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BACKGROUND AND IMPORTANCE: Juvenile nasopharyngeal angiofibroma (JNA) is a rare, locally aggressive vascular tumor that primarily affect adolescent males. This work illustrates a step-by-step surgical approach of an advanced-stage JNA resection in a prepubescent 5-year-old child, utilizing a hybrid endoscopic endonasal and transmaxillary approach that provides highly effective results without employing traditional open techniques. CLINICAL PRESENTATION: A previously healthy 5-year-old male presented with one-year history of nasal obstruction, mouth breathing, and recurrent otitis media. The patient was found to have a large, space-occupying hypervascular tumor obstructing the nasopharynx. Preoperative radiographic imaging revealed an extensive heterogeneous, avidly enhancing mass that occupied the nasopharynx, right pterygopalatine fossa, infratemporal fossa, masticator space, and middle cranial fossa. Following superselective endovascular embolization, a hybrid endoscopic endonasal approach was planned for JNA resection, incorporating an anterior maxillotomy to allow for direct access to lateral compartments not classically amenable to conventional transnasal corridors. CONCLUSION: This study demonstrates the technical feasibility of a combined endoscopic endonasal and transmaxillary approach for single-stage JNA resection with intracranial extension in pediatric patients. Key principles include tumor embolization, dynamic endoscopic visualization, avoidance of brain retraction, direct access to critical neurovascular structures, and minimizing craniofacial morbidity.

Inherited platelet disorders (IPDs) are a group of rare conditions affecting platelet number, function, or both. Clinical manifestations vary widely, from asymptomatic cases to patients with severe bleeding, syndromic features, or early-onset blood cancers. Some are diagnosed due to family history. Early and accurate diagnosis—through both clinical and molecular evaluation—is essential for effective patient management and to avoid inappropriate treatments due to misdiagnosis. Genetic confirmation aids in prognosis, follow-up planning, family screening, genetic counseling, and donor selection for stem cell transplantation if required. However, diagnosing IPD is still challenging due to the disorders’ complexity and the limitations of current lab tests. This review outlines the diagnostic process for IPD and provides evidence-based, practical recommendations informed by scientific literature and clinical experience.

ABSTRACTObjectiveTo build consensus from different stakeholders on the content and digital interactivity of a shared decision making (SDM) tool to guide patient‐clinician collaborative conversations about treatment for bipolar depression.Patients and MethodsThis study was conducted between September 2022 and September 2023. In the first phase, we conducted a narrative review on pharmacological, neuromodulatory, and psychotherapeutic treatments available for bipolar depression. For each option, we assessed treatment effectiveness, side effects, need for clinical monitoring, clinical considerations, and cost. In the second phase, committees comprised of mental health clinicians and people with lived experience with bipolar disorder from a national mood disorders advocacy group identified key features and content to be included in the SDM tool. A thematic analysis of these data then contributed to populate the SDM tool.ResultsTwenty‐one evidence‐based treatment options identified from the narrative review were presented to the four convened committees (clinical, lived experience, peer council, and integrated steering committees) in five meetings. After discussions and thematic analysis, 12 outcomes of interest for each of the therapeutic interventions were delineated for inclusion in a web‐based SDM tool. A detailed description of the development process and SDM tool is provided.ConclusionThis is the first partnership between clinicians and persons with bipolar disorder lived experience charged with the development of a patient‐centered SDM tool to integrate clinical evidence with real‐world clinical practice and patient preferences for use during clinical encounters. Human‐centered design and testing in real clinical encounters will now contribute to refining the instrument and readying it for rigorous evaluation and implementation in practice.

