We present a patient with left orbital metastasis of cutaneous melanoma, treated with 30 Gy in 10 fraction radiation therapy followed by a combination of programmed death-1 inhibitor, nivolumab, and lymphocyte-activation gene inhibitor, relatlimab. The patient achieved a complete response to treatment, with no evidence of recurrence of the orbital mass, 17 months after treatment initiation.

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.

BACKGROUND AND PURPOSE:MR-Linac (MRL) is well-suited for treatment of oligometastatic disease (OMD) in muscle due to its superior soft tissue contrast. The purpose of this study was to assess dosimetric differences and quantify margins when CT-guidance (CTgRT) is used for OMD treatment compared to MR-guidance (MRgRT) on the MRL. MATERIALS AND METHODS:Five patients with intramuscular oligometastasis were treated with the MRL using daily MRgRT. To simulate CT-based alignment, an in-house deep learning model was used to generate synthetic-CT images from MR images for each fraction. The synthetic-CTs were independently aligned to the corresponding simulation-CTs by seven physicists using rigid registration. The difference between CTgRT and MRgRT alignment was calculated to quantify the inter-fractional image-guidance uncertainty and estimate PTV margins. Dose from the clinical beam sets was recalculated on the synthetic-CTs for comparative analysis. RESULTS:The CTgRT alignment compared to MRgRT were -0.59 ± 3.49 mm, 2.04 ± 3.96 mm, and 1.23 ± 1.20 mm in left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively. Compared to clinical plans, the dosimetric parameters of recalculated synthetic-CT plans, V95 and D95, were significantly lower, while the homogeneity index was significantly higher (p < 0.001 for each metric). Compared to MRgRT, CTgRT required additional treatment margins of 10.0 mm in LR, 11.5 mm in SI, and 4.6 mm in AP directions. CONCLUSIONS:We quantified the dosimetric difference in treating intramuscular metastases using MRgRT versus CTgRT and showed that treatment margin can be reduced by at least 5 mm in each direction with MRgRT.

PURPOSE:Select patients with metastatic soft tissue sarcoma (STS) may benefit from more aggressive treatment of their primary tumor. We report on the use of combined modality treatment (CMT) using preoperative radiation therapy (RT) followed by surgery to improve local control. METHODS AND MATERIALS:We retrospectively reviewed the data of 19 patients with metastatic STS consecutively treated at our institution with CMT between 2018 and 2023. All patients received moderately hypofractionated 40.05 Gy in 15 fractions followed by surgery. Patients were selected for CMT based on factors that were likely to predict longer survival despite having metastatic disease such as oligometastatic disease (≤5 lesions) and favorable response to systemic therapy. RESULTS:The median size of the primary tumor was 7.6 cm (IQR, 4.4-12.7 cm). Fourteen patients (74%) received systemic therapy immediately before (n = 10) or after (n = 4) CMT. Seven patients (37%) underwent additional metastasis-directed local therapy following CMT to other sites. Pain reduction after CMT was documented in 89% of patients who presented with pain (n = 8 of 9). Median follow-up was 21 months. Two-year local recurrence-free survival, progression-free/distant recurrence-free survival, and overall/cancer-specific survival were 92%, 29%, and 65%, respectively. One patient (5%) had local recurrence. For patients who were not planned to have adjuvant systemic therapy, median systemic therapy-free survival was 15 months. The rate of wound complications within 120 days of surgery was 16%. No planned adjuvant therapy was delayed because of wound complications; all patients commenced systemic therapy within 3 months of surgery. The rate of late RT toxicities was 26%; there were no grade ≥3 late toxicities. CONCLUSIONS:For properly selected patients with metastatic STS with good performance status and long expected survival, a CMT strategy for the primary tumor with moderately hypofractionated preoperative RT offers favorable local control, low toxicity, and pain mitigation without significant effect on systemic therapy resumption.

