Citations

Abstract Approximately two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) are diagnosed in advanced stage, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). Identifying biomarkers for high-risk patients who need aggressive treatment is crucial. We present mutational, transcriptomic and proteomic studies of 103 Chinese HPSCC patients, observing a higher prevalence and poorer prognosis in males comparing to females. Genes in estrogen response pathways are up-regulated and proteins phosphorylated by protein kinase C (PKC) and Cyclin-dependent kinases (CDKs) are aberrantly regulated. We identify aberrant copy number regions including SOX2 (3q26.33), FGFR (8p11.23), CCND1 (11q13.3), CDKN2A/2B (9p21.3), and MYC (8q24.21). HPV status combined with highly mutated genes as predictive markers was assessed, including SYNE1 in HPV(-), MUC4 in HPV(+) patients. We confirm the presence of four known gene expression (GE) subtypes of HNSCC in our HPSCC cohort and present the genomic alterations, patient characteristics and survival status of each subtype. A predictive model involving clinical factors and transcriptomic expression of six genes was established and cross-site validated. The findings open new opportunities for stratifying high-risk patients and molecular targets for novel therapeutic strategies. Citation Format: Yanxin Ren, Wei Xiong, Chun Feng, Dan Yu, Xiaoyan Wang, Qing Yang, Siting Yu, Hongjiang Zhang, Bangyun Huo, Honglu Jiang, Zuli Li, Junlin Wang, Yu-Xiong Su, Ping Yang, Yong Liao, Qi Zhong, Junwen Wang. Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4999.

Abstract Background: Although colorectal cancer survival rates are improving, the risk of incident type 2 diabetes mellitus (T2D) among Asian, Native Hawaiian, and Pacific Islander (ANHPI) ethnic groups is poorly understood. This study aims to identify high-risk groups and quantify the risk across different periods. Methods: Using the SEER–Medicare database, colorectal cancer survivors who were ANHPI were matched to non-Hispanic White (NHW) survivors at a ratio of 1:3. Multivariable Cox regression models computed HRs and 95% confidence intervals (CI) for incident T2D. Results: The study included 6,463 NHW and 2,901 ANHPI colorectal cancer survivors diagnosed between 2000 and 2017. Among them, 715 NHW and 484 ANHPI developed T2D during 39,097 and 10,769 person-years of follow-up, respectively. ANHPI colorectal cancer survivors had an elevated T2D risk compared with NHW across all follow-up periods (HRoverall: 1.84, 95% CI, 1.51–2.25; HR1–5 years: 1.83, 95% CI, 1.45–2.30). Southeast and East Asians demonstrated the highest T2D risks. Colon cancer was linked to early postdiagnosis T2D risk, whereas rectal cancer was associated with later risk. No significant association was observed for Native Hawaiians and Pacific Islanders. Conclusions: ANHPI colorectal cancer survivors face a greater risk of T2D, particularly among Southeast and East Asians. These findings highlight the need for evidence-based survivorship strategies to prevent T2D and reduce ethnic disparities. Impact: This is the first study to examine T2D risk among ANHPI colorectal cancer survivors, providing critical insights to inform tailored diabetes prevention and survivorship care.

Abstract Objective The objective was to determine if migraine is independently associated with a greater odds of spontaneous coronary artery dissection (SCAD) in a case–control study. Background There is growing evidence that migraine is associated with SCAD, a non‐atherosclerotic, non‐traumatic cause of myocardial infarction. However, few studies have examined the independent association between migraine and SCAD. Methods A total of 1295 SCAD cases and 1291 (1:1) age, sex, and race/ethnicity matched controls presenting to the Boston, Massachusetts area, using the International Classification of Diseases ninth revision and 10th revision codes from our Research Patient Data Registry, were identified between the years 1990 and 2022. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated. For mediation, total effects, natural direct, and indirect effects were estimated using causal inference. Receiver operating characteristic (ROC) curves and area under the curve (AUC) was used to determine predictive power. Statistical significance was defined as p < 0.05. Results Adjusting for age, sex, and race/ethnicity, the data demonstrated an almost two‐fold increased odds of SCAD in patients with migraine (aOR 1.96, 95% CI 1.48–2.6; p < 0.001). There was no effect of aura phenotype on this association. Fibromuscular dysplasia (FMD) was found only in patients with SCAD ( n = 133). After accounting for vascular risk factors, there was no longer an independent association between migraine and SCAD (aOR 0.90, 95% CI 0.63–1.29; p = 0.568). Using a model that adjusted for only demographic variables produced a ROC curve with the lowest predictive power (AUC 0.55) for SCAD, while the vascular risk factor‐adjusted model had a higher predictive power (AUC 0.83). Hypertension appeared to mediate some of the effect of migraine on SCAD (proportion of effect mediated 0.70). FMD was highly associated with an increased risk of SCAD. There remained no independent association between SCAD and migraine when FMD was included in the model. Conclusions The migraine–SCAD association can be partially attributed to the connection between migraine and vascular comorbidities including hypertension and FMD.

