Citations

ABSTRACT Background Retrospective evaluations of multidisciplinary team (MDT) review of pancreatic cystic lesions (PCL) demonstrate improved PCL management. Endoscopic ultrasound (EUS) evaluates PCL for worrisome features; however, its influence on MDT is unclear and may be attenuated by anchoring/confirmation bias. We aimed to evaluate the impact of EUS and the overall performance of MDT evaluation of PCL. Methods Four mock MDT sessions at two institutions were presented imaging from 40 consecutive PCL cases (20 “high‐risk” with advanced neoplasia, 20 “low‐risk” with pathologic low‐grade dysplasia or ≥ 3 years of non‐progression on surveillance), with and without upfront EUS/FNA (cytology, CEA, Amylase), in a randomized, crossover design. Group 1 adjudicated without EUS, Group 2 adjudicated with EUS, and Group 3 adjudicated with EUS after initially adjudicating without it. Results The cohort included branch‐duct ( n = 20), mixed type ( n = 6), and main duct ( n = 4) IPMN, MCN ( n = 5), and non‐mucinous PCL ( n = 5). Group 2 (EUS) correctly identified mucinous PCL with 97% sensitivity and 70% specificity, significantly higher than Group 1 (No EUS) (Sensitivity 91%, Specificity 20%; p = 0.04). Group 3 (Unblinded to EUS) performed significantly worse in mucinous PCL identification compared with Group 2, indicating cognitive bias (Sensitivity 97%, Specificity 10% ( p = 0.0003)). Group 2 correctly identified high‐risk PCL that required surgical intervention with 85% sensitivity and 85% specificity, significantly higher than Group 1 (Sensitivity 60%, Specificity 75%; p = 0.0016) and Group 3 (Sensitivity 73%, Specificity 80%, p = 0.0485). Conclusion While susceptible to cognitive bias, EUS significantly improves MDT assessment of PCL. MDT establishes a high bar for iterative additions of biomarkers to PCL analysis.

Introduction Sepsis is a global health priority with nearly 50 million cases annually. Cardiovascular dysfunction is common, frequently manifesting as hypotension that persists despite fluid resuscitation. Most affected patients require the use of intravenous (IV) vasoactive agents, typically necessitating intensive care unit (ICU)-level monitoring, invasive interventions and contributing substantially to healthcare costs. Midodrine, an oral alpha-1 agonist approved for orthostatic hypotension, has increasingly been used off-label as a vasopressor-sparing (reducing IV vasopressor use) strategy in sepsis, despite limited and inconsistent evidence. This pragmatic, randomised, open-label trial evaluates the efficacy and safety of midodrine in patients with sepsis-associated hypotension. We hypothesise that, compared with standard care, midodrine administration will reduce the duration of IV vasopressor use. Methods and analysis A total of 308 adult patients with sepsis-associated hypotension will be enrolled (154 per arm). The intervention group will, in addition to standard of care, receive enteral midodrine 10 mg three times daily. Outcomes will be ascertained pragmatically via electronic health record-based data retrieval and adjudicated by research coordinators blinded to treatment assignment. The primary outcome is time alive and off IV vasopressors in the first 28 days (in hours) after randomisation. Secondary outcomes include cumulative vasopressor exposure; use and duration of central venous access; cumulative fluid balance over the first 48 hours and up to 7 days of ICU stay; ICU and hospital length of stay; and ICU-, hospital-, and organ support-free days through day 28. Safety outcomes include adverse events potentially attributable to midodrine during hospitalisation including acute kidney injury. Primary analyses will follow an intention-to-treat framework, including all randomised participants according to their assigned treatment groups. Primary and secondary outcomes will be compared using a van Elteren test stratified by randomisation factors. A predefined secondary Bayesian analysis of the primary outcome will provide complementary estimates of treatment effect. Safety outcomes will be summarised descriptively without formal between-arm hypothesis testing. Ethics and dissemination The Mayo Clinic Institutional Review Board approved this protocol and required written informed consent from all participants (IRB# 24–0 00 121). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT06319248 .

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC ( P <0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P =0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8) , APC (n=3) , FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.

