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Importance The incidence of human papillomavirus type 16 (HPV16–positive) recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is rising. Approved therapies offer a durable response to a minority of patients. Objective To determine the efficacy and safety of a therapeutic HPV16-targeted immunotherapy, PDS0101, in combination with pembrolizumab in participants with HPV16-positive R/M HNSCC, with separate evaluation of immune checkpoint inhibitor (ICI)–naive and ICI-resistant cohorts. Design, Setting, and Participants VERSATILE-002 was a phase 2, open-label, multicenter nonrandomized clinical trial conducted at 26 oncology centers from March 29, 2021, to May 15, 2025, across the US, UK, and Ireland using the Simon 2-stage optimal design. Efficacy analyses were performed on modified intent-to-treat (mITT) population; safety analyses included all participants who received 1 or more doses. Eighty-eight participants with histologically confirmed R/M HPV16-positive HNSCC were enrolled, of whom 87 (98.9%) received treatment and composed the safety population. Seventy five (85.2%) were in the mITT population used for efficacy analyses, of whom 53 (70.7%) were ICI-naive with a programmed cell death ligand 1 combined positive score of 1 or greater and 22 (29.3%) were ICI-resistant. Exposures Pembrolizumab (200 mg, intravenously, every 3 weeks for up to 35 cycles) plus subcutaneous PDS0101 (5 scheduled doses per protocol). Main Outcomes and Measures The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors , version 1.1, by a masked independent central reviewer. Secondary end points included progression-free survival (PFS), median overall survival (mOS), and safety, with exploratory end points of duration of response, disease control rate, and response rates by programmed cell death ligand 1 status. Results Of the 75 patients in the mITT population, the mean (SD) age was 64.0 (8.3) years; 4 individuals (5%) were female and 71 (95%) were male; and 2 individuals (3%) were Asian, 1 (1%) was Black, 5 (7%) were Hispanic, and 71 (95%) were White. Among 53 ICI-naive participants in the mITT cohort, ORR by the central reviewer was 34.0%, median PFS was 5.3 months (95% CI, 2.10-9.00), and mOS was 39.3 months (95% CI, 23.90 to not evaluable). Among 22 ICI-resistant patients in the mITT cohort, no objective responses were observed and the primary end point (ORR by central reviewer) was not met, but mOS was 14.8 months (95% CI, 8.50-26.00). The treatment was well tolerated, with 13.8% experiencing grade 3 or higher treatment-related adverse events. Conclusions and Relevance The results of this nonrandomized clinical trial suggest that PDS0101 plus pembrolizumab showed antitumor activity in ICI-naive HPV16-positive R/M HNSCC, with favorable safety, response rates, and survival outcomes. The findings support further evaluation in a first-line setting. Trial Registration ClinicalTrials.gov Identifier: NCT04260126

Introduction: Laryngopharyngeal symptoms (LPS) refer to aerodigestive complaints that may result from the retrograde flow of gastric contents into the upper aerodigestive tract. These symptoms may be under-recognised in populations exposed to mechanical or environmental stressors. Divers may be at increased risk due to factors such as pressure changes and body positioning. This study characterised the prevalence and severity of LPS among divers and identified associated risk factors. Methods: A cross-sectional, anonymous survey was distributed to members of the Divers Alert Network (DAN). Collected data included demographics, diving-related behaviours, medical history, and LPS burden measured using the Reflux Symptom Index (RSI). Results: Of the 309 survey responses analysed, 47.2% were male with a median age of 50.0 years (IQR: 40.0−60.0). Among 291 divers with complete RSI data, 26.1% (95% CI, 21.4–31.5%) had abnormal RSI scores, representing a +16.0 percentage-point increase (95% CI, 11.3%−21.4%) over non-diving population estimates (P < 0.001). In multivariable analysis, female sex (adjusted prevalence rate [aPR] 1.59, 95% CI 1.07–2.37) and gastroesophageal reflux disease (GERD) history (aPR 1.75, 95% CI 1.16–2.65) were independent predictors. Recreational divers had a lower risk (aPR 0.59, 95% CI 0.39–0.90). Approximately 5% of respondents described their symptoms as life-threatening. Conclusions: Divers may represent an under-recognised population at elevated risk for LPS. Female sex and GERD history were associated with greater symptom burden, while recreational diving appeared less provocative compared to technical diving. These findings may have implications for risk stratification and symptom management in the diving community.