PurposeThe presence of microsatellites in cutaneous melanoma has historically been associated with a poor prognosis. Whether adjuvant primary site radiation therapy (RT) mitigates risk of recurrence is unknown.MethodsAll patients with cutaneous melanoma who underwent primary site wide local excision at our center between 2016 and 2023 with histopathologic evidence of microsatellites and no clinically involved lymph nodes, in-transit disease, or macrosatellites were retrospectively reviewed. We investigated the association of patient, disease, and treatment factors with recurrence and survival outcomes.ResultsWe identified 153 eligible patients with microsatellites. With a median follow-up of 31 months from resection, 3-year local recurrence-free survival (LRFS) was 78% and 3-year disease-free survival (DFS) was 42%. The majority received adjuvant systemic therapy (55%, n = 85 immune checkpoint inhibition; 5%, n = 7 BRAF/MEK-directed therapy). Fifty-nine patients (39%) received postoperative RT after wide local excision. On multivariate analyses with inverse propensity score weighting, receipt of adjuvant primary site RT was associated with longer local recurrence-free survival (LRFS, hazard ratio 0.22, p = 0.04), which appears to drive longer disease-free survival (DFS, hazard ratio 0.46, p = 0.007).ConclusionsIn the contemporary therapeutic era, even with the majority of patients receiving adjuvant immune checkpoint inhibition or targeted therapy, adjuvant RT is associated with higher local control and DFS. Patients with microsatellitosis should be referred for consideration of postoperative RT.

Background/Objectives: Immune checkpoint inhibitors (ICIs) and other systemic therapies can extend the survival of many patients with advanced melanoma, renewing interest in complementary strategies for unresectable or metastatic disease. Therapeutic cancer vaccines represent a possible approach. Recent evidence suggests commercially available mRNA vaccines can sensitize tumors to ICIs, challenging prior assumptions about neoantigen presentation. Despite renewed public interest in personalized cancer vaccine development, the proliferation of narrative and scoping reviews has not been matched by systematic mechanistic synthesis—platforms investigated across the 2010s and 2020s have not been rigorously compared within a single article. Accordingly, this review focuses on major vaccine platforms and proposes a comparative framework for understanding therapeutic melanoma vaccine development and immunologic rationale. Methods: Melanoma vaccine clinical trials listed on ClinicalTrials.gov were identified from 2010 to 2025. Eligible studies were screened and included in a qualitative review evaluating trial characteristics, vaccine platforms, study design, and reported outcomes. Results: There is one active Phase III clinical trial for melanoma vaccines in the US. Key principles of melanoma vaccinology include adjuvant, antigen, and delivery platform selection. From 2010 to 2025, four vaccine candidates advanced to Phase III trials, two provided Phase III results for peer review, one trial is ongoing, and no vaccines have been FDA-approved. Inconsistent reporting of outcomes and a lack of published results limited comparability across studies, precluding formal meta-analysis. Conclusions: Therapeutic melanoma vaccine options remain limited by translational challenges in study design and reporting gaps. This review synthesizes contemporary clinical trial activity and immunologic principles to inform future research.

Mucosal melanoma (MM) is a rare and aggressive melanoma subtype with poor outcomes and poorly understood risk factors, including the contribution of germline pathogenic variants (PVs). In this study, 346 MM patients treated at MD Anderson Cancer Center underwent germline sequencing of 322 known cancer susceptibility genes, with PV frequencies compared to population controls (gnomAD and TOPMed) using Fisher's exact test. The cohort had a median age at diagnosis of 64 years and was predominantly female (62%) and White (84.0%). Anatomical subtypes of MM included gastrointestinal (36%), head and neck (33%), and genitourinary (31%). Among patients with somatic testing results (n = 303), KIT mutations (26%) were most common, followed by NRAS (17%), BRAFNon-V600 (6.6%), and BRAFV600 (2.6%). Germline PVs were identified in 37 patients (10.7%), most frequently in CHEK2 (n = 9, 23.0%), ATM (n = 8, 20.5%), and MITF (n = 6, 15.4%). MITF p.E318K (OR 6.0; 95% CI 2.2-13.2) and CHEK2 c.1100delC (OR 6.7; 95% CI 1.8-17.5) were significantly enriched compared to population control rates. Patients with germline PVs were more likely to have two or more affected first-degree relatives (49.0% vs. 29.1%, p = 0.019). These findings highlight a meaningful germline contribution to MM risk and support the incorporation of genetic testing in this population.

