient preference or prespecified AEs. Neoadjuvant EVE may be useful in potentiating surgical resection of large or anatomically complex AMLs. Clinical trial information: NCT02539459.