Citations

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P< .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P< .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

BACKGROUND AND OBJECTIVES: Perioperative protocols facilitate earlier discharge without compromising safety in nonfunctioning pituitary adenomas, but no large multicenter studies in the United States have investigated protocols regarding Cushing disease (CD). We sought to characterize perioperative protocols and how their implementation influences clinical outcomes in patients with CD. METHODS: A retrospective analysis was conducted using data from the Registry of Adenomas of the Pituitary and Related Disorders consortium comprising 13 US academic pituitary centers. Institutions were surveyed regarding perioperative procedures for patients undergoing transsphenoidal tumor resection for CD. The impacts of institutional procedures and approaches to implementation on length of stay (LOS) and unplanned 90-day readmission were evaluated. RESULTS: Thirteen institutions contributed survey responses and clinical data for a total of 832 patients meeting inclusion criteria. Ten (76.9%) institutions reported having a postoperative protocol, 9 (69.2%) used a formal document to outline their protocol, and 3 (23.1%) had protocols implemented into hospital policy. Mean LOS was significantly reduced in centers with an established protocol (3.14 vs 3.42 days, P = .032), and more so with a formal document (3.10 vs 3.48 days, P = .001) or hospital policy (2.72 vs 3.36 days, P < .001). Patients treated after protocol implementation experienced shorter LOS ( P < .001). Other factors associated with reduced LOS were presence of a separate CD pathway, intraoperative checklist specific to pituitary surgery, non-narcotic pain regimen, Foley removal order, dedicated outpatient advanced practice provider follow-up, and target discharge date ≤2 days. Intraoperative checklist ( P = .045), non-narcotic pain regimen ( P = .048), nasal packing ( P = .005), and 1-day target discharge date ( P = .032) were important factors against readmission. Compared with microscopic surgery, endoscopic surgery was associated with shorter LOS but increased readmission odds. CONCLUSION: This is the first multicenter study to illustrate that implementation of perioperative protocols is associated with a reduction in LOS and readmission risk in patients with CD.

Importance Brain imaging biomarkers may (1) identify underlying mechanisms of intervention effects and (2) define brain characteristics of those most likely to benefit cognitively from the intervention. Objective To test whether (1) a lifestyle intervention is related to brain changes, (2) brain changes are correlated with intervention-specific cognition changes, and (3) brain imaging biomarkers provide information about who is likely to benefit from a lifestyle intervention. Design, Setting, and Participants In this randomized clinical trial, the POINTER Imaging study was an ancillary study of the 2-year, single-blind multicenter US POINTER clinical trial in which neuroimaging data were collected on eligible enrolled participants. The study was conducted from May 2019 to March 2023 (final follow-up, May 14, 2025). Participants were enrolled into the POINTER Imaging study following a standard procedure at 5 clinical sites in the US. Participant eligibility criteria included an age of 60 to 79 years, sedentary lifestyle, and suboptimal diet, plus at least 2 additional risk criteria for cognitive decline and no contraindications for neuroimaging. Interventions Participants were randomly assigned to receive the structured or self-guided intervention. Both interventions emphasized increased physical and cognitive activity, healthy nutrition, social engagement, and cardiovascular health monitoring, but they differed in intensity and accountability. Main Outcomes and Measures There were 4 primary imaging outcomes: global β-amyloid (Aβ) burden, tau burden in the entorhinal cortex (ERC), hippocampal (HC) volume, and white matter hyperintensity volume. The primary cognitive measure was a global cognitive composite. Results Among 1943 parent trial participants who were assessed for eligibility, 983 underwent at least 1 magnetic resonance imaging or positron emission tomography scanning session. The mean (SD) age was 68.4 (5.2) years; 605 participants (61.5%) were female and 378 male (38.5%). Five hundred sixteen participants received the structured intervention and 467 the self-guided intervention. There were no intervention group differences in longitudinal cognitive or imaging outcomes. Intervention group differences were not associated with or moderated by Aβ status or accumulation. There was a negative association between change in ERC tau and change in global cognition in the self-guided group that was attenuated in the structured group (difference in association: 0.289; 95% CI, 0.029 to 0.550; interaction P = .03). Lower baseline HC volume was associated with greater cognitive benefit for participants in the structured group vs the self-guided group (lower HC: 0.077 SD; 95% CI, 0.022 to 0.132; higher HC: 0.002 SD; 95% CI, −0.037 to 0.041; interaction P = .03). Conclusion and Relevance This study found that a high-intensity multidomain lifestyle intervention did not affect brain biomarker trajectories and was not associated with Aβ pathology, but older adults with specific at-risk brain characteristics, including lower baseline HC volume, showed a greater cognitive benefit of the structured intervention. Trial Registration ClinicalTrials.gov Identifier: NCT03688126