TPS11595 Background: High-risk, localized soft tissue sarcoma (STS) remains associated with high rates of distant relapse despite modern multimodality therapy. Immune checkpoint inhibition (ICI) has demonstrated activity in certain metastatic STS subtypes with signals of enhanced response when combined with doxorubicin in the advanced/metastatic setting, as well as improved disease-free survival when combined with radiotherapy (RT) in the neoadjuvant setting; however, the optimal integration of neoadjuvant chemotherapy, immunotherapy, and RT in resectable disease is unknown. This single-arm phase II trial evaluates whether neoadjuvant atezolizumab combined with doxorubicin, followed by concurrent atezolizumab with preoperative RT and adjuvant atezolizumab, can improve relapse outcomes in patients with resectable, high-risk STS of the extremity and trunk. Methods: SATURN-STS is an investigator-initiated phase II study enrolling 50 adults with treatment-naïve, localized, intermediate- to high-grade STS >5 cm, including undifferentiated pleomorphic sarcoma, myxofibrosarcoma, de-differentiated/pleomorphic liposarcoma, leiomyosarcoma, and unclassified sarcoma. Neoadjuvant treatment includes 4–6 cycles of doxorubicin (60–75 mg/m²) plus atezolizumab (1200 mg IV q3w), followed by atezolizumab with preoperative RT (50 Gy in 25 fractions or 42.75 Gy in 15 fractions), surgical resection, and up to 16 cycles of adjuvant atezolizumab. Radiographic imaging is performed at baseline, during neoadjuvant therapy, post-RT prior to surgery, and throughout follow-up. Longitudinal tissue is acquired for translational analyses with biopsy prior to initiation of chemoimmunotherapy and prior to RT/immunotherapy combination, followed by collection at the time of surgery. The primary endpoint is time-to-relapse (TTR), defined from time of surgical resection to the date of documented disease recurrence, compared to a historical control using a single-arm, time-to-event Bayesian monitoring approach. Secondary endpoints include objective response (RECIST 1.1), pathologic response, local recurrence-free survival, distant metastasis-free survival, progression-free survival, overall survival, and safety (CTCAE v5.0). Exploratory objectives include profiling immune microenvironment changes, genomic correlatives, circulating tumor DNA, and spatial analyses. As of January 2026, 6 patients have initiated treatment at an accrual rate of 1-2 patients per month. Clinical trial registration: NCT07049848. Support: The University of Texas MD Anderson Cancer Center and Genentech Strategic Alliance Grant. Clinical trial information: NCT07049848 .

Soft tissue sarcoma (STS) of the chest wall is a relatively uncommon presentation of STS, though a common subtype of truncal STS. Wide en-bloc resection is the foundation of multimodality treatment of STS, but surgical resection alone can produce suboptimal outcomes for many patients. In this article, we summarize existing literature on the role of radiotherapy in the management of chest wall STS and provide an overview of its recommended use with a focus on the ASTRO Guideline on Radiation Therapy for Treatment of Soft Tissue Sarcoma in Adults.

e14582 Background: Patients (pts) with advanced-stage, resectable cutaneous squamous cell carcinoma (CSCC) have historically been treated with up-front surgery (US) +/- adjuvant radiotherapy (RT). More recently, the use of neoadjuvant immunotherapy (NEO) has shown promising outcomes. We aimed to describe our institutional experience with these approaches. Methods: We identified 300 pts with stage III (n = 139) or IV (n = 161) resectable CSCC treated 2010-2024 without prior RT. We compared patient characteristics with US (n = 194) vs. NEO (n = 106). Pathologic responses were classified as previously described. Treatment cohort features were compared by Chi-square or Fisher’s exact tests. Event-free survival (EFS) was calculated by the Kaplan-Meier method and defined as time from surgery to disease recurrence or death for US pts and progressive disease without subsequent surgery, recurrence or death for NEO pts. The effect of NEO vs. US was assessed by Log-Rank test. Results: Median age was 71 years (IQR 64-79). Recurrent disease at presentation was similar between cohorts (US-34%, n = 49 vs. NEO-28%, n = 30, p = 0.57). Pts receiving US had lower stage disease (stage III: US-54%, n = 104 vs. NEO-33%, n = 35, p < 0.001) and were more likely to be immunocompromised (US-19%, n = 37 vs. NEO-8%, n = 8, p = 0.008). In the NEO cohort, after a median 3 cycles anti-PD1, 82% (n = 87) of pts proceeded to surgery. Of these, 47 (54%) had a pathologic complete response (pCR), 10 (11%) near-pCR, 8 (9%) pathologic partial response (pPR) and the remaining were pathologic non-responders (pNR). Of the NEO patients who did not have surgery (n = 19, 18%): 11 declined surgery after clinical response, 2 declined surgery after progression, 2 died of other causes and 4 were lost to follow up. Post-op RT was more common after US (72%, n = 141 vs. NEO-26%, n = 28, p = < 0.001). Adjuvant chemotherapy (US-10% vs. NEO-5%) or immunotherapy (US-0% vs. NEO-9%) were infrequently applied. Median follow-up was 33 months for both US (IQR 16-76) and NEO (IQR 18-51). 2-year EFS was greater in the NEO cohort compared to US (90% vs 79%, p = 0.013). Any pathologic response at surgery after NEO (pCR, near-pCR, pPR) was associated with improved outcomes compared to pNR (2-yr EFS 98% vs. 61%, p = < 0.001). Conclusions: In a single-institution, retrospective series, NEO was associated with improved 2-year EFS compared to US. These data support the completion of an ongoing randomized phase 3 trial (NCT06568172) comparing NEO to US.