Purpose: During diagnostic cerebral angiography, catheter navigation requires manual contrast “puff” injections, while subsequent 2D/3D runs often use automated power injectors. Using power injectors for navigation puffs has not been described. We present a closed-circuit dual-port injector system (Nemoto Press Duo Elite) that integrates both navigation puff delivery and diagnostic run injection into a single automated platform, eliminating all manual tableside contrast handling. A foot pedal interface enables operator-controlled puff timing, potentially reducing contrast waste and air embolism risk while improving single-operator ergonomics with future remote robotic implications.Materials and Methods: This retrospective comparative cohort study compared 19 consecutive patients undergoing diagnostic cerebral angiography with foot pedal-controlled puff injections (June–July 2023) to 19 historical controls using manual hand injections (May 2021). Both groups used 90% contrast concentration. Fluoroscopy time, radiation dose, contrast utilization, and safety outcomes were compared.Results: Groups were demographically matched (mean age 52.1±14.2 vs. 50.2±12.9 years; 73.7% female). All 38 procedures achieved diagnostic adequacy with no complications. The foot pedal group demonstrated significantly shorter procedure time per vessel (11.5±4.4 vs. 18.9±10.5 min/vessel, P=0.010) with no significant differences in fluoroscopy time (P=0.171), radiation dose (P=0.690), or contrast delivered (88.7±30.9 vs. 88.2±42.5 mL, P=0.966). A trend toward improved contrast efficiency was observed (23.4±9.4 vs. 27.4±10.4 mL/vessel, P=0.226). Despite undergoing significantly more 3D rotational runs (1.3±1.0 vs. 0.6±0.7, P=0.030), the foot pedal group maintained comparable safety metrics, strengthening the non-inferiority findings.Conclusion: A closed-circuit dual-port injector system integrating automated navigation puff delivery with diagnostic run injection demonstrates non-inferiority to manual injection for diagnostic cerebral angiography, with shorter procedure time per vessel (39% reduction, P=0.010), though interpretation is limited by differences in indication distribution. By eliminating manual tableside contrast handling, this approach enables precise digital contrast accounting and reduces air embolism risk, establishing a foundation for remote and robotic angiography applications.

Abstract Background: Early detection is the most potent strategy to improve survival in PDA, but its success hinges on an unresolved question: does radiologically invisible disease represent biologically early or indolent disease, or established malignancy beneath the threshold of detection? We leveraged prediagnostic CTs—incidental scans obtained 3-36 months prior to diagnosis without a focal mass—to define the relationship between imaging phenotype and tumor biology. Methods: From a multi-institutional pool of 5,046 biopsy-confirmed PDAs, we assembled a cohort of 346 prediagnostic CTs, which were independently evaluated by three radiologists using a standardized protocol. Based on majority vote, CTs were dichotomized into imaging-occult (IO) (normal pancreas) and imaging-apparent (IA) (abnormal pancreas with indirect signs such as focal atrophy, duct dilatation, etc.) groups. Tumor size and metastases (M) at diagnosis, and overall survival (OS) were compared using multivariable linear (size), logistic (M1), and Cox proportional hazards (OS) models, adjusting for lead time to diagnosis, age, sex, diabetes, CA 19-9, and surgical resection status, to isolate the independent biological relevance of the imaging phenotype. Results: IO phenotype was seen in 150 patients (mean age 66.7±11.2; 37.3% females) while 196 had IA phenotype (mean age 69.9±10.6; 49.5% females). Median lead time was 396 days (range: 90-1088) with the IA group being enriched in 3-12-month lead time (57.7% vs 33.3%; p&lt;0.001). Both groups had comparable diabetes rates (IA 33.2% vs IO 32.7%; p=1.0), median CA 19-9 (IA 193 vs IO 322 U/mL; p=0.41), and surgical resection (IA 38.3% vs IO 38.0%; p = 1.0). While unadjusted mean tumor size at diagnosis was larger in IA group (3.8 cm vs 3.2 cm), there was no difference after adjusting for clinical factors (-7.1% difference; 95% CI: -17.2, 4.2; p=0.21). Metastases were also comparable (M rate: IA 22.4% vs IO 27.3%; adjusted OR 0.97; 95% CI: 0.50, 1.88; p=0.93). Adjusted Cox models demonstrated equivalent OS (median: 18.7 vs 17.6 months; HR 1.06; p=0.66), which persisted even when stratified by surgical status (HR 1.07; 95% CI: 0.83, 1.38; p=0.61). Even in the critical 3-12 months lead time (n=163), OS remained equivalent (HR 0.89; p=0.62), and groups did not differ in either tumor size (-6.4%; 95% CI: -22.4, 12.9; p=0.49) or metastases (OR 0.48; 95% CI 0.14, 1.59; p=0.23). Conclusions: A normal-appearing pancreas on prediagnostic imaging is common yet signifies neither early nor indolent disease—it harbors PDA biologically equivalent to the imaging-apparent pancreatic phenotype. Because the disease at this stage lies beyond human perceptual capacity, AI augmentation represents the only potential path to realizing the survival benefit of early detection. Citation Format: Khurram Khaliq Bhinder, Sovanlal Mukherjee, Armin Zarrintan, Angela Ammirabile, Ahmed Khan Jadoon, Ziding Feng, Suresh T. Chari, Ajit H. Goenka. Dissociation between prediagnostic imaging phenotype and tumor biology defines the early detection challenge in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB205.