Aberrant activation of the Hippo–YAP/TAZ–TEAD transcriptional axis is a recurrent feature of multiple solid tumors and contributes to tumor maintenance, lineage plasticity, and therapeutic resistance. Recent medicinal chemistry has shown that TEAD proteins are druggable, but the rate at which in silico screening nominates compounds that prove functionally active in cells remains poorly defined, and negative validation results are rarely reported. Here we describe an experimental assessment of a focused set of computationally nominated candidate compounds, selected from a structure-guided virtual screen of the YAP–TEAD interface across approximately 917,000 library compounds and three predicted binding sites. Candidates were evaluated using long-term (144 hour) CellTiter-Glo proliferation assays in three Hippo-altered malignant pleural mesothelioma cell lines (MSTO-211H, NCI-H2052, NCI-H226), with the validated TEAD inhibitor K-975 and cisplatin as positive controls, and an exploratory TEAD-responsive luciferase reporter in MCF7 cells. K-975 produced dose-dependent antiproliferative activity in MSTO-211H and NCI-H2052, with reduced sensitivity in NCI-H226, while cisplatin reduced viability in all lines. In contrast, the computationally nominated compounds, including AG-690/36549045, AN-655/40856217, and additional library members, did not produce measurable antiproliferative activity at the concentrations tested. In the exploratory reporter, apparent suppression of TEAD activity consistently co-occurred with loss of cell viability, a pattern consistent with cytotoxicity rather than selective transcriptional inhibition; no TEAD-active reference compound was co-tested within the reporter panel, and no direct YAP–TEAD biochemical or target-engagement assay was performed. These results describe a case in which computational nomination at the YAP–TEAD interface showed limited concordance with cell-based activity and provide a transparent account of negative findings to inform expectations for early-stage discovery targeting Hippo-dependent transcriptional programs.

PURPOSE Detection of bone marrow disease has been a major component of rhabdomyosarcoma (RMS) staging with bilateral bone marrow aspirates/biopsies (BMAB) from the iliac crests considered the diagnostic gold standard. This study's goal was to determine if 2- 18 F-labeled fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) or PET/magnetic resonance imaging (MRI) may replace BMAB in RMS staging. METHODS Patients were recruited in Europe and North America. Medical records, FDG PET/CT or FDG PET/MRI (PET), and BMAB reports were collected retrospectively. Images were re-reviewed by nuclear medicine physicians at the patients' home institutions if PET reports indicated increased FDG uptake at bone/bone marrow sites or if tumor cells were detected in bone marrow samples. RESULTS PET imaging and BMAB were performed before chemotherapy and tumor resection in 301 patients with FDG-avid RMS. Bone marrow metastases were detected by PET and BMAB in 54, by PET only in 24, and by BMAB only in one of 301 patients with FDG-avid primary tumors. Absence of bone marrow metastases was confirmed by PET and BMAB in 222 of 301 patients. These observations translated into 98% sensitivity and 90% specificity for PET in detecting bone marrow metastases when BMAB was considered as gold standard. FDG-avid marrow disease was patchy (1-5 foci) in one third of cases. Patients with marrow disease indicated by PET and BMAB had more FDG-avid bone marrow foci, more metastatic sites, and lower survival than those with marrow disease indicated by PET only, suggesting more advanced disease stages. CONCLUSION Bone marrow sampling may be omitted in patients without evidence of FDG-avid bone marrow disease by PET. If there are FDG-avid bone marrow lesions, further investigation by MRI and/or biopsy should be considered.