Background/Objectives: FLASH radiotherapy (RT) has shown potential to reduce normal tissue toxicity compared with conventional (CONV) RT while maintaining tumor control. FLASH RT is characterized by ultra-high dose rate delivery, commonly using mean dose rates ≥ 40 Gy/s and sub-second delivery times. Most preclinical studies have used single-fraction regimens, leaving the feasibility and normal tissue impact of clinically relevant fractionation largely unexplored. We evaluated electron FLASH RT given in a standard five-fraction regimen to a porcine skin model, simulating adjuvant treatment workflow for high-risk cutaneous melanoma. Method: Three Yorkshire-Landrace swine received paired five-fraction electron irradiations to dorsolateral skin using either FLASH RT (mean dose rates 175-246 Gy/s) or CONV RT (8 Gy/min). Radiation was delivered with a 9-MeV electron beam; field diameters of 4, 7, or 10 cm; and doses of 5 × 6, 5 × 7, or 5 × 8 Gy. Dosimetry was validated with several dosimeters and real-time beam monitoring, confirming dose accuracy within 3%. Skin toxicity was assessed over 22-24 weeks using clinical grading, erythema spectrophotometry, and histopathologic evaluation. Results: FLASH RT was well tolerated at 5 × 6 Gy and 5 × 7 Gy, with no significant differences in peak radiation dermatitis, erythema index, or histologic damage compared with CONV RT. At 5 × 8 Gy, both modalities caused unacceptable toxicity, including moist desquamation and necrosis. No volume-dependent effects were observed. Conclusions: Although a FLASH-specific normal tissue sparing effect was not observed, this study demonstrates the technical feasibility and safety of delivering fractionated electron FLASH RT in a large animal model using a clinically relevant workflow. These findings support further investigation of physical beam parameters and biological modifiers, such as tissue oxygenation, and inform the clinical translation of fractionated FLASH RT for cutaneous malignancies.

ABSTRACT Objective We aim to evaluate outcomes for patients with resectable SNMM treated in the immunotherapy era. Methods Thirty‐seven patients with resectable SNM were identified using our institutional database between 2016 and 2023. Results Patients receiving neoadjuvant Ipi/Nivo (46%, n = 17) were more likely to have disease involving the sinuses and/or the skull base (71% vs. 35%, p = 0.05). The overall response rate to Ipi/Nivo was 24%. Two‐year LRFS from the start of therapy was 63%, and from the end of local therapy was 78%. Two‐year PFS was 49%. The patients who received Ipi/Nivo with evidence of response ( n = 4, 24%) had better PFS (2‐year PFS 100% vs. 15%, p = 0.02) and LRFS (2‐year LRFS 100% vs. 31%, p = 0.08). Conclusions Outcomes for resectable SNMM patients continue to be poor in the immunotherapy era. In the context of selection bias, neoadjuvant Ipi/Nivo was not associated with better outcomes in all‐comers. However, those with evidence of response to Ipi/Nivo had better prognosis.

Over the last decade, the standard of care for patients with melanoma and Merkel cell carcinoma has undergone dramatic changes. These advancements have been largely driven by improvements in systemic therapy, altering treatment options for patients at every stage from localized to regional to distant disease. The optimal role of radiation therapy in this contemporary context is not always clear. Herein, the authors review the evidence regarding the role of radiation therapy for locoregional disease in these aggressive cutaneous malignancies in the modern era.