Abstract Background Approximately 12 000 adolescents and young adults (ages 15-39, AYAs) are diagnosed with a primary central nervous system (CNS) tumor each year. DNA methylation profiling has transformed CNS tumor classification by refining diagnostic accuracy and identifying biologically distinct subtypes, but its application has not been systematically evaluated in the AYA population. In this study, we examined the spectrum of CNS tumor types across age groups, with a focus on the AYA population. Methods We assembled a large dataset of CNS tumor samples with age annotations and methylation profiles matching with high confidence to a CNS tumor type using the NCI/Bethesda classifier. Prevalence of tumor type, methylation class and DNA copy number aberrations were compared across age strata (pediatric, AYA, and adult). Results The cohort of 21 712 CNS tumors included 5351 tumors from AYAs (25%), which showed a mixed pattern, with tumors typical of childhood (eg, medulloblastoma) as well as those common in older adults (eg, glioblastoma). Several tumor types were specifically enriched in the AYA, including IDH-mutant astrocytoma, pleomorphic xanthoastrocytoma, posterior fossa group B ependymoma, and diffuse hemispheric glioma, H3 G34-mutant, among others. Distinct methylation subclasses of multiple tumor types were observed in the AYA, and patterns of genomic aberrations showed age-specific distributions. Conclusion Large-scale methylation profiling revealed unique classification patterns of CNS tumors in AYAs, with specific tumor types, subclasses, and genomic alterations enriched in this population. These data may serve as a valuable reference resource for better understanding the spectrum of CNS tumors affecting AYA patients.

Abstract STUDY QUESTION What is the fertility preservation (FP) utilization rate among transgender and gender diverse (TGD) patients at the Transgender and Intersex Specialty Care Clinic (TISCC) within the Mayo Clinic? SUMMARY ANSWER The rate of utilization of FP services by TGD patients at Mayo Clinic’s TISCC was determined to be 6.62%. WHAT IS KNOWN ALREADY TGD patients encounter several barriers when pursuing FP, which may contribute to a lower utilization rate of these services. These barriers include financial constraints and lack of insurance coverage, as well as societal and healthcare provider attitudes; TGD individuals face discrimination or lack of understanding, making it uncomfortable or difficult to discuss FP options. Additionally, there continues to be a lack of inclusive policies and support within healthcare systems that can further impede access to FP services for TGD individuals. STUDY DESIGN, SIZE, DURATION The study was executed in two phases. In the first phase, a retrospective cohort study was completed with TGD patients who provided electronic health record (EHR) research authorization from Mayo Clinic’s TISCC in Rochester, MN between 1 January 2015 and 30 July 2021. Search terms related to FP were used to determine the FP utilization rate among this patient population. In the second phase of the study, two sets of patients, (i) patients who were included in the cohort study in Phase 1, and (ii) members of JASMYN, a community organization specializing in care and wellness coordination for Lesbian, Gay, Bisexual, and Transgender (LGBT) teens and young adults in North Florida. Individuals were invited to participate in a qualitative interview exploring their cumulative healthcare experiences accessing gender-affirming care. Interviews were conducted from January 2023 to June 2023. Interviews examined participants’ perceptions of FP options, motivations for pursuing FP, and barriers to accessing both gender and fertility care. When applicable, participants also discussed their experiences pursuing FP and reflected on their satisfaction with their fertility and family planning decisions. PARTICIPANTS/MATERIALS, SETTING, METHODS In phase 1, a total of N = 1189 patients sought care from Mayo Clinic’s TISCC in Rochester, MN. Out of these patients, N = 589 patients provided research authorization and were included in the retrospective cohort study. The study team assessed whether FP terms were mentioned in each patient’s EHR, and whether patients scheduled and attended appointments with either the Department of Reproductive Endocrinology or the Department of Urology. FP search terms included sperm cryopreservation, sperm extraction, sperm aspiration, testicular tissue cryopreservation, oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation. In phase 2, N = 36 participants were