Citations

Abstract Motor speech disorders (MSDs) are early markers of neurological disease, but expert perceptual analysis is rarely available outside specialized centers. Automated speech analysis offers a scalable alternative, yet prior studies have not systematically compared modeling approaches or assessed clinically relevant metrics in independent datasets. This study compared static acoustic features, articulatory informed Phonet features, and self-supervised pretrained models for binary and multi label MSD classification. We trained and evaluated models on 583 speech samples using speaker level splits. Baseline models included logistic regression and Gated Recurrent Units (GRUs) trained on eGeMAPS and MFCCs. We extracted three types of Phonet derived features and evaluated pretrained HuBERT and SSAST models in frozen, partially fine-tuned, and fully fine-tuned configurations. Binary classification distinguished MSDs from controls, while multi label classification identified six MSD subtypes. Models were assessed using validation AUC, and cut points were tested on two independent datasets. Pretrained and Phonet based models substantially outperformed static acoustic features. In binary classification, HuBERT achieved the highest AUC (0.95), while compact Phonet derived GRUs achieved comparable performance (up to 0.94). These models generalized well to independent datasets, maintaining high sensitivity (0.94) and specificity (0.97). In multi label classification, Phonet models achieved the highest macro average AUC (0.86), but threshold-based subtype performance declined on unseen data. Automated MSD detection is feasible and clinically promising. Binary classification generalized well, whereas multi label classification showed limited threshold stability across datasets.

Abstract INTRODUCTION: Pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT) are DICER1-related tumors for which novel therapies are urgently needed. A subset of Wilms tumors are also associated with germline or somatic variants in DICER1. Current therapies include cytotoxic chemotherapy, radiation, and surgery, but there are limited options for patients with recurrent disease. Antibody-Drug Conjugates (ADC) have emerged as promising therapies for several solid tumors. Aberrantly expressed cell surface proteins, including Preferentially Expressed Antigen in Melanoma (PRAME), represent potential targets for immunotherapeutic treatments like CAR-T cell and antibody-based therapies in malignant cancers, including DICER1-associated tumors. METHODS: Individuals diagnosed with PPB, SLCT, and Wilms tumor who enrolled in the International PPB/DICER1 Registry, International OTST Registry, and/or UT Southwestern Pediatric Hematology-Oncology Biorepository were selected for analysis. We analyzed ten PPB samples (four PDX, six primary tumor), four SLCT samples (all primary tumor), and 54 Wilms tumor samples (4 PDX, 50 primary tumor). DICER1 hotspot variants were verified in all 14 PPB and SLCT samples, while none of the Wilms tumor samples we analyzed exhibited DICER1 hotspot variants. Mapped and normalized whole-transcriptome sequencing reads were used to examine expression of 73 targets of antibody- or cell-based therapies that are clinically approved or under clinical investigation on clinicaltrials.gov. Genes with a median expression exceeding 2.5 transcripts per million (TPM) were considered expressed in a given tumor type; this threshold was selected to be permissive in identifying potential targets for further evaluation. RESULTS: Of the 73 genes of interest, 21 targetable cell-surface genes met a median expression threshold of 2.5 TPM in at least one tumor type: 11 genes in PPB, 16 in SLCT, and 14 in Wilms. Seven genes (FN1, PRAME, MCAM, CD248, IL11RA, CD276 (B7-H3), and MRC2) were expressed at this level in all three tumor types. Additional genes were expressed above this level in only two of the tumor types; PDGFRA in PPB and SLCT; GPC2 and TYRO3 in SLCT and Wilms tumor; and CSPG4, ERBB2, FZD10 in PPB and Wilms tumor. Six genes were exclusively expressed in SLCT (AXL, GPNMB, PROM1, KDR, ITGA6, FGFR4), and two were unique to Wilms tumor (GPC1, ULBP3). Of these, PRAME was previously reported as frequently expressed in DICER1-associated tumors; little has been reported about the remaining potential targets. CONCLUSION: PPB, SLCT, and Wilms tumor express several potential immunotherapy targets by RNA-seq. Expression of these potential targets should be investigated by immunostaining in a wider panel of tumors. Further study on the potential for ADCs or CAR-T cell therapies to treat DICER1-related conditions is needed. Citation Format: Brenya McNally, BS, Paige H.R. Mallinger, MS, David Huntsman, MD, FRCPC, FCCMG, Yemin Wang, PhD, Joyce Zhang, PhD, Claudette R. Fraire, PhD, Peter J. Schoettler, MD, Kris Ann P. Schultz, MD, Kenneth S. Chen, MD. Identifying potential cell-surface targets for therapeutic treatment of DICER1-related cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A018.

Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

ABSTRACT We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015–2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow‐up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core‐binding factor (CBF; N = 72; 13%), primary non‐CBF ( N = 403; 74%), post‐myelodysplastic syndromes (MDS) or post‐myelodysplastic/myeloproliferative neoplasms (post‐MDS‐MDS/MPN; N = 28; 5%), post‐MPN ( N = 15; 3%), and therapy‐related (t‐AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% ( p < 0.01) and 5‐year transplant‐censored survival rates 68%, 57%, 21%, 0%, and 55% ( p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non‐CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3 ‐ITD (OR 0.4; p < 0.01) or NPM1 MUT / FLT3 WT (OR 0.1; p < 0.01) superior CR/CRi while KRAS MUT (HR 8.8; p < 0.01), TP53 MUT (HR 5.4; p < 0.01), and TET2 MUT (HR 2.3; p = 0.01) predicted inferior and NPM1 MUT / FLT3 WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively‐treated AML should start with subtype specification and recognition of the limited value of NGS in non‐primary AML. Post‐MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post‐MDS‐MDS/MPN AML. In primary non‐CBF AML, in addition to previously established risk factors, the favorable impact of FLT3 ‐ITD on achieving CR/CRi and the unfavorable impact of KRAS MUT and TET2 MUT on transplant‐censored survival were noted and require confirmation from additional studies.

Hepatic resection (HR) and liver transplantation (LT) are curative-intent treatments for hepatocellular carcinoma (HCC). Patients without cirrhosis are typically analyzed as a single group, obscuring potentially important differences between those with histologically normal liver and those with non-cirrhotic parenchymal disease. We aimed to characterize long-term outcomes following HR stratified by underlying parenchymal quality, with a contemporary LT cohort as an external benchmark. Retrospective cohort study of 662 adults undergoing curative-intent surgery for HCC at 2 tertiary centers (2010–2024). Resection patients (n=380) were stratified by non-tumor parenchymal histology into HR-Normal (n=84), HR-Diseased non-cirrhotic (n=159), and HR-Cirrhotic (n=137). A total of 282 LT recipients served as an external reference but were not entered into comparative models. Overall survival (OS) was analyzed by Kaplan–Meier and multivariable Cox regression, and recurrence by Fine–Gray competing-risks regression. Ninety-day mortality was low across resection strata (1.2%–3.2%). OS differed significantly across parenchymal groups (log-rank p =0.01), driven by superior outcomes in HR-Normal patients compared with both HR-Cirrhotic ( p =0.008) and HR-Diseased ( p =0.005). HR-Cirrhotic and HR-Diseased did not differ ( p =0.97). Five-year OS was 74.4%, 59.8% and 57.2%, respectively. On multivariable Cox regression, both cirrhosis (HR 2.03, 95% CI 1.16–3.54, p =0.01) and diseased non-cirrhotic parenchyma (HR 2.04, 95% CI 1.21–3.43, p =0.008) independently predicted death versus normal liver. Fine–Gray analysis confirmed higher recurrence risk in cirrhotic (sHR 2.09, p =0.01) and diseased non-cirrhotic (sHR 1.80, p =0.04) groups. The LT benchmark cohort achieved a 5-year OS of 82.4%. Histologically normal liver identifies a distinct HR subgroup with favorable oncologic outcomes. The conventional cirrhotic/non-cirrhotic dichotomy underestimates the prognostic impact of underlying parenchymal disease.

Myelodysplastic syndromes with isolated deletion of chromosome 5q [MDS-del(5q)] constitute a distinct biological entity traditionally associated with favorable outcomes, although up to one quarter of patients progress to acute myeloid leukemia (AML). Existing prognostic models, developed in heterogeneous MDS populations, may not adequately capture risk within this subgroup. We assembled an international cohort of 682 patients with MDS-del(5q) to evaluate the performance of the IPSS-R and IPSS-M, identify prognostic variables, and develop a disease-specific prognostic tool, the IPSS-del(5q). Most patients were classified as lower-risk by IPSS-R (94.4%) and IPSS-M (85.5%), yet both systems showed limited discriminatory ability (C-indices ≈0.5). Independent adverse prognostic factors included age ≥70 years, male sex, anemia (hemoglobin ≤10 g/dL), thrombocytopenia (platelets ≤100×10⁹/L), the presence of one additional chromosomal abnormality, ≥2 gene mutations, SF3B1 mutations, and high-risk TP53 status. Six variables were included in the IPSS-del(5q), stratifying patients into standard-risk (74.3%) and high-risk (25.7%) groups with significantly different LFS (69.2 vs. 32.0 months; p&lt;0.01). Moreover, this model reclassified 19.1% of lower-risk IPSS-R and 14.6% of lower-risk IPSS-M patients into the high-risk IPSS-del(5q) group. However, its discriminative power remained modest, with a C-index of 0.60. Overall, this study provides the most comprehensive prognostic evaluation of MDS-del(5q) to date, demonstrates the limited discriminatory capacity of existing MDS scores in this entity, and underscores the need to develop refined disease-specific prognostic approaches for this MDS subtype.