e18031 Background: HPV+ OPSCC has better outcomes than HPV negative OPSCC but more distant metastatic potential. ICM in HPV+ OPSCC are rare. Data regarding risk factors, clinical presentation and outcomes after ICM diagnosis is limited. This study describes clinical characteristics and outcomes of patients (pts) with HPV+ OPSCC who develop ICM. Methods: Retrospective analysis of pts with HPV+ OPSCC and ICM between 2010 - 2024. Demographic, clinicopathologic, and survival data was collected. Skull base recurrences were excluded. Univariate and multivariate analyses used Cox proportional hazard models; continuous variables binarized by receiver operator curves. Survival assessed via Kaplan-Meier method; reported as median (95% CI). Calculations use BlueSky (v10.3.1). Results: Among 1,999 pts with HPV+ OPSCC, 16 (0.8%) had ICM. Pt characteristics and treatment are summarized in Table 1. Primary tumor sites were base of tongue (56%), tonsil (38%), and unknown (13%). Most pts (n=8, 50%) presented with stage IV disease (6 extracranial metastasis (ECM), 1 ICM only, 1 both). Frontal and parietal lobes were the most frequent ICM sites. Neurological symptoms were present in 10 (62%) pts; ICM was incidentally found in 6 (38%) pts. Median overall survival (mOS) from initial diagnosis was 34 months (21 – not reached) and median time from diagnosis to ICM was 24 months (range 1-112). mOS following ICM detection was 10.9 months (4 -18). On multivariate analysis, only surgical resection (hazard ratio [HR] 0.03, p<0.01) and radiotherapy (HR 0.01, p<0.02) were independently associated with post-ICM survival. With median follow up of 100 months, 14 pts (88%) had died; 2 (12%) were alive. Conclusions: ICM from HPV+ OPSCC are rare but devastating with a mOS <1 year from detection. Most pts were symptomatic, had de novo metastatic disease, and had other sites of metastases. Surgical resection and radiation were associated with improved OS. Multicenter efforts to investigate predictors, multiomic sequencing and identification of pt subsets who may benefit from ICM screening are warranted. Baseline characteristics of Pts with ICM in HPV+ OPSCC. Variable Summary statistics (n=16) Median age (range) 58 (34-71) Male 14 (88%) Smoking history 10 (60%) Clinical stage at diagnosis Stage I: 4 (25%) Stage II: 2 (12.5%) Stage III: 2 (12.5%) Stage IV: 8 (50%) Symptoms at ICM diagnosis Incidental: 6 (38%)Neurological: 10 (62%) Seizure (n=3) Motor/Sensory symptoms (n=3) Altered mental status (n=2) Cognitive symptoms (n=1) Dizziness (n=1) ICM site Frontal lobe: 7 (44%) Parietal lobe: 7 (44%) Occipital lobe: 4 (25%) Temporal lobe: 2 (13%) Cerebellum: 2 (13%) Concurrent ECM Bone: 11 (69%) Lung: 9 (56%) Lymph node: 6 (38%) Liver: 5 (31%) Kidney: 1 (6%) Cranial nerve: 1 (6%) Treatment after ICM Radiotherapy: 15 (94%) Chemotherapy: 10 (63%) Immunotherapy: 9 (56%) Surgery: 8 (50%)

6106 Background: Treatment options for pts with R/M SGC are limited. Responses to chemotherapy (CT) are low with high toxicity and responses to immune checkpoint inhibition (ICI) are <10%. Pemetrexed (PTX) is safe and tolerable with responses reported in pts with R/M SGC. 1 Given enhanced responses with PTX and pembrolizumab (PMB) for lung cancer, we hypothesized that PTX and PMB will have activity for SGC. Herein we present the efficacy results in pts with non-adenoid cystic carcinoma (ACC). Methods: MC200708 is a single arm phase II study of PTX and PMB in pts with R/M SGC (NCT04895735). Pts were treated in 2 cohorts: ACC (cohort A) and non-ACC (cohort B). Key eligibility criteria: ≥18 years, ECOG 0-1, measurable disease. Prior ICI and/or PTX was allowed. Key exclusion criteria: serious comorbidities, autoimmune disease, and brain metastases. Simon’s 2-stage design was used for each cohort. Primary