Citations

Abstract Objectives To implementation an automated multi-institutional pipeline that delivers breast-cancer risk integrated with polygenic risk scores, monogenic variants, family history, and clinical factors, emphasizing operational challenges and their solutions. Materials and Methods A five-stage process was executed at ten sites. Data streams from REDCap surveys, PRS and monogenic reports, and MeTree pedigrees were normalized and forwarded through a REDCap plug-in to the CanRisk API. Results Integrated risk was returned to >10 000 women; 3.6% were ≥25 % lifetime risk and 0.9% carried pathogenic variants. Pipeline generated score aligns well with manual generated ones. Major barriers such as heterogeneous pedigree formats, missing data, edge-case handling, and evolving model versions were identified and resolved through mapping rules, imputations, and iterative testing. Discussion Cross-platform data harmonization and stakeholder alignment were decisive for success. Borderline-risk communication and model-version drift remain open issues. Conclusion Large-scale PRS-integrated breast-cancer risk reporting is feasible but requires robust interoperability standards and iterative governance.

BACKGROUND: The use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has significantly increased in recent years. GLP-1 RAs delay gastric emptying, resulting in early satiety and weight loss. This may increase the risk of pulmonary aspiration of residual gastric contents (RGC) during anesthesia delivery. Evidence is urgently needed to guide perioperative anesthesia management for patients taking GLP-1 RAs. This study evaluated preoperative factors that may be associated with high RGC. METHODS: Adult patients who were taking GLP-1 RAs and scheduled to receive anesthesia at 3 hospitals between June 30, 2023, and August 15, 2024, were evaluated via preoperative point-of-care gastric ultrasonography (GUS). The primary outcome was high RGC, defined by the presence of solids food or >1.5 mL/kg of clear liquids on GUS, and its association with preoperative factors (eg, existing medical conditions, indication and route of taking GLP-1 RAs, length of taking GLP-1 RAs, days of withholding GLP-1 RAs before surgery, and preoperative fasting periods). Data are presented as median (interquartile range [IQR]). RESULTS: Among the 316 patients (60.9 years [52.1–68.9] of age; 167 [52.8%] females) included in the study, 113 (35.8%) had high RGC. A higher percentage (5.3%; 6/113) of patients in the high RGC group had an opioid prescription for pain management within 3 months of the GUS assessment compared to the low RGC group (1.0%; 2/203; P = .027). No statistical difference was found between the groups in other existing medical conditions, indication and route of taking GLP-1 RAs, and length of taking GLP-1 RAs. Of the 294 patients taking weekly injections, there were 187 (63.6%) with low RGC and 107 (36.4%) with high RGC. Patients with low RGC withheld their GLP-1 RAs for 8 days [5–10], while patients with high RGC withheld for 6 days [3–9] ( P = .003). Receiver operating characteristic (ROC) analysis found ≤7.5 days of withholding the medication as cutoff for increased prevalence of high RGC in patients taking GLP-1 RA injections. Patients with low RGC fasted from solid food for 20.0 hours [14.8–40.8], and patients with high RGC fasted from solid food for 15.0 hours [12.8–19.0] ( P < .001). ROC found ≤21.3 hours of fasting from solid food as the cutoff for increased prevalence of high RGC. CONCLUSIONS: GLP-1 RA usage may delay gastric emptying. In preoperatively fasting adults, ≤7.5 days of withholding injections and ≤21.3 hours of fasting from solid food are associated with high RGC.

Ischemic cardiomyopathy (ICM) is a leading cause of heart failure characterized by extensive remodeling of the cardiac extracellular matrix (ECM). While initially adaptive, ECM deposition following ischemic injury eventually turns maladaptive, promoting adverse cardiac remodeling. The strong link between the extent of fibrosis and adverse clinical outcomes has led to growing interest in ECM-targeted therapies to prevent or reverse maladaptive cardiac remodeling in ICM; yet, the precise composition of the ECM in ICM remains poorly defined. In this study, we employed sequential protein extraction enabled by the photocleavable surfactant Azo to enrich ECM proteins from left ventricular tissues of patients with end-stage ICM and nonfailing donor hearts. High-resolution mass spectrometry–based quantitative proteomics identified and quantified over 6,000 unique protein groups, including 315 ECM proteins. We discovered significant upregulation of key ECM components, particularly glycoproteins, proteoglycans, collagens, and ECM regulators. Notably, LOXL1 , FBLN1 , and VCAN were among the most differentially expressed. Functional enrichment analyses revealed enhanced TGFB signaling, integrin-mediated adhesion, and complement activation in ICM tissues, suggesting a feedback loop driving continued ECM deposition in the end-stage failing heart. Together, our findings provide a comprehensive proteomic landscape of ECM alterations in the end-stage ICM myocardium and identify promising molecular targets for therapeutic intervention.