interviewed, with N = 25 participants recruited from Mayo Clinic’s TISCC in Rochester, MN, and N = 11 participants recruited from JASMYN in Jacksonville, FL. Participants recruited from the Mayo Clinic participated in a video-call-based interview and those enrolled from JASMYN were interviewed in person. MAIN RESULTS AND THE ROLE OF CHANCE The study team observed a 6.62% utilization rate of FP services among N = 589 patients (median age: 28 years; age range: 8–78 years) included in the retrospective cohort study. N = 39 patients completed FP, with N = 14 receiving these services at other institutions before seeking care with the TISCC at Mayo Clinic. N = 25 patients pursued FP services within the Mayo Clinic. Patients with testes were more likely to complete FP via sperm cryopreservation when compared to the utilization of egg cryopreservation among patients with ovaries. Participants who completed an interview in Phase 2 (median age 27 years; age range: 22–80 years) reflected on their decision on whether to preserve their fertility and what factors influenced these decisions, and how their satisfaction with this decision has changed over their lifespan. The major themes reported here include the desire for biological children, planning gender care around fertility desires, conversations about FP options, physical and psychosocial barriers to pursuing FP, reflections on personal FP decisions, and reflections on having to make decisions about FP at a young age. LIMITATIONS, REASONS FOR CAUTION All participants who completed an interview have done so voluntarily; as such, there is a possibility of selection and recall bias. WIDER IMPLICATIONS OF THE FINDINGS Findings suggest that there is a need for more structured conversations around FP when TGD patients seek medical and surgical gender-affirming care. Accessibility, including financial barriers and limited insurance coverage, continues to limit the utilization of FP services among TGD patients. Increased affordability through insurance coverage may additionally improve FP utilization. STUDY FUNDING/COMPETING INTEREST(S) This project was funded by the Mayo Clinic Department of Obstetrics and Gynecology and the Mayo Clinic Center for Clinical and Translational Science (CCaTS), grant number UL1TR002377. This project was also supported by Clinical and Translational Science Award (CTSA) Grant Number TL1TR002380 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Felicity Enders reports grants from the National Institutes of Health and the Agency for Healthcare Research and Quality paid to her institution; speakers’ fees for lectures or presentations from Mount Sinai, University of Washington, University of Minnesota, University of Rochester, Cincinnati University, the National Institutes of Health, Duke University, Wake Forest University, the Patient Centered Outcomes Research Institute, Johns Hopkins University; travel support from the Association for Clinical and Translational Science and Cold Spring Harbor Laboratory; and an unpaid leadership role on the Board of Directors of the Association for Clinical and Translational Science. All other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Introduction Preoperative testosterone exposure has been associated with various health outcomes, but its impact on postoperative complications in patients undergoing total shoulder arthroplasty (TSA) has not been fully explored. This study aims to evaluate the association between preoperative testosterone exposure and postoperative medical and surgical complications in patients undergoing TSA. Methods A retrospective cohort study was conducted using the PearlDiver database. Patients who underwent TSA and used preoperative testosterone within 3 months of the index procedure were identified and matched 1:4 to controls without testosterone use using propensity score matching. Matching was performed based on age, gender, comorbidities, Charlson comorbidity index, obesity, tobacco use, and hypogonadism to balance the groups. Postoperative complications were assessed at 90 days and five years. Statistical comparisons were made using odds ratios (ORs) with 95% confidence intervals (CIs), and a p -value of <0.05 was considered statistically significant. Results The matched cohort included 677 testosterone users and 2554 controls. There were no statistically significant differences between the testosterone and control groups in 90-day complications such as myocardial infarction (OR 2.52, P = 0.31), pneumonia (OR 0.86, P = 0.70), and deep vein thrombosis (no cases in the testosterone group). Over five years, the testosterone group had a significantly higher risk of periprosthetic joint infection (4.1% vs. 2.4%, OR 1.76, 95% CI 1.10–2.75, P = 0.015), but no differences in revision rates, dislocation, aseptic loosening, or stiffness were observed. Conclusion Preoperative testosterone exposure was associated with a higher risk of periprosthetic joint infection following TSA, but no significant differences were found in major medical complications or revision rates.

