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.

T cell aging contributes to the lower vaccine efficacy in older adults, yet the molecular mechanism remains elusive. Here, we show the density of initially responding naïve CD4 + T cells is instructive in T follicular helper (TFH) cell fate decisions and declines with age. A lower number of initially responding cells did not affect TFH differentiation at peak responses after immunization but accounted for an increased contraction phase manifesting as a larger loss of CXCR5 expression. Mechanistically, cells activated at a lower initial density had more sustained mammalian target of rapamycin complex 1 (mTORC1) activities that impair CXCR5 maintenance. YAP-dependent regulation of SLC7A5 involved in the cell density–dependent regulation of mTORC1 activities and TFH loss. Old mice fed with a leucine-restricted diet after peak responses showed smaller TFH loss and improved humoral immune responses. Attenuating mTORC1 signaling after peak response is a strategy to boost vaccine responses in older individuals.

Objective: Over 3 million Americans have heart failure with preserved ejection fraction (HFpEF). Effective guideline directed medical treatments (GDMT) are increasingly available but patients with HFpEF are likely under-detected (particularly women) and not receiving GDMT. Limited data are available informing the extent of HFpEF under-detection in the community. Hypothesis: Among patients with undifferentiated dyspnea and a high risk for unrecognized HFpEF, fewer than 50% will receive a HFpEF diagnosis during two years of follow-up; underrecognition will be greater among women. Methods: We identified 22,134 patients aged ≥30 in the Rochester Epidemiology Project (a medical records linkage system comprising a 27-county region of southeastern Minnesota and western Wisconsin) with evidence of unexplained dyspnea (≥2 ICD codes for dyspnea separated by >1 day) without prior documented etiology including HF or lung disease, during the time period 2018-2022. We calculated the recently validated HFpEF-Age-BMI-Atrial Fibrillation (HFpEF-ABA) score to estimate the probability of underlying HFpEF. Cox proportional hazards models regressed risk for incident HFpEF diagnosis on HFpEF-ABA score (dichotomized as ≥80% vs. <80%) with multivariable adjustment for sex, race and ethnicity. HRs(95%CIs) are presented. Results: Patients were 59±16 yrs, 50.8% women, 88.6% white, 3.1% Black, 3.7% other race, 4.6% Hispanic. Atrial fibrillation prevalence was 9.4% and mean BMI=31.4±7.8. Prevalence of HFpEF-ABA≥80% was 22.4%(n=4,958): 22.7% among women and 22.1% among men. The cumulative incidence of clinically-recognized HFpEF diagnosis at two years follow-up was 9.7% among women and 12.8% among men (log-rank p<0.01). HFpEF incidence was elevated with high HFpEF-ABA scores(≥80%): HR(95%CI) among women=3.72 (3.35, 4.14), and men=3.42 (3.11, 3.76). Among those with clinically diagnosed HFpEF during follow-up, mean time from date of first dyspnea ICD code to HFpEF diagnosis was 1.26 years overall: 1.31 and 1.21 years in women and men, respectively (p=0.05). Conclusions: One in five patients with undifferentiated dyspnea have probable undiagnosed HFpEF, and of that group, only 30% receive a clinical diagnosis, requiring an average of over 1 year to be recognized. The rate of diagnosis is even lower among women than men. Further study is warranted to implement evidence-based algorithms supporting detection of undiagnosed HFpEF in the community, especially in women.