Abstract Background: The Pancreatic Cancer Detection Consortium (PCDC) is an NCI-sponsored initiative to improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC). A key strategy in this initiative is to develop prospective, multi-center, longitudinal biospecimen collections from individuals without PDAC who are at high-risk of PDAC due to family history, germline variants, or the presence of pancreatic cystic lesions. The biospecimen collections, linked to clinically relevant data, will enable Phase 3 biomarker validation studies. Methods: The PCDC currently includes 10 funded Research Units (RUs): City of Hope/TGen, Dana Farber Cancer Institute, Johns Hopkins Medical Institute, Mayo Clinic/University of Pennsylvania, MD Anderson Cancer Center, Oregon Health and Science University, University of Nebraska, University of Pittsburgh Medical Center, University of California (UC) San Diego, UC San Franciso. Non-protected patient health information and biospecimen data is logged into a central Medidata Rave® database managed by a Management and Data Coordination Unit (MDCU) at Mayo Clinic (NCT06271291). Biospecimens collected include blood and pancreatic cyst fluid. Two options for blood collections exist: 1) 20 mL EDTA, 10 mL no additive if samples can be frozen within 4 hours of collection; 2) 10 mL EDTA, 10 mL Streck, 10 mL no additive if samples cannot be frozen within 4 (but less than 12) hours. Cyst fluid (up to 1000 uL), if available as clinical residual, will be obtained at the time of clinically indicated operative resection or endoscopic ultrasound guided aspiration procedures. All samples must be processed per standardized methods outlined in the lab manual and aliquoted into 500 uL (blood) or 100 uL (cyst fluid) units and frozen (-70oC). Long-term biospecimen storage will be set up at NCI Frederick National Laboratory (FNL). Single Institutional Review Board (sIRB) oversight is provided by Mayo Clinic. A collaborative research agreement has been executed to allow sharing of data and biospecimens between and within PCDC RU members, the MDCU, NCI and NCI FNL. Results: The enrollment of patients began February 7, 2025 with additional sites joining as necessary sIRB reliance documents and training is completed. The protocol is approved for up to 30,000 patients, age 18 years and older. 14 have been enrolled from 1 site as of July 10, 2025. Study endpoints include diagnosis of PDAC, death or complete pancreatectomy for non-PDAC reasons. Biospecimens and questionnaires will be collected annually. Summary and Future Plans: The PCDC has designed a Phase 3 biobank following EDRN study design principles. Biospecimens will be stored at NCI FNL. Access to the biobank resource will be overseen by the PCDC Steering Committee. We anticipate this being a rich Phase 3 biospecimen resource for the pancreatic cancer early detection research community. Citation Format: Janet E. Olson, Shounak Majumder, Jennifer J. Brooks, Emily J. Kirsch, Bridget H. Schmidt, Bill R. Bamlet, Erin E. Carlson, Ann L. Oberg. On the development of the Pancreatic Cancer Detection Consortium (PCDC) Prospective Cohorts biobank [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B069.

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.

ABSTRACT Glioblastoma (GBM), the most aggressive primary brain tumour in adults, presents significant challenges due to its universal recurrence and limited survival rates. A key driver of GBM progression is the subpopulation of brain tumour‐initiating cells (BTICs), which contribute to therapy resistance and interact with the tumour microenvironment, particularly the cellular components in the subventricular zone (SVZ). Extracellular vesicles (EVs) are critical mediators of intercellular communication, carrying bioactive molecules, such as proteins and RNAs, that can modulate the behaviour of recipient cells. This study investigates the role of EVs in GBM's communication with non‐cancer cells. We utilised the proximity‐labelling system TurboID to achieve global and unbiased labelling of proteins within GBM‐derived EVs. By inducing TurboID expression in primary‐cultured human BTICs from GBM patients, we achieved efficient biotinylation of EV proteins without compromising vesicle integrity, and performed proteomic analysis of biotinylated proteins, which revealed a diverse cargo within BTIC‐EVs. Our method marks the first implementation of TurboID for unbiased global labelling of EV protein cargo in primary cells. This approach facilitates the investigation of EV‐mediated communication and potential therapeutic targets, contributing to the understanding of GBM's complex interactions with the brain's microenvironment and identification of biomarkers for improved diagnosis and treatment response.

