Citations

This cohort study examines the validity of an electronic health record data model for organ transplantation.

Abstract Objectives The lack of uniform terminology and abbreviations for anti-synthetase syndrome has led to significant challenges in research and clinical practice. This study aimed to establish an international consensus on a standardized nomenclature and abbreviation among a diverse group of global myositis experts and patient representatives. Methods This qualitative project was approved by the International Myositis Assessment and Clinical Studies Group (IMACS). Based on the outcomes of a literature review and preliminary survey, list of terms for nomenclature and abbreviations was finalized. Subsequently, two rounds of the Delphi survey were conducted among myositis experts and patient participants to ascertain current practices and preferences. Using Nominal Group Technique (NGT), the project steering committee developed a consensus nomenclature and abbreviation. Results A total of 241 and 132 myositis experts from six continents, 35 countries and 9 specialities participated in round 1 and round 2 of the Delphi survey, respectively. The results indicated a preference for the terms anti-synthetase syndrome, antisynthetase syndrome and anti-tRNA synthetase syndrome. The abbreviations ASS, ASyS and ASSD were most used, though ASS received notable disapproval. The steering committee, including twenty-five myositis experts and three patient representatives from diverse backgrounds and geographical locations, reached a consensus on ‘anti-synthetase syndrome’ as the preferred nomenclature and ASyS as the preferred abbreviation, with 100% and 93.1% votes, respectively. Conclusion The terms anti-synthetase syndrome and ASyS should be adopted as the standard nomenclature and abbreviation in both research and clinical practice. This standardization is expected to increase consistency within the literature.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. mainly because of late-stage diagnosis. Heritable genetic information can improve risk stratification for individuals with moderate to high-risk of PDAC for targeted screening and early detection. We aimed to develop an enhanced polygenic risk score (PRS) for PDAC using a Bayesian approach, LDpred2, that reweights risk estimates attributed to millions of polymorphisms (SNPs) estimated from genome-wide association studies (GWASs). We then compared the performance of LDpred2 with the commonly used genetic risk score (GRS) approach that is based only on genome-wide significant SNPs. Methods: GWAS summary statistics were obtained from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case Control Consortium for 9040 cases and 12496 controls and were used to compute weights for a GRS (17 SNPs) using a p-value threshold of 5e-8 and weights for an enhanced PRS (1.3 million SNPs) using LDpred2. These weights were then used to compute risk scores in an independent validation sample of 2616 cases and 45407 controls from the Mayo Clinic. We used logistic regression to test for associations of the GRS and PRS with PDAC risk, adjusting for age, sex, and the first 10 principal components of ancestry. Results: The validation sample was of mostly European ancestries (>95%). Cases were slightly older than controls (median age: 66 yrs. vs. 63 yrs.) and had a higher frequency of men than controls (57% vs. 42%). Comparisons between the GRS and the PRS are shown in Table 1. DeLong’s test comparing the AUCs between the two genetic scores showed the PRS significantly outperformed the GRS (AUC = 0.68 vs. 0.67; p = 7.6e-7). Conclusions: The LDpred2 PRS model that used a larger set of SNPs significantly improved prediction of PDAC. Comparing the top percentile of the PRS versus the rest showed that the PRS is a clinically significant risk score (OR > 3) for PDAC and could inform clinical decision making and genetic counseling of individuals identified as having a high risk of PDAC. Citation Format: Samuel O. Antwi, Brandon J. Coombes, Nicholas B. Larson, Erin E. Carlson, Kari G. Rabe, Hunter J. Atkinson, Shounak Majumder, Jun Zhong, David McKean, Pancreatic Cancer Cohort & Case Control Consortia (PanScan and PanC4), Brian M. Wolpin, Rachael Z. Stolzenberg-Solomon, Alison P. Klein, Laufey T. Amundadottir, Ann L. Oberg. Enhanced polygenic risk score for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB331.