Introduction Video visits in primary care have decreased significantly since their surge early in the COVID-19 pandemic. Methods Clinicians including physicians, nurse practitioners, and physician assistants in the Mayo Clinic Department of Family Medicine were invited to dedicate one to two half-days per month exclusively to video visits. Schedules for these half-day sessions remained restricted to video appointments until the day prior. If at least 80% of slots were not filled by then, remaining openings were converted to in-person visits. If the half-day sessions were at least 80% full with video visits, clinicians had the option of performing these sessions remotely. Results Of 155 eligible clinicians, 34 (22%) participated voluntarily in this scheduling intervention. For the participating clinicians, the average video visit rate increased from 6.3% per month preintervention to 11.5% postintervention ( p < 0.001). On a departmental level, the trend line for the percent of outpatient visits via video visit was decreasing by −0.1% per month preintervention. The postintervention slope of the trend line was 0.3% per month ( p < 0.001). The majority (65%) of the time the half-day video visit schedules filled at least 80% and did not require conversion to allow in-person visits allowing clinicians to work remotely if they chose. Conclusion Allowing family medicine clinicians to perform 1–2 half-day schedules dedicated to only video visits increases the percentage of video visit performed per month both for individual clinicians and on a departmental level.

Objective: To compare 1-year changes in estimated 10-year and lifetime atherosclerotic cardiovascular disease (ASCVD) risk following metabolic and bariatric surgery (MBS) versus glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy among adults with obesity. Summary Background Data: Obesity is a major driver of ASCVD through adverse metabolic and inflammatory pathways. Metabolic and bariatric surgery and GLP-1 receptor agonists represent the most effective contemporary treatments for obesity and are increasingly used to mitigate cardiovascular risk. However, their comparative effects on integrated short-term and lifetime ASCVD risk in real-world clinical practice remain incompletely characterized. Methods: We conducted a retrospective cohort study of adults with obesity (body mass index ≥30 kg/m²) who underwent MBS or initiated GLP-1RA therapy between 2020 and 2023 within a large tertiary health care system in the United States. Participants were identified from electronic health records and followed for 12 months. Primary outcomes were 1-year changes in estimated 10-year and lifetime ASCVD risk. Secondary outcomes included percent total body weight loss, blood pressure, and lipid parameters. Multivariable linear regression models were used to adjust for baseline body mass index and baseline ASCVD risk. Results: The final cohort included 812 patients, of whom 579 underwent MBS and 233 initiated GLP-1RA therapy. At baseline, patients receiving GLP-1RAs were older and had higher estimated ASCVD risk. At 1 year, reductions in 10-year ASCVD risk were similar between groups (−0.8% vs. −1.1%; P =.36). In contrast, lifetime ASCVD risk decreased significantly more following MBS than GLP-1RA therapy (−8.6% vs. −1.7%; P <.001). MBS was associated with greater percent total body weight loss (−27.8% vs. −11.1%; P <.001) and more favorable lipid changes, including larger reductions in low-density lipoprotein cholesterol and greater increases in high-density lipoprotein cholesterol. After adjustment, MBS remained independently associated with a greater reduction in lifetime ASCVD risk compared with GLP-1RA therapy (β −6.92; 95% CI −9.22 to −4.62). Conclusions: In this real-world cohort, both MBS and GLP-1RA therapy were associated with improvements in estimated cardiovascular risk, but MBS conferred substantially greater reductions in lifetime ASCVD risk, accompanied by superior weight loss and lipid improvements. These findings highlight the complementary roles of surgical and pharmacologic therapies in obesity management and may inform strategies to optimize long-term cardiovascular risk reduction.

Abstract INTRODUCTION Repetitive head impacts (RHI) from contact sports may cause a unique pattern of white matter hyperintensities (WMH) on T2‐weighted fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), termed RHI‐associated WMH (RHI‐WMH). These lesions are punctate, circular, and located at the gray–white matter boundary, an area vulnerable to trauma‐related damage. METHODS We investigated the association of RHI with these lesions in two aging cohorts: (1) former American football players versus asymptomatic unexposed men and (2) individuals with RHI from various contact sports versus non‐RHI participants. RHI‐WMH were assessed using visual ratings and a novel automated quantification pipeline. RESULTS Individuals with RHI had greater RHI‐WMH by both detection methods in both cohorts. RHI‐WMH were associated with plasma neurofilament light and p‐tau231, and flortaucipir positron emission tomography (PET) uptake. DISCUSSION RHI‐WMH may represent a new supportive biomarker for the detection of RHI‐related neuropathologies later in life.