BackgroundDedifferentiated liposarcoma (DDLPS) is one of the most common types of soft tissue sarcoma (STS) characterized by liposarcomatous differentiation and a predilection for the retroperitoneum. Despite the growing number of histology-specific immune checkpoint blockade (ICB) trials in STS, it is still difficult to identify the radiographic objective response rate (ORR) for DDLPS in the real world setting. This study aimed to evaluate the ORR and survival of patients with DDLPS treated with ICB at a single center.MethodsWe conducted a retrospective study of 31 patients with pathologically confirmed DDLPS treated with ICB at MD Anderson Cancer Center between 2018 and 2023. Patient demographics, disease characteristics, treatment history, and response to ICB were analyzed. Immunohistochemical analysis was performed on tumor samples to assess immune-related markers.ResultsORR by RECIST 1.1 was 3.2% (n=1/31). Among all patients (n=31), 6% achieved partial radiographic response, while 39% had stable disease, and 55% showed progressive disease. Median progression-free survival (PFS) was 3.5 (95%CI:1.9, 4.7) months, and overall survival (OS) after ICB initiation was 19.7 (95%CI: 8.8, not reached) months. Patients without prior systemic therapy demonstrated better OS (p=0.004). Immunohistochemistry revealed no relationship between pre- or post-ICB expression of CD8, CD20, CD21 and PDL-1 and response.ConclusionWhile the response to ICB in DDLPS remains limited, specific immune markers may influence treatment outcomes. CD20/21 post-ICB appear more important for prognosis. Further research is warranted to identify predictive factors for ICB efficacy in DDLPS.

PURPOSE:Adjuvant radiation therapy (RT) to a cutaneous target has been associated with elevated risk of surgical complications such as graft, flap, or skin substitute reconstruction failure. We sought to better quantify the risk of surgical site complications after hypofractionated adjuvant RT delivered in the modern era to patients undergoing surgical reconstruction for their primary site cutaneous melanoma. METHODS AND MATERIALS:We reviewed clinical data on all patients treated for cutaneous melanoma at our center between 2008 and 2021 with primary tumor resection and reconstruction (graft, flap, or skin substitute), followed by 5 × 6 Gy RT. Details on post-treatment complications were assessed. RESULTS:A total of 193 patients with melanoma undergoing surgical reconstruction followed by hypofractionated RT were identified. Most patients carried at least 1 risk factor for wound healing complications (70% with cardiovascular disease, 64% overweight, and 23% with diabetes). Most tumors were located in the head and neck (89%). Patients initiated RT a median of 7 weeks (IQR, 5-9 weeks) from surgical reconstruction. Skin grafts were used in 62% of reconstructions, and flaps used in 44%. Electron-based RT was used for the majority of patients (n = 166, 86%). Ten patients (5%) required surgical revision after reconstruction, with half occurring after RT. The primary reconstruction for all 5 patients requiring surgical revision after RT was graft reconstruction of the scalp, with a wide range of times from reconstruction to RT (5-11 weeks) and a wide range of times from RT to surgical revision (2-28 months). CONCLUSIONS:The risk of surgical revision after adjuvant hypofractionated RT to a surgical reconstruction involving a graft, flap, or skin substitute is low. Half of graft failures occurred before adjuvant RT and half after, which suggests that adjuvant RT only marginally increases the risk of postreconstruction complications if adequate time for healing is given.

Purpose:Abdominopelvic soft-tissue sarcomas (AP-STS) are selectively treated with radiation therapy (RT) followed by surgery. We investigated dosimetric factors predictive of acute and long-term gastrointestinal (GI) toxicities in patients treated with preoperative RT for AP-STS. Methods and Materials:We performed a retrospective cohort study of patients treated for nonmetastatic AP-STS with preoperative RT and surgery from 2005 to 2020. Individual loops of small and large bowel, as well as a "Bowel Bag" space, were autocontoured using a clinically validated deep learning-based approach (nnU-Net) and then manually reviewed. Chi-square or Fisher's exact test was used to assess how bowel dosimetry related to the development of GI toxicities. In particular, the effect on GI toxicity of exceeding bowel constraints as defined in the consensus guidelines was evaluated. Recurrence outcomes were analyzed using the Kaplan-Meier method. Results:We evaluated 76 patients with a median follow-up of 46 months (IQR, 42-50). Approximately half of the tumors were located in the retroperitoneal space (n = 39, 51%). A total of 60 patients (79%) presented with de novo disease, and 21% (n = 16) were recurrent presentations that had not received prior RT. Fourteen patients (18%) had a local recurrence alone, 23 (30%) a distant recurrence alone, and 3 (4%) combined local and distant recurrence. As a result of RT, 23 patients (30%) had acute grade 1 to 2 diarrhea, and 14 (18%) had grade 1 nausea. There were no acute grade 3 toxicities. Six patients (8%) had any long-term RT-related toxicity, including 1 small bowel obstruction. Patients were more likely to have an acute GI toxicity if bowel bag V45>195 cm3 (P = .05). Conclusions:Traditional RT volumetric bowel dose constraints are frequently exceeded, given the large size of AP-STS at presentation and the corresponding large RT volumes. Exceeding the conventional bowel dosimetric constraints should not dissuade the use of RT, but instead signal the need for aggressive prophylactic management of potential toxicities.