ImportanceUnderstanding the global barriers to otolaryngology–head and neck surgery (OHNS) care is crucial in addressing disparities in access to care, particularly in low-income and middle-income countries (LMICs).ObjectiveTo characterize barriers to comprehensive otolaryngology care across World Bank income groups.Design, Setting, and ParticipantsUsing an online cross-sectional survey that was administered by the Global OHNS Initiative via international and national professional societies, personal contacts, and social media, this study captured the perceptions of otolaryngologists regarding barriers to OHNS care at the levels of the country, health sector, clinician, and patient. Participants included otolaryngologists from the 194 World Health Organization member states and Taiwan. Eligibility criteria included a medical degree and specialized training in managing conditions of the ear, nose, and throat. The nonresponse rate was not recorded. The data collection period spanned from October 2022 to June 2023.ExposuresExposures included World Bank income group classification.Main Outcomes and MeasuresThe primary outcomes were Likert scale responses regarding frequency of barriers to OHNS care. The a priori hypothesis was that LMICs would report more frequent barriers to OHNS care.ResultsThe study involved 146 otolaryngologists (47 female individuals [32%]), with 69 (47%) from high-income countries and 77 (53%) from LMICs. Male individuals represented 45 high-income country respondents (65%) and 54 LMIC respondents (70%). Barriers were reported across income groups at all levels of the health system, with a higher frequency in LMICs. Several barriers were reported to be more substantial in LMICs, such as the national volume and distribution of otolaryngologists, financial compensation for clinicians, and patient stigma, and others were common across income settings, such as the availability of operating rooms and inflexible working hours. Common concerns included national and health sector barriers: OHNS workforce, referral networks, government support; clinician barriers: excessive clinician workloads, understaffing, poor administration support; patient barriers: distance to health care facilities, financial burdens such as medical costs and foregone wages, stigma, and health literacy.Conclusions and RelevanceThe results of this cross-sectional study suggest that there are barriers to otolaryngology care globally that affected all levels of the health care system. This work may inform prioritization of otolaryngology within research and policy, and it emphasizes the need for effective strategies to expand access to otolaryngology care, particularly in lower-income settings.

Abstract The International League Against Epilepsy (ILAE) has updated the operational classification of epileptic seizures, building upon the framework established in 2017. This revision, informed by the implementation experience, involved a working group appointed by the ILAE Executive Committee. Comprising 37 members from all ILAE regions, the group utilized a modified Delphi process, requiring a consensus threshold of more than two thirds for any proposal. Following public comments, the Executive Committee appointed seven additional experts to the revision task force to address and incorporate the issues raised, as appropriate. The updated classification maintains four main seizure classes: Focal, Generalized, Unknown (whether focal or generalized), and Unclassified. Taxonomic rules distinguish classifiers, which are considered to reflect biological classes and directly impact clinical management, from descriptors, which indicate other important seizure characteristics. Focal seizures and those of unknown origin are further classified by the patient's state of consciousness (impaired or preserved) during the seizure, defined operationally through clinical assessment of awareness and responsiveness. If the state of consciousness is undetermined, the seizure is classified under the parent term, that is, the main seizure class (focal seizure or seizure of unknown origin). Generalized seizures are grouped into absence seizures, generalized tonic–clonic seizures, and other generalized seizures, now including recognition of negative myoclonus as a seizure type. Seizures are described in the basic version as with or without observable manifestations, whereas an expanded version utilizes the chronological sequence of seizure semiology. This updated classification comprises four main classes and 21 seizure types. Special emphasis was placed on ensuring translatability into languages beyond English. Its aim is to establish a common language for all health care professionals involved in epilepsy care, from resource‐limited areas to highly specialized centers, and to provide accessible terms for patients and caregivers.

Abstract Background: Epidemiology studies have linked frequent consumption of well-done cooked red meat with aggressive prostate cancer (CaP) risk, whereas rare intake or consuming medium-cooked meat is not. Providing public information about the impact of well-done cooking and its potential role in CaP risk may foster the adoption of evidence-based lifestyle modification of meat consumption to lower CaP risk. This pilot study aimed to provide preliminary data on the occurrence of CaP and the pattern of consumption of cooked red beef among ethnically diverse males in the US. Methods: The proposed project is an exploratory study focused on the assessment of the consumption of various beef dishes among ethnically diverse males in the United States. The study included 408 ethnically diverse males from Florida, Georgia, and Texas. Participants were recruited primarily from partnering restaurants, pharmacies, barbershops and collaborating community businesses using QR codes on the study flyer. Participants completed the self-administered survey that captured demographics, as well as information on beef consumption patterns, including cooking methods, frequency and degree of cooking, and the occurrence of CaP. The data were analyzed using descriptive statistics (frequency and percentages) to summarize demographics and variables on beef dishes. Chi-square was employed to determine the relationship between beef consumption patterns, demographic variables, and CaP occurrence. Results: The study showed that about half (49.8%) of the participants were between ages 44-63 years and 34.2% were 30-43 years old. The participants were quite diverse, as 51.7%, 16.3%, 13.1%, 11.%, and 2.7% were African American, African immigrants, White, Caribbean immigrants, and Hispanics, respectively. Rural dwellers comprised 34.2%, 26.8% were suburban, and 35.7% lived in urban areas. Educational status showed that 22.7%, 27.8%, and 22.7% were completed high school, college graduates, and associate degrees. The beef consumption pattern shows that 23.6%, 33.3%, 40.1%, and 30.3% regularly had boiled, fried, grilled, and barbequed beef, respectively, but 63, 2% reported never eating boiled beef. Doneness preferences differed among participants; 26%, 43.9%, 49.3, and 45.1% preferred well-done, while 1.7%, 1.5%, 2..9%, and 2.7% preferred rare, and 9%, 14.5%, 17.4%, and 15.7% preferred medium boiled, fried, grilled, and barbeques beef, respectively. Only 4.4% of the participants reported being diagnosed with CaP in the past. The pattern of beef consumption, such as the degree of doneness, was found for boiled (p=0.045), fried (p<0.001), grilled (p<0.001), and barbequed (p<0.001) beef, as well as frequency of consumption of (p<0.001), fried (p<0.001), grilled (p=0.001), and barbequed (p<0.001) to be associated with CaP. Conclusion: Beef consumption pattern was found to be associated with the risk of CaP among participants. Citation Format: Opeyemi Oreoluwa Bolajoko, Daniel W. Lee, Catherine Adebukola Oladoyinbo, Ernie Kaninjing, Samuel O. Antwi, Dee M. Glaser-Boivin, Robert J. Turesky, Folakemi T. Odedina. Pattern of beef consumption and prostate cancer risk among males in the United States [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 7112.