Abstract Phosphatase and Tensin Homolog (PTEN) is a critical tumor suppressor frequently mutated in cancers, notably endometrial cancer (EC), where it drives early carcinogenesis. PTEN mutations disrupt lipid phosphatase activity, causing PI3K/AKT/mTOR pathway hyperactivation. However, clinical trials targeting this pathway in advanced EC yield suboptimal outcomes, with PTEN loss showing poorly predictive value for therapeutic response, indicating other mechanisms are involved. TCGA Pan-Cancer Atlas data show a 39.1% co-mutation rate of PTEN and PIK3CA in EC, much higher than the 3.6% pan-cancer rate, challenging the idea of mutual exclusivity in driver mutations within the same pathway. PTEN missense mutations are most common in EC (41.44%), with R130 as a hotspot, especially among PIK3CA-mutant patients (45.28%), while other cancers with frequent PTEN mutations show much lower R130 rates. These findings suggest PTEN R130 missense mutants undergo positive selection and may have unique oncogenic effects in EC.To characterize these mutants, a Tet-on inducible system in PTEN-null SPAC-1-S EC cells compared wild-type PTEN (PTENWT), loss of function mutant PTENR173C, and ultrahigh frequency mutant PTENR130G. PTENWT suppressed proliferation, PTENR173C showed reduced tumor suppressive activity, while PTENR130G increased proliferation, indicating a PTENWT-independent tumor-promoting function. In MFE 296 cells with PTEN R130Q/N332fs mutations, knockdown of PTENR130Q suppressed proliferation, providing functional evidence that PTENR130G has PTENWT-independent oncogenic activity in EC. To elucidate the underlying mechanisms, we performed quantitative proteomic and BioSITe analyses in SPAC-1-S cells inducibly expressing PTENWT or PTENR130G, enabling comprehensive mapping of the unique signaling alterations specific to this ultrahigh-frequency PTENR130G mutant. Our initial analysis revealed that PTENWT induction caused broad transcriptional suppression of oncogenic and structural pathways, including MAPK/ERBB, focal adhesion, ECM-receptor interaction, and lysosomal function, consistent with restored tumor-suppressive activity. In contrast, PTENR130G induction led to a distinct transcriptional response; while partially repressing lysosomal and adhesion pathways, stress-adaptive and metabolic programs like TGF-β signaling and glutathione metabolism remained active or were reactivated. These results suggest PTENR130G not only loses PTEN’s inhibitory functions but may gain new transcriptional and metabolic activities that promote cell survival and tumor progression. Overall, our analysis indicates wildtype PTEN restores signaling restraint, while PTENR130G reprograms the transcriptome toward a pro-cancer, stress-resilient state, suggesting a gain-of-function oncogenic role. Citation Format: Xiangyi Kong, Li Wang, Md Kamrul Hasan Khan, Jidong Wang, Huaijun Zhou, Xinyan Wu. Unique oncogenic mechanisms of ultrahigh-frequency mutant PTENR130Gin endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7654.