In women with dense breasts, adding molecular breast imaging to digital breast tomosynthesis (DBT) increased both overall and invasive cancer detection rates, while modestly raising the recall rate compared with DBT alone.

Abstract Introduction: The purpose of this study is to evaluate the effectiveness of opportunistic salpingectomy (OS), a procedure that aims to remove only the fallopian tubes of general population risk women, for the prevention of epithelial ovarian cancer. Currently, the method of prevention for individuals at high risk of ovarian cancer involves a bilateral salpingo-oophorectomy (BSO), a procedure that removes both the fallopian tubes and ovaries. However, this procedure is not recommended for individuals of the general population, who make up about 80% of ovarian cancers, due to negative health implications to the cardiovascular and skeletal systems because of surgically induced menopause. The effectiveness of the OS in preventing ovarian cancers and how the procedure impacts the histotype distribution of ovarian cancers remains unknown. Study Methods: This study uses a population-based approach and a case-based approach to determine the effectiveness of OS and its impact on histotype distribution, respectively. For the population-based analysis, we will search through clinical databases to acquire cases of individuals who have had an OS and a tumor. A control population who have their fallopian tubes in-tact will also be acquired. A cox-proportional hazard analysis will be performed to determine the effectiveness of the procedure. Using pathological records, the case-based ascertainment of tumors from individuals who have had an OS will be selected and reviewed for histotype confirmation. Fallopian tubes of these patients will also be reviewed for precursor lesions. This cohort will be compared to a historical histotype distribution of ovarian cancers. Results: For the population-based approach, we have to date, identified less than five serous ovarian cancers in individuals who have had an OS (n=40, 477). A comparator surgery was used as a control and showed 21 cancers. For the case-based approach, we have partnered with 23 collaborating institutions from around the world to identify tumors in individuals who have had an OS. We have identified 26 epithelial ovarian cancers, with the most lethal gynecological histotype, high grade serous carcinoma (HGSC), accounting for 23.1% of the total proportion of epithelial ovarian cancer cases (n=6/26). This is significantly less than the historical histotype distribution of HGSC, which is 69.3% (Fisher’s exact test, p&lt;0.0001). One HGSC case had a precursor lesion called a serous tubal intraepithelial carcinoma (STIC) while reviewing fallopian tubes of this individual. TP53 mutation analysis on one HGSC tumor sample showed a frameshift mutation in TP53 (c229fs) with the tumor and the corresponding STIC staining negative for p53 protein expression by immunohistochemistry. Conclusion: This evidence demonstrates the effectiveness of opportunistic salpingectomy for the prevention of ovarian cancer and shows a histotype distribution shift, with the most lethal gynecological malignancy having a significant reduction in cases following the procedure. Citation Format: Ramlogan Sowamber, Alice J. Mei, Paramdeep Kaur, Julianne McLeod, Emily McKay, Alex Lukey, Jamie Bakkum-Gamez, Natalia Buza, Paul Cohen, Kyle Devins, Rhonda Farrell, Christine Garcia, Blake Gilks, Ellen Goode, Anjelica Hodgson, Brooke Howitt, Pei Hui, Jutta Huvila, Anthony Karnezis, Kianoosh Keyhanian, Mary Kinloch, Martin Köbel, Felix KF. Kommoss, Lawrence Kushi, Janice S. Kwon, Kara Long-Roche, Anais Malpica, Jessica N. McAlpine, Dianne Miller, Esther Oliva, Andrea Palicelli, Aleksandra Paliga, Carlos Parra-Herran, Celeste Leigh Pearce, Sharnel Perera, Jurgen M. Piek, Haiyan Qiu, Joseph Rabban, Robert Rome, Miranda Steenbeek, Rebecca Stone, Aline Talhouk, Kristin M. Tischer, Britton Trabert, Penelope M. Webb, John R. Zalcberg, Gillian E. Hanley, David G. Huntsman. Evaluating the effectiveness of opportunistic salpingectomy (OS) for the prevention of epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr B045.