Abstract Breast cancer (BC) is the most common cancer diagnosed in American women. The majority of breast cancers express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2). However, 15-20% lack expression of all three and are called triple-negative breast cancer (TNBC). TNBC accounts for a disproportionately large amount of morbidity and mortality due to its aggressive nature and the paucity of effective adjuvant maintenance therapy, driving an urgent need for novel therapeutics. Z-endoxifen (ENDX) is a potent tamoxifen metabolite that dually targets ERα and protein kinase C beta I (PKCβI). We recently described next-generation molecules, the first-in-class endoxifen-PROTAC (ENDX-PROTAC) compounds which incorporate ENDX as the warhead and cereblon (CRBN) as the E3 ubiquitin ligase recruitment moiety (Jayaraman 2024, SABCS). We used the PRISM screen of over 900 cancer cell lines to determine that ENDX-PROTACs have broad antitumor activity in both TNBC and ER+ breast cancer in addition to, leukemia, pancreatic, lymphoma, lung, melanoma, and ovarian cancer cells, among others. ENDX-PROTACs primarily target a key translation termination factor, G to S phase transition 1 (GSPT1). Here, we demonstrate for the first time that these compounds also cause marked DNA damage. The lead compounds of this series, EPrC-007 and EPrC-009 demonstrated potent anti-proliferative effects in MDA-MB-231, BT549, and MDA-MB-436 TNBC cell lines. EPrC-007 induced substantial DNA double strand breaks in MDA-MB-231 cells as assessed by γ-H2AX Western blotting. Interrogation of DNA repair pathways revealed activation of ATM/CHK2 and downregulation of ATR/CHK1, suggesting inhibition of DNA repair as a potential mechanism. Additionally, EPrC-007 also induced γ-H2AX foci in MDA-MB-231 and BT549 cells, but not in the MCF10A normal breast tissue cell line, suggesting selective anti-tumor activity. Since we suspect that EPrC-007 blocks DNA repair machinery, we next sought to determine if these molecules would synergize with DNA damaging agents or other DNA repair inhibitors. Promisingly, EPrC-007 demonstrated remarkable synergy with olaparib (poly-(ADP-ribose) polymerase (PARP) inhibitor), hydroxyurea (ribonucleotide reductase inhibitor), and cisplatin (direct DNA damaging agent), but not camptothecin (topoisomerase I inhibitor). Importantly, only olaparib co-treatment demonstrated synergy in the PARP- and PROTAC-resistant HCC1143 TNBC cell line. Furthermore, the combination of EPrC-007 with olaparib induced markedly more γ-H2AX foci than either agent alone, confirming synergy at the DNA damage level. Taken together, our studies demonstrate the remarkable potential of ENDX-PROTACs in the single-agent setting as well as in combination with PARP inhibitors. Citation Format: Aamod S. Dekhne, Swaathi Jayaraman, Lucy Rai Thulung, Becky Bruinsma, Baustin M. Welch, Samuel Wyatt, Esther P. Rodman, Sayantani Bhattacharya, Thomas R. Caulfield, John R. Hawse, Matthew J. Schellenberg, Matthew P. Goetz. Novel endoxifen-based proteolysis targeting chimera (PROTAC) small molecules synergize with olaparib and exhibit potent antitumor activity in triple negative breast cancer through induction of DNA damage [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 1666.