endpoint was overall response rate (ORR). Secondary endpoints: progression free survival (PFS), overall survival (OS), and toxicity. All pts received PTX 500 mg/m2 IV + PMB 200 mg IV q3 weeks until progression or treatment intolerance. Imaging was q3 cycles. Results: 25 pts were enrolled Aug 2021-Feb 2024; 1 cancelled prior to treatment. Of 24 eligible and treated pts, median age was 59.5 years (46-77), 66.7% male, performance status 0 (62.5%) or 1 (37.5%). Histologies were salivary duct carcinoma (SDC, 11), acinic cell carcinoma (8), mucoepidermoid carcinoma (MEC, 3), myoepithelial carcinoma (1), and carcinoma NOS (1). 7 pts had no prior therapies (29.2%). The remaining pts had 1 (33.3%), 2 (29.2%), or ≥ 3 lines of therapy (8.3%). 83.3% of pts had no prior ICI. Median cycles of treatment was 8 (2-34), and duration of response was 12.5 months (4.1-20.6). 9 of 24 pts had a confirmed partial response (PR) for ORR of 37.5% (CI: 18.8-59.4). PRs were seen in 7 pts with SDC (7 of 11, 63.6% PR), 1 with MEC, and 1 with acinic cell. Stable disease (SD) was seen in 5 (20.8%), progressive disease in 8 (33.3%), and 2 didn’t have post-baseline imaging, but were considered non-responders per protocol. Clinical benefit rate was 58.3% (CI: 36.6-77.9). With median follow-up of 12.0 months (2-34.7), median OS is 20.7 months (CI: 17.3-not reached) and median PFS is 6.2 months (CI: 2.1-17.3). 1-year OS and PFS rate is 76.3% (95% CI: 59.9-97.2) and 36.1% (CI: 21.01-62.2), respectively. Common toxicities were grade 1 fatigue and nausea. 6 pts (25.0%) had ≥1 grade 3-4 toxicity possibly related to treatment, mostly hematologic. The 4 pts with grade 3-4 non-heme toxicity had grade 3 fatigue, rash, and heart failure, and 1 grade 4 hypokalemia. Correlative studies investigating biomarkers of response are underway. Conclusions: PTX and PMB has activity in pts with R/M SGC, with promising responses in pts with SDC and median response duration of 1 year. 1 Viscuse et al. Head Neck 2019;41(6):E99-103. Clinical trial information: NCT04895735 .

6061 Background: PDS0101 is a T cell stimulating immunotherapy (therapeutic vaccine) targeting HPV16. The combination of PDS0101 + pembrolizumab (5 cycles) has shown durable clinical responses in HPV-positive recurrent/metastatic HNSCC. MC200710 is a window of opportunity study in patients with HPV-associated oropharyngeal squamous cell carcinoma (HPV+ OPSCC). This prospective phase II trial utilized 2 cycles of neoadjuvant PDS0101 aloneor in combination with pembrolizumab prior to surgical resection or chemoradiotherapy (CRT). Herein, we report the initial results, including primary endpoint of ctDNA response. Methods: Between June 2022 and September 2024, 20 patients (10 per Arm) with locally advanced HPV+ OPSCC were enrolled in a sequential alternating design. Arm A received 2 cycles of PDS0101 and Arm B received 2 cycles of PDS0101 and pembrolizumab with all patients undergoing subsequent surgery or CRT. Assessments were done at baseline, post cycle 1, and post cycle 2 (prior to surgery or CRT). The coprimary endpoint of ctDNA response was defined as a ≥50% decline in ctDNA post cycle 2 compared to baseline as quantified using NavDx (TTMV fragments/mL). Radiologic objective response rate (ORR) was assessed as per RECIST 1.1. Toxicity through the neoadjuvant period was assessed using CTCAE criteria and recurrence rates following surgery or CRT are reported. Results: Patients were similar between arms: male 90%, median age 61 years, cT1/T2 70%, cN1 65%, and no smoking history 65%. All patients completed both cycles of therapy with 13 (65%) undergoing primary operative management and 7 CRT (35%). The most common toxicity was injection site reaction 85% grade 1, 15% grade 2, 0% grade 3, consistent with prior studies. One patient