Abstract Oncology Advanced Practice Providers (APPs), including Advanced Practice Registered Nurses, Physician Assistants, and Clinical Pharmacists (CPs), play a vital role in delivering high-quality, patient-centered cancer care across the United States. Despite their widespread presence in oncology practices, APPs remain underutilized in cancer clinical research, representing a missed opportunity to expand trial access and improve patient outcomes. Clinical trials are essential to advancing oncology care, yet participation remains critically low among adult patients. Given Oncology APPs’ and CPs’ central role in cancer care delivery, their meaningful engagement in oncology clinical trial research is imperative as the standard of oncology care. This position article, with contributions from 5 professional societies, presents solutions and resources to barriers limiting APPs’ and CPs’ involvement in cancer clinical research, including gaps in education, role expectations, limited protected time, restrictive policies, insufficient financial support, and underrecognition of contributions. Integrating APPs and CPs more fully into the clinical research enterprise is essential to improving trial access, patient outcomes, closing equity gaps, and accelerating innovation in oncology care.

Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger’s MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] &lt; 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p&lt;5×10-8; MAF&gt;0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p&lt;2.4×10-6) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2), BRCA2 (OR=2.0, 95% CI=1.7-2.3), CHEK2 (OR=1.6, 95% CI=1.5-1.8), ATM (OR=1.6, 95% CI=1.4-1.9), FAM111A (OR=1.4, 95% CI=1.3-1.5), BIK (OR=1.4, 95% CI=1.2-1.6), SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium [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 LB390.

Abstract Introduction: Epoxy fatty acid (EpFA) mechanisms of hormone therapy resistance (HTR) in ER+HER2- breast cancer (BC) are poorly understood. EETs are EpFAs that contribute to BC progression and HTR by promoting oxidative phosphorylation (OXPHOS). However, it remains unclear how EETs contribute to HTR. In this study, two fulvestrant resistant (FR) subclones of the letrozole resistant (LR) MCF-7AC1 line were isolated (termed LR/FR) and were incidentally resistant to the CDKi palbociclib (PR) (termed MCF-7AC1 LR/FR/PR or multiply resistant - MCF-7AC1 MR). These HTR cell lines exhibited CYP3A4 upregulation (2.3- to 4.3-fold) and increased cellular (±)14,15-EET levels, which were suppressed by biguanide treatment (P&lt;0.05). Structure activity studies led to the design of hexyl cuban-1-yl biguanide (HCB) and fluorinated HCB derivatives C5F2-HCB and C6F3-HCB, which inhibited CYP3A4-mediated EET biosynthesis and growth of the HTR lines. HCB fluorination improved pharmacokinetics (PK) and toxicity. Methods: HCB and fluorinated HCBs were tested for impact on EET biosynthesis, OXPHOS, PK, and growth inhibition and reversal of hypoxia in the MCF-7AC1 MR tumor model. Results: Fulvestrant selection for MCF-7AC1 MR cell lines resulted in undetectable cyclin D1 and estrogen receptor (ERα) expression, while cyclin E1, CDK4, CDK6, CYP3A4, and c-MYC were upregulated (P&lt;0.001). MCF-7 MR cells demonstrated 1.8, 1.4, and 1.2- fold higher levels of (±)8,9, (±)11,12, and (±)14,15-EET compared to parental MCF-7 cells (P&lt;0.05). The most potent fluorinated HCB, C6F3-HCB, suppressed cellular levels of (±)8,9-EET, (±)11,12-EET, and (±)14,15-EET by 53-60% (P&lt;0.029). The MCF-7AC1 MR cells were more potently inhibited by HCBs and fluorinated derivatives compared to the MCF-7 cell line. Comparing an MCF-7 MR line vs. MCF-7, HCB exhibited IC50 values of 4.1 vs. 7.0 uM, C5F2-HCB 10 vs. 25 uM, and C6F3-HCB 5.4 vs. 12 uM (P values all &lt;0.05). C5F2-HCB exhibited the best PK and treatment of the MCF-7AC1 MR xenograft model showed reversal of hypoxia (P&lt;0.05) and transient inhibition by C5F2-HCB (P=0.025 at 20 days). P/F also transiently inhibited this model (P=0.006 at 20 days). C5F2-HCB and P/F showed synergy in vitro (CI=0.46) leading to testing of C5F2-HCB/P/F in vivo enabled by acceptable toxicity of the triplet in mice. This combination showed synergy in vivo vs. standard of care palbociclib/fulvestrant by nonparametric statistical tests (Mann Whitney; P=0.0389; Kolmogorov-Smirnov; P=0.0473), providing a pathway for possible clinical development of the combination. Conclusions: MR BC cell lines exhibit upregulation of CYP3A4 and biosynthesis of EETs, indicating a role for EETs in HTR. The C5F2-HCB/P/F exhibits activity against the highly resistant MCF-7 MR xenograft with acceptable toxicity indicating an avenue for clinical development. Citation Format: Zhijun Guo, Jianxun Lei, Christian T. Wells, Allison M. Makovec, Andrew C. Yates, Swaathi Jayaraman, John R. Hawse, Joshua A. McCarra, Qing Cao, Michael J. Pryzbilla, Brenda L. Koniar, Beverly J. Norris, Craig M. Florey, Robert J. Schumacher, Michael A. Farrar, Kaylee L. Schwertfeger, Elizabeth A. Ambrose, Henry Wong, Gunda I. Georg, Antonino D'Assoro, Matthew P. Goetz, David A. Potter. Fluorinated cuban-1-yl biguanides overcome hormone therapy resistance to standard of care fulvestrant, and palbociclib [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 LB196.