Abstract Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a fast-rising global public health problem. About 10% of patients with MASLD will develop hepatocellular carcinoma (HCC), but molecular markers for predicting future risk of HCC development in patients with MASLD are lacking. We investigated whether protein biomarkers in pre-malignant plasma samples can predict susceptibility to HCC in the setting of MASLD. Methods: A nested case-control study was performed among patients with MASLD who later developed HCC (cases) and MASLD patients who never progressed to HCC (controls), matched on age at MASLD diagnosis (± 1-year), sex, the year of blood sample collection, and length of follow-up (± 1-year). MASLD at baseline was determined by the presence of hepatic steatosis (assessed by imaging or biopsy) plus at least one cardiometabolic condition (obesity, diabetes mellitus, hypertension, or dyslipidemia). Archival baseline plasma samples stored at -80oC were used to perform the SomaScan 7k v4.0 assay. We also performed genotyping of the well-established HCC susceptibility variant, PNPLA3-rs738409 (I148M), among the cases and controls. The study sample was split into discovery (70%) and validation (30%) sets, and we selected promising protein biomarkers in the discovery set using differential expression analysis with volcano plots and Bonferroni-corrected p-values. A final set of significant proteins was used for prediction modeling in the validation sample, calculating area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and accuracy. Results: The study sample included 54 MASLD to HCC cases and 54 MASLD controls, split into discovery and validation sets. We identified five significantly differentially expressed proteins in the discovery set, four overexpressed (TSP2, GPR56, MIC-1, TIMP-1) and one under-expressed (IGFALS) in the cases versus controls. Fitting the five proteins in the validation sample yielded an AUC=0.88, sensitivity=0.87, specificity=0.75, and accuracy=0.81. Adding PNPLA3-rs738409 to the model improved the model’s specificity and accuracy (AUC=0.88, sensitivity=0.87; specificity=0.81, accuracy=0.84). Conclusions: Our findings show that a five-protein biomarker panel can robustly predict future HCC development in patients with MASLD. Adding a well-established HCC genetic risk variant, PNPLA3-rs738409, slightly improved the model’s performance. These initial findings provide evidence of HCC prediction with baseline plasma biomarkers and genetic risk variants, toward improving risk stratification and enhancing early detection of HCC in the setting of metabolic perturbations. Citation Format: Ampem Darko Jnr Siaw, Sebastian M. Armasu, Jacob A. Frank, Irene K. Yan, Kirk J. Wangensteen, Tushar Patel, Samuel O. Antwi. Protein biomarkers of HCC development in patients with metabolic liver disease [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 2350.

Abstract Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects about 32% of adults worldwide and is projected to increase in many parts of the world. Liver cancer is a recognized complication of end-stage MASLD. An estimated 20% of patients with MASLD will progress to cirrhosis, a premalignant state in liver cancer evolution. Because MASLD is usually asymptomatic, its progression to cirrhosis can be difficult to detect early for timely intervention. There are currently no known biological markers for predicting cirrhosis risk in patients with MASLD, making it challenging to identify patients at risk of disease progression. The aim of this study was to identify plasma protein biomarkers that can predict future cirrhosis development in patients with MASLD. Methods: We performed a nested case-control study among patients with MASLD at baseline who later progressed to cirrhosis and control patients with MASLD at baseline who never progressed to cirrhosis, matched on age at MASLD diagnosis (± 1-year), sex, race, year of blood sample collection, and length of follow-up (± 1-year). An aptamer-based array (SOMAscan™) platform was used to measure over 7000 proteins in baseline plasma samples obtained from the participants. The study sample was split 70/30 for training and validation analyses. We identified plasma protein biomarkers significantly differentially expressed in the training sample, adjusting for multiple testing with Bonferroni-corrected p-values. The significant set of proteins from the training set was used for prediction modeling in the validation sample, computing prediction metrics (area under the curve [AUC], sensitivity, specificity, and accuracy). Results: A total of 64 MASLD to cirrhosis cases matched to 64 MASLD controls were included in the analysis. Six protein biomarkers (PTPRU, ATL2, MFAP4, C7, CSTN2, and COLEC11) were overexpressed in cases, compared to controls, in the training data. Prediction modeling of the six-protein biomarker panel in the validation sample yielded an AUC = 0.85, sensitivity = 0.72, specificity = 0.78, and accuracy = 0.75. Conclusions: We have identified a panel of six plasma protein biomarkers that predict risk of cirrhosis development in patients with MASLD. These proteins could serve as candidates for future mechanistic studies on MASLD progression to advanced liver disease. If validated in larger studies and with assays suitable for clinical laboratory testing (e.g., ELISA), these protein biomarkers could be useful clinically for cirrhosis risk prediction in MASLD patients, and hence those at risk of liver cancer, enabling timely surveillance or interventions to prevent disease progression. Citation Format: Pasang Sherpa, Sebastian M. Armasu, Jacob A. Frank, Irene K. Yan, Kirk J. Wangensteen, Tushar Patel, Samuel O. Antwi. Predicting cirrhosis risk in patients with metabolic dysfunction-associated steatotic liver disease [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 2335.