experienced grade 2 pneumonitis during the neoadjuvant window (Arm B). There was one grade 3 toxicity (5%) possibly attributable to study intervention with one patient experiencing transient hepatitis requiring hospitalization (Arm A). Zero of 10 patients in Arm A had a ≥50% decline in ctDNA from baseline while 5 of 10 patients (50%) met this primary endpoint in ARM B (p=0.03). After Cycle 2, based on RECIST 1.1, no Arm A patients had a partial response (PR), with 7 having stable disease (SD); Arm B had 2 patients with PR and 8 with SD. With median follow up of 6 months, 2 patients in Arm A recurred and 0 patients in Arm B. Conclusions: The combination of PDS0101 and pembrolizumab met the trial’s primary endpoint of ctDNA response and shows promise for further evaluation. ctDNA can be used to assess early response and future studies could use ctDNA to adapt neoadjuvant therapy. Based on these findings, a neoadjuvant dose optimization study in HPV16+ oropharyngeal carcinoma is warranted and evaluation of PDS0101 and pembrolizumab in comparison to pembrolizumab alone. Clinical trial information: NCT05232851 .

TPS2677 Background: Despite the success in hematologic malignancies, CAR T therapies face significant challenges in solid tumors due to the lack of tumor-specific targets that distinguish cancer from normal cells. EGFR plays a critical role in oncogenesis across several cancers and is often upregulated (TCGA 2022). While monoclonal antibodies targeting EGFR have demonstrated efficacy, these approaches are often limited by on-target, off-tumor toxicities, such as skin rash, which constrains dose escalation and efficacy (Macdonald, et al. J Am Acad Dermatol . 2015). A2B395 is an allogeneic, logic-gated, EGFR-targeted Tmod CAR T therapy designed to address these limitations and provide a convenient and consistent off-the-shelf option. This therapy incorporates 2 CARs: an activator targeting EGFR, and a blocker targeting HLA-A*02. The activator recognizes EGFR on both tumor and normal cells, while the blocker inhibits CAR T activity against normal cells with preserved HLA expression and decreases the risk for graft-versus-host disease (Hamburger, et al. Mol Immunol . 2020). To address potential host-vs-graft response, an shRNA expression module targeting B2M is included in the Tmod construct, which significantly reduces major histocompatibility complex class I levels and subsequent host immune response (DiAndreth, et al. Clin Immunol. 2022). Importantly, the Tmod system is modular and adaptable to multiple targets. Initial data on autologous Tmod CAR T therapy suggest reduced off-tumor toxicity and encouraging clinical efficacy (Grierson, et al. SITC 2024. Abstract 588). A2B395 represents a novel approach for EGFR-expressing solid tumors with HLA-A*02 LOH. Methods: DENALI-1 (NCT06682793) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B395 in adults. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH at any time in the course of their disease via next-generation sequencing (Tempus AI, Inc.). Key inclusion criteria include histologically confirmed recurrent unresectable, locally advanced, or metastatic cancers associated with EGFR expression, including colorectal, non-small cell lung, squamous cell head and neck, triple negative breast, and renal cell cancers. Patients must have received ≥1 line of prior therapy, such as a checkpoint inhibitor, molecular targeted therapy, or chemotherapy. The primary objective of phase 1 is to evaluate safety, tolerability, and the recommended phase 2 dose (RP2D) using a Bayesian optimal interval design for dose escalation. The dose-expansion phase will confirm RP2D and collect biomarker data. Phase 2 will assess overall response rate per RECIST v1.1. Clinical trial information: NCT06682793 .