Abstract Oncogenic translocations involving the MET gene have been reported in several cancer types, but detailed clinicogenomic characterization of these cancers is not well defined. In addition, prospective clinical trials evaluating the antitumor activity of MET inhibitors in MET rearrangement–positive cancers are limited. In this study, in a pan-cancer analysis of &gt;46,000 solid tumors with comprehensive genomic profiling, we identified oncogenic MET rearrangements in ∼0.04% of cancers. Preliminary analysis from a phase II clinical trial of the type I MET tyrosine kinase inhibitor (TKI) vebreltinib in MET fusion–positive solid tumors demonstrated an objective response rate of 50% and disease control rate of 79%, with antitumor activity seen in diverse cancer types, including lung adenocarcinoma and intrahepatic cholangiocarcinoma, among others. Similar to MET exon 14–altered lung cancer, secondary mutations in the kinase domain can confer resistance to MET TKIs in MET fusion–positive cancers. Overall, these data categorize MET rearrangements as actionable targets in solid tumors. Significance: MET rearrangement–positive cancers are not well-characterized, and optimal treatment strategies are yet to be defined. Through comprehensive genomic analysis, preclinical modeling, and preliminary results of a phase II clinical trial, we demonstrate that MET fusions are a unique molecular subtype of cancers targetable with vebreltinib, a TKI in development.

Intensive care units (ICUs) serve patients with life-threatening conditions. However, the availability of ICU resources remains scarce worldwide. Therefore, it is critical to conduct ICU outcome predictions at an early stage and promote efficient use of ICU resources. However, the current ICU outcome prediction methods have limitations such as unsatisfactory accuracy and dependence on resource-demanding laboratory tests or expert domain knowledge. In this research, we design a wavelet transform based additive convolutional neural network (WT-A-CNN) that requires only patients’ vital sign series and information at ICU admission for real-time ICU outcome predictions. The model is evaluated using a large real-world ICU database and outperforms state-of-the-art baselines on both ICU mortality and length-of-stay prediction tasks. Furthermore, the additive structure of the model can be used for model interpretation and analyzing which input signal is more useful for ICU outcome prediction for different patient cohorts. Our work provides an efficient tool for ICU outcome predictions, allowing healthcare providers to act promptly on patients at risk and reduce the negative impacts on patient outcomes.

Précis: 240-degree and 360-degree goniotomy (GT) demonstrated similar efficacy in intraocular pressure (IOP) reduction, both outperforming 120-degree GT in patients with juvenile open angle glaucoma (JOAG) at postoperative 6-month follow-up. Objective: To compare the surgical efficacy and safety of 120-degree, 240-degree, and 360-degree GT for patients with JOAG. Patients and Methods: This multicenter retrospective study included 102 eyes of 102 patients with JOAG, who underwent GT with a follow-up of at least 6 months. Patients were categorized into 3 groups: (1) 120-degree GT, (2) 240-degree GT, and (3) 360-degree GT. IOP, glaucoma medications, and complications were recorded at baseline and the final visit. Complete success and qualified success were defined as a postoperative IOP ≤21 mm Hg without and with medications, respectively. Results: Mean age of the participants was 24.4 ± 7.9 years. After a mean follow-up of 8.1 ± 2.7 months, complete success rates were similar between the 240-degree GT (45.2%) and the 360-degree GT (63.2%; P = 0.135), and both were superior to 120-degree GT (18.2%; P < 0.05). Qualified success rates among patients in the 120-degree, 240-degree, and 360-degree GT groups were 93.9%, 96.8%, and 100%, respectively, and showed no statistically significant difference (P = 0.292). 360-degree GT required fewer medications than 240-degree GT and 120-degree GT (P < 0.05), with no significant difference in medications between 120-degree GT and 240-degree GT (P > 0.05). Hyphema was the most common postoperative complication, with a significantly higher incidence in the 360-degree GT (68.4%) compared with the 240-degree GT (41.9%) and 120-degree GT (33.3%; P < 0.05). Conclusions: 240-degree and 360-degree GT showed similar efficacy in IOP reduction and were superior to 120-degree GT. More extensive GT may provide better outcomes in JOAG.

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P &lt; 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

The 2024 Annual Congress of the International Liver Transplantation Society (ILTS) was from May 1–4 in Houston, Texas, USA, under the theme “Liver Disease and Transplantation: Breaking Barriers and Exploring New Frontiers.” In addition to a robust scientific program, the congress also hosted a hands-on cadaveric robotic liver surgery course, a machine perfusion workshop, and a transesophageal echocardiography course. In this report, the ILTS Vanguard and Basic Sciences Committees present a summary of the congress proceedings.