Objectives While extracorporeal shockwave therapy (ESWT) may be an efficacious adjunctive treatment option for musculoskeletal injuries, current research is limited by significant heterogeneity within treatment protocols. This study aims to establish international expert consensus recommendations on ESWT terminology, parameters, procedural considerations, contraindications and side effects in the application of ESWT to sports injuries. Methods A systematic literature search was performed on the use of ESWT for musculoskeletal and sports medicine injuries to identify potential panellists, followed by the development of a steering committee-led questionnaire. A three-stage, modified Delphi questionnaire was provided to a panel of 41 international clinical and research experts across 13 countries. Panellists had the opportunity to suggest edits to existing statements or recommend additional statements in Round 1. Consensus was defined as≥75% agreement. Results All 41 panellists completed Rounds 1, 2 and 3. Consensus was reached on 69/118 statements (58.5%), including recommendations on terminology and fundamental concepts, indications for use, procedural aspects for tendinopathy and bone pathologies, treatment correlations with imaging, periprocedural and postprocedural considerations, absolute and relative contraindications and potential side effects. Of the 49 statements that did not reach consensus, 17/49 (34.7%) were related to procedural aspects of bone pathology. Conclusion This international panel presents recommendations on ESWT terminology, indications and treatment considerations to guide ESWT use and decision-making by sports medicine clinicians. While our panel supported the use of ESWT in the treatment of bone pathologies, certain procedural aspects of ESWT specific to these injuries did not reach consensus and require further investigation.

140 Background: In the phase II EXTEND iADT omPC basket, MDT+iADT improved progression-free survival (PFS) vs iADT. Here we present the primary results of the EXTEND cADT omPC basket. We further report a pre-specified combined analysis with updated results from the iADT basket and examine the effects of MDT on immunity. Methods: Patients with 1 to 5 omPC metastases were randomized 1:1 to MDT+cADT vs cADT (NCT03599765). MDT consisted of definitive local therapy. cADT consisted of ADT +/- second-generation anti-androgens. The primary endpoint was per-protocol PFS, defined by biochemical criteria (Prostate Cancer Working Group 3), radiologic measures (RECIST v1.1), clinical progression, or death. 87 patients were needed to show superiority at a one-sided P of 0.10 by log-rank test. CDR3 regions in rearranged T cell receptor (TCR) β-chains from pre- and post-enrollment peripheral blood were sequenced with immunoSEQ (Adaptive Biotech). TCR repertoire modulation was defined as having TCR expansion plus contraction using a false-discovery-corrected betabinomial model. TCR sequencing from the ORIOLE trial (NCT02680587) was assessed for external validation. Results: From 2018 to 2022, 87 randomized patients were treated per protocol (MDT+cADT: 45; cADT: 42). 39% had castrate resistant omPC. MDT was definitive radiotherapy in all cases. With median follow-up of 31 mo, median PFS was 47 mo after MDT+cADT vs 22 mo after cADT (HR 0.50; 95% CI 0.23 to 1.08; one-sided P = 0.036). In the combined analysis (N=174) with median follow-up of 42 mo, MDT+ADT improved PFS (HR 0.45; 95% CI 0.30 to 0.69; P < 0.001), radiologic PFS (HR 0.63; 95% CI 0.40 to 0.97; P = 0.038), and castration-resistance free-survival (HR 0.40; 95% CI 0.19 to 0.82; P = 0.013). MDT+ADT had higher odds of TCR repertoire modulation vs ADT (55% vs 15%, P < 0.001). This finding was validated in the ORIOLE trial (MDT: 57% vs observation: 19%, P = 0.03). Among the subset of patients with extreme responses, random forest modeling of 37 clinical/immune variables identified TCR repertoire modulation as the variable with highest importance; further, MDT+ADT induced TCR repertoire modulation in all patients with favorable responses (i.e. PFS > 4 years) and none with unfavorable responses (i.e. PFS < 1 year). Among all patients randomized to MDT+ADT, TCR repertoire modulation was associated with longer PFS (HR 0.21; 95% CI 0.06 to 0.76; P = 0.02). Conclusions: MDT+cADT met the PFS primary endpoint of the phase II EXTEND trial, warranting phase III testing. From the combined analysis, MDT+ADT may also improve longer term outcomes including radiologic PFS and castration-resistance-free survival. Improved outcomes may result from MDT-induced immunomodulation, with implications for future trial design. Clinical trial information: NCT03599765 .

ABSTRACT We report a case of a primary cutaneous spindle cell sarcoma (SCS) with FN1 :: FGFR1 fusion. The tumor lacked the typical histologic and immunohistochemical features associated with other FN1 ‐rearranged neoplasms, such as phosphaturic mesenchymal tumors (PMT) and calcified chondroid mesenchymal neoplasms (CCMN). Unlike PMTs, which often feature a cartilaginous matrix and are associated with tumor‐induced osteomalacia (TIO), the present case lacked these characteristics and did not show FGF23 mRNA expression. Immunohistochemically, the tumor cells showed patchy staining for CD34 but were negative for markers such as ERG, desmin, S100, and pan‐TRK. The fusion event in this case involves the loss of the FGFR1 Ig1 (D1) domain, a mechanism proposed to drive oncogenesis by releasing FGFR1 from autoinhibition. Despite the preservation of other FGFR1 domains, no evidence of FGF23 signaling was detected, and the patient had no clinical history of TIO. This case underscores the complexity of oncogenesis in FN1 :: FGFR1 ‐rearranged neoplasms, a form of “promiscuous” gene fusion, where similar fusions lead to diverse tumor phenotypes. It emphasizes the importance of incorporating molecular testing in diagnosing spindle cell sarcomas, particularly those occurring in acral sites, to identify this underrecognized entity.