Abstract Background: [212Pb]VMT-a-NET is a novel, next generation alpha therapy agent for advanced somatostatin receptor 2 positive (SSTR2+) neuroendocrine tumors (NETs). Here, we present safety and efficacy update from the dose-finding phase 1/2a clinical trial (NCT05636618). Methods: Adults with well-differentiated unresectable or metastatic NETs, who were peptide receptor radionuclide therapy-naïve, showed progressive disease after at least one prior line of systemic therapy and demonstrated SSTR2-expression on PET images were treated with up to four cycles of study therapy at the assigned dose level. Participants were followed for dose-limiting toxicity (DLT) observation up to 42 days after the first dose. Efficacy was evaluated by investigators according to RECIST criteria v1.1. Results: As of 10-Dec-2025 (data cut-off [DCO]) a total of 56 participants were enrolled into Cohorts 1, 2 and 3, and received at least 1 dose of [212Pb]VMT-a-NET (n=2 in Cohort 1, n=46 in Cohort 2, and n=8 in Cohort 3 at a dose level of 2.5 mCi, 5 mCi, and 6 mCi, respectively). For data analysis purposes, participants were categorized into two different groups: a safety group and an efficacy group. The safety group included all participants treated by the DCO (n=56), while the efficacy group included only the Cohort 1 participants (n=2) and the first half of participants treated in Cohort 2 (n=23). Among all participants treated with at least 1 dose of [212Pb]VMT-a-NET (n=56), no DLTs, no grade 5 adverse events (AEs), no treatment-related discontinuations, no serious renal complications, no dysphagia and no clinically significant treatment-related myelosuppression were observed. Median follow-up time for all patients treated was 40 weeks (range: 6-97). Among the 25 participants followed for efficacy (n=2 in Cohort 1 and n=23 in Cohort 2), 19 out of 25 were with no progression as of the DCO. Median follow-up time for participants included in the efficacy group was 49 weeks (range: 6-97). Investigator-assessed RECIST v1.1 objective responses were observed in 9 out of 23 participants (39%) enrolled in the first half of Cohort 2 (8 confirmed). The 2 patients enrolled in Cohort 1 at 2.5 mCi still have stable disease after 2 years of follow up. Updated safety outcomes for all participants along with updated efficacy findings for participants in Cohorts 1 and 2 with sufficient maturity will be presented during the congress. Conclusions: Treatment with [212Pb]VMT-α-NET continues to be well-tolerated among all patients treated (n=56), and to show promising efficacy at the dose levels of 2.5 mCi and 5 mCi. The study is ongoing with Cohort 3 (6 mCi) currently open for enrollment. Citation Format: Thorvardur R. Halfdanarson, Richard L. Wahl, Vineeth Sukrithan, Brandon R. Mancini, Seyed A. Mosallaie, Savitha Balaraman, Gregory S. Sibley, Jason Starr, Lowell B. Anthony, Chih Y. Liao, Samuel H. Mehr, Jared Weiss, Robert A. Ramirez, Lucia Baratto, Wenjing Yang, Alaa Hanna, Stephen M. Keefe, Markus Puhlmann, Vikas Prasad. [212Pb]VMT-a-NET in advanced SSTR2+ neuroendocrine tumors: safety and preliminary efficacy results from dose-finding cohorts 1,2 and 3 [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 CT088.