PURPOSE EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. METHODS Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

Abstract Objective To evaluate the connection between symptom burden and sexual quality of life in women with idiopathic subglottic stenosis (iSGS). iSGS is a rare fibroinflammatory disorder involving progressive airway narrowing and respiratory distress. While the impact on physical functioning is well‐established, the influence of iSGS on sexual health, a key component of quality of life, remains unexplored. Study Design Anonymized cross‐sectional survey using validated questionnaires. Setting Online international iSGS support group (Living with Idiopathic Subglottic Stenosis). Methods The Dyspnea Index (DI), the Female Sexual Quality of Life (SQOL‐F) questionnaire, and the Medical Outcomes Health Survey (SF‐36) were distributed to an iSGS support group. Only complete responses were analyzed. Associations between DI and sexual quality of life were evaluated using correlation and linear regression. Median‐based symptom burden groupings were used for secondary descriptive comparisons. Results 682 completed all items in the assigned questionnaires and met inclusion criteria. DI scores were inversely correlated with SQOL‐F (Rho = −0.305, P < .001). SQOL‐F was consistently lower among those with high symptom burden across nearly all items; only partner communication showed no difference. Each one‐point increase in DI predicted a 0.61‐point decrease in SQOL‐F ( B = −0.609, P < .001). High‐burden patients also reported significantly lower SF‐36 Physical (PCS) and Mental (MCS) Component Scores. Conclusions Greater airway symptom burden in iSGS is associated with significantly diminished sexual and general health‐related quality of life. These findings reinforce a need for patient‐centered care that considers both physical and psychosocial well‐being.

Abstract Background Light chain cardiac amyloidosis (AL-CM) is an infiltrative cardiomyopathy associated with significant morbidity and mortality. Early diagnosis and risk stratification is critical for prognostication and management, particularly identifying patients most likely to need heart transplants. The systemic light chain amyloidosis (sAL) score is derived from echocardiographic parameters: relative wall thickness (RWT), E/e' ratio, global longitudinal strain (GLS), and tricuspid annular plane systolic excursion (TAPSE) and is validated in the diagnosis of AL-CM [1]. Its prognostic value for development of atrial fibrillation, progression of heart failure, and hospitalizations remains unclear. This study evaluates the association between the sAL score, arrhythmias, and functional outcomes in patients with confirmed AL-CM. Methods A retrospective review of patients seen at our hospital, with confirmed AL-CM diagnosed between June 2014 and October 2021 was conducted on an IRB-approved protocol. The sAL score was collected at the time of diagnosis. Binary outcomes were evaluated using a weighted Mann-Whitney U test, with effect size calculated as r=Z/sqrt(N). Ordinal and continuous outcomes were analysed using weighted Spearman correlation, with Spearman’s rho reported as the effect size. Results 37 patients with AL-CM were included (51.4% male), with a median age of 70 years [IQR 66–76], a median sAL score of 5 [IQR 3–6], and a median left ventricular ejection fraction (LVEF) of 55% [IQR 50–60] at diagnosis. 24 patients had their AL-CM diagnosed by cardiac MRI and positive Congo red on peripheral biopsy (e.g., fat pad); the other 13 had positive endomyocardial biopsy. 22 patients had sAL scores ≥ 5 with overall survival of 17/22 (77.3%) and median follow-up of 53 months. 15 patients had sAL scores &lt; 5 with overall survival of 14/15 (93.3%) and median follow-up of 57 months. 4 patients had atrial fibrillation or flutter at diagnosis. 6 patients developed atrial fibrillation or flutter with a median onset of 15 months after diagnosis. Higher sAL scores at diagnosis were associated with development of new-onset atrial fibrillation or flutter (median sAL 4.5 vs 5, p = 5.75×10^-10, r = 1.02), heart failure hospitalizations (median sAL 5 vs 5, p = 1.94×10^-6, r = 0.78), and ≥30% eGFR decline at 12 months (median sAL 4.5 vs 6, p=8.69×10^-24, r = 1.65). Higher sAL scores were moderately correlated with NYHA class (rho = 0.44, p = 0.00378) and strongly correlated with diastolic dysfunction grade (rho = 0.549, p = 9.99×10^-6) but not associated with change in LVEF (p = 0.51 and p = 0.62, respectively). Conclusion sAL scores of ≥5 at diagnosis were associated with worse functional and clinical outcomes in patients with proven AL-CM. These findings suggest the sAL score predicts electrophysiological changes, supporting its potential role in early risk stratification and disease monitoring.