Importance Circulating tumor human papillomavirus DNA (ctHPVDNA) is an important biomarker for the presence of HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), but little is known about early postoperative kinetics of ctHPVDNA clearance. Objective To investigate early postoperative kinetics of ctHPVDNA in patients with HPV-associated OPSCC. Design, Setting, and Participants This prospective cohort study was conducted at a single tertiary care center from January 4, 2020, to January 26, 2023. Patients with newly diagnosed HPV-associated OPSCC undergoing surgical management were enrolled. HPV status was defined as positive if findings of p16 immunohistochemistry and/or HPV DNA in situ hybridization and/or E6/E7 RNA in situ hybridization were positive. Exclusion criteria included history of prior head and neck cancer and metastatic disease at presentation. Data were analyzed from September 1, 2024, to April 25, 2025. Exposures Transoral robotic surgery with concurrent neck dissection. Main Outcomes and Measures Blood was drawn prior to surgery (pretreatment), 1 to 2 days after surgery (postoperative days 1 to 2), and approximately 2 weeks after surgery (postoperative week 2; range, 8 to 20 days). ctHPVDNA was quantified by a tumor tissue–modified viral (TTMV) HPV DNA test. Correlations were tested between the pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels using Gaussian regression. Concordance between detectability at postoperative day 1 to 2 and postoperative week 2 was explored using negative predictive value and positive predictive value. Results Of 57 included patients with detectable pretreatment TTMV HPV DNA, 51 (89%) were male, and the median (IQR) age was 59 (54-66) years. A total of 35 patients (61%) had blood draws at all 3 time points; 16 (28%) had detectable TTMV HPV DNA on postoperative day 1 to 2. Pretreatment and postoperative day 1 to 2 TTMV HPV DNA levels had a medium positive linear correlation ( r = 0.31; 95% CI, 0.04-0.54). Undetectable TTMV HPV DNA on postoperative day 1 to 2 blood draw had a negative predictive value of 0.95 (95% CI, 0.74-1.00) for an undetectable level on postoperative week 2 blood draw, but a detectable level on postoperative day 1 to 2 blood draw only had a positive predictive value of 0.19 (95% CI, 0.04-0.46). Of the 16 patients with detectable TTMV HPV DNA pretreatment and at postoperative day 1 to 2, only 3 (19%) continued to have detectable TTMV HPV DNA at postoperative week 2. One patient had undetectable levels at postoperative day 1 to 2 and detectable levels at postoperative week 2. Conclusions and Relevance In this study, ctHPVDNA detectability early after surgery did not predict detectability at 2 weeks after surgery. ctHPVDNA clearance early after surgery could predict a negative test at 2 weeks. A negative blood draw finding on postoperative day 1 may be used to omit a postoperative blood draw at 2 weeks for minimal residual disease detection in future clinical trials.

Abstract This study explores parallels between systemic hypoxia adaptation in high-altitude populations and tumorigenesis. We identified EPAS1, a gene critical for hypoxia adaptation in populations such as Tibetans and Sherpas, as playing a similar adaptive role in tumors arising under hypoxic conditions. Tumors from patients with chronic hypoxia displayed impaired DNA repair and frequent emergence of EPAS1 variants, with frequencies reaching up to 90%, echoing the positive selection seen in high-altitude dwellers. Mechanistically, EPAS1 gain-of-function mutations promote COX4I2 expression, reducing cellular oxygen consumption and supporting tumor proliferation in hypoxia. Analysis of clinical data from patients with hypoxia revealed tissue-specific and time-sensitive tumorigenic effects, particularly impacting oxygen-sensitive cells in the postnatal period. Our findings suggest that EPAS1-driven adaptation mechanisms in high-altitude populations provide a model for understanding tumor evolution under hypoxic stress, highlighting how genetic adaptations to diverse stressors in natural populations may yield insights into tumorigenesis and cancer progression. Significance: This study reveals a broad convergence in genetic adaptation to hypoxia between natural populations and tumors, suggesting that insights from natural populations could enhance our understanding of cancer biology and identify novel therapeutic targets. See related commentary by Lee, p. 875