Abstract Introduction: Next generation of Theranostics studies are looking at novel combinations with radiation sensitizers to enhance PRRT’s efficacy. Here, we present safety and efficacy data from a multi-center phase 1 study of a [¹⁷⁷Lu]lutetium-dotatate -triapine combination in patients with GEP-NETs. Methods: The study consisted of two phases (dose escalation and expansion) administering the recommended phase 2 doses (RP2D) for the two agents. All patients received 200 mCi of [¹⁷⁷Lu]lutetium-dotatate on day 1 of four 8-week cycles, in combination with oral triapine administered at assigned dose levels (100 mg, 150 mg or 200mg) from days 1 to 14 of each cycle. Results: A total of 31 (A: 15 ; B: 16 ) patients received treatment. Nine patients experienced dose-limiting toxicities; Grade 3 anemia (n=1), Grade 5 cardiac arrest (n=1), and Grade 4 neutropenia (n=7). Based on the overall safety and pharmacokinetics data, a [¹⁷⁷Lu]lutetium-dotatate (200 mCi) plus triapine (150 mg) dose was selected as the RP2D for the expansion phase. Grade ≥3 treatment related adverse events were observed in 77% patients: anemia (23%), nausea and vomiting (3% ), lymphopenia ( 58%), neutropenia ( 35%) and leukopenia ( 39%). The majority of cytopenias were transient and resolved within two weeks. Among the 28 evaluable patients, the objective response rate (ORR) was 21.4% and the median progression-free survival (mPFS) has not been reached (median follow-up period: 23.7 months). Conclusions: The combination of [¹⁷⁷Lu]lutetium-dotatate (200 mCi) and oral triapine (150 mg D1-14) was well tolerated and demonstrated preliminary activity in patients with well-differentiated GEP-NETs. (NCT04234568).

Importance Limited granular data exist on breast cancer in transgender, nonbinary, and/or gender-diverse (TGD) individuals. Objective To describe patient demographic and tumor clinicopathological variables, clinically relevant risk factors, method of breast cancer detection, treatment characteristics, and locoregional outcomes and to estimate a 5-year breast cancer–specific survival (BCSS). Design, Setting, and Participants This cohort study obtained data on patients treated from 1990 to 2023 from 22 US academic medical centers using institutional databases, electronic medical records, and tumor registries. Included participants were TGD individuals 18 years or older with stage 0 to IV breast cancer. A comparative breast cancer cohort was selected from the 2016 to 2021 Surveillance, Epidemiology, and End Results Program (SEER) breast cancer dataset. Data were analyzed from January to October 2025. Exposure Breast cancer. Main Outcomes and Measures Estimated 5-year BCSS and locoregional recurrence rates. Wilcoxon rank sum and χ 2 tests were used to compare continuous and categorical variables. Kaplan-Meier analysis was used to estimate 5-year BCSS. Results A total of 112 TGD persons (median [IQR] age at diagnosis, 42.5 [36.5-51.0] years; 104 individuals [92.9%] were assigned female at birth) with breast cancer and 1 with bilateral disease were included in the analysis. Forty-three patients (38.4%) used gender-affirming hormone therapy before diagnosis. Among the entire cohort, 58 patients (51.8%) detected their own breast cancer, 68 (60.7%) had a familial breast cancer history, and 16 (14.3%) had a pathogenic germline variant. Tumors were predominantly hormone receptor positive (96 [85.7%]) and early stage (29 [25.7%] ductal carcinoma in situ [DCIS]; 51 [45.1%] stage I). The TGD cohort, compared with patients with breast cancer in the SEER dataset (N = 480 915), was younger (median [IQR] age, 42.5 [36.5-51.0] years vs 62.0 [52.0-72.0] years), had a higher proportion of persons assigned male at birth (8 [7.1%] vs 3522 [0.7%]), more often had progesterone receptor–positive disease (89 [79.5%] vs 335 491 [69.8%]), and presented with earlier-stage disease (eg, DCIS: 29 [25.9%] vs 79 604 [16.6%]). With a median (IQR) follow-up time for the TGD cohort of 38 (24-74) months, 5-year BCSS was favorable at 96.2% (95% CI, 85.3%-99.0%). Conclusions and Relevance This cohort study of TGD patients with breast cancer found that this population was young and often detected their own tumors via self-examination, suggesting opportunities to improve early detection through screening for individuals at elevated risk. Although short-term BCSS appeared favorable, prospective research is essential to define evidence-based guidelines and elucidate long-term outcomes.