Citations

Abstract Background: Despite efficacy in metastatic clear cell renal cell carcinoma (ccRCC), immunotherapy currently has no role in the neoadjuvant setting. Suppressive tumor-associated macrophages (TAMs) are known to mediate resistance to immune checkpoint blockade (ICB) in ccRCC. In preclinical studies, IL-1β blockade reprograms TAMs toward an anti-tumor phenotype and promotes T cell activation, creating a tumor microenvironment (TME) more sensitive to ICB. To test this in patients, we conducted a correlative-rich neoadjuvant trial of IL-1β + PD-1 inhibition in localized ccRCC. Methods: SPARC-1 is a single-center, phase 1b study assessing the safety and feasibility of neoadjuvant canakinumab (αIL-1β) and spartalizumab (αPD-1) in patients with localized ccRCC (T1b-T4NanyM0 or TanyN1M0). All patients received 2 doses of canakinumab (300mg IV, Q4w) and spartalizumab (400mg IV, Q4w), 6 weeks (±7 days) prior to nephrectomy. The primary endpoint was safety and feasibility. Key secondary and exploratory endpoints included 12-month metastasis-free survival rate, pathologic response rate, and quantification of immune cell infiltration. To characterize immunologic reprogramming, fresh tumor specimens were collected at nephrectomy for single-cell RNA sequencing (scRNAseq) and multiparametric flow cytometry. Tissue from a treatment naïve cohort was collected for comparative analysis (n=16). Results: From August 15th, 2018, to January 30th, 2025, 14 patients were enrolled. There were no severe treatment-related adverse events (Grade ≥ 3) attributed to canakinumab or spartalizumab. At a median follow-up of 12.0 months (range, 6.3-12.0 months), the 12-month metastasis-free survival was 100%. Based on the ASSURE nomogram, the mean predicted 12-month recurrence risk was 16.7% (range, 4.7-46.5%). ScRNAseq revealed that treatment with αIL-1β + αPD-1 increased the frequency of TREM2+APOE+ TAMs (p=0.035), a population typically associated with immune suppression. However, these TAMs exhibited a phenotypic shift toward a less immunosuppressive state, with reduced IL-1β expression and increased CXCL9:SPP1 ratio, consistent with anti-tumor TAM polarization. Immune profiling revealed an increased CD8/CD4 T cell ratio (p=0.042) with modest enrichment of activated CD8+ T cells after treatment, supporting a more pro-inflammatory TME. Conclusions: The neoadjuvant combination of canakinumab (αIL-1β) and spartalizumab (αPD-1) is well-tolerated, feasible, and demonstrated promising clinical activity with no progression of disease observed in a localized ccRCC population at high risk of recurrence. Correlative analyses demonstrated that combined IL-1β and PD-1 blockade reprograms immunosuppressive TAMs, providing evidence that dual IL-1β and PD-1 inhibition can overcome myeloid-driven resistance in ccRCC. Clinical Trial Information: NCT04028245 Citation Format: Patrick J. McCann, Aleksandar Obradovic, Casey R. Ager, David H. Aggen, Catherine S. Spina, Chelsea L. Rahiman, Kaitlyn R. Campbell, Caroline Laplaca, Peyton C. Johnston, Amanda Kim, Katherine Gomez, Kriti Bagri Manjrekar, Mark N. Stein, Charles G. Drake, Karie Runcie, Matthew Dallos. Neoadjuvant IL-1β and PD-1 inhibition in localized clear-cell renal cell carcinoma: Clinical and correlative analyses of the phase 1b SPARC-1 trial [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 CT017.

Treatment guidelines for Clostridioides difficile infection (CDI) have been published by infectious disease and gastroenterology professional societies; however, adherence in clinical practice remains poorly characterized, particularly for recurrent disease. We conducted a retrospective chart review of 100 patients with CDI (350 episodes: 115 initial, 235 recurrent) referred to a tertiary complicated CDI clinic between 2018 and 2023. Guideline adherence was assessed by comparing treatment with IDSA/SHEA and ACG recommendations, and referring diagnoses were compared with final specialist diagnoses. Guideline adherence was significantly higher in initial compared to recurrent episodes (70.4% vs. 41.3%, p < 0.0001). Among guideline non-adherent recurrent episodes, 51.3% used standard antibiotic regimens inappropriate for the recurrence tier. Specialist review reclassified 12.0% of episodes, with colonization increasing from 2.6% to 8.9%. Misdiagnosed colonization cases had a 6.2-fold higher treatment failure rate than confirmed CDI (39.3% vs. 6.3%, p < 0.0001). Guideline non-adherence showed a non-significant trend toward treatment failure (10.0% vs. 6.7%, p = 0.31). Guideline adherence for recurrent CDI is inadequate in pre-referral settings, and diagnostic misclassification is common. Early specialist involvement may improve both diagnostic accuracy and treatment appropriateness for patients with recurrent CDI.

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Background: Long-term outcomes of femoroacetabular impingement (FAI) surgery, particularly survivorship, are critical to guide treatment decision-making and patient counseling, yet only a limited number of studies have reported mid- to long-term survivorship. The purpose of this study was to report survivorship rates at a mean 10-year follow-up in a large, multicenter FAI surgery cohort and to identify clinical predictors of survivorship. Methods: A prospective, multicenter cohort study assessed patients treated for FAI with hip arthroscopy or surgical dislocation from 2008 to 2012. At a minimum of 8 years, 362 hips (80.1%) had follow-up that permitted assessment of total hip arthroplasty (THA)-free survivorship. A Cox proportional-hazards model was developed to identify risk factors for THA. Results: tThe cohort included 362 hips with a mean patient age of 32.1 years; 53% were in females, and 95.6% were in Caucasian patients. The THA-free survivorship of the cohort was 90.6% at a mean of 10.4 ± 1.6 years postoperatively. Risk factors for THA were older age at surgery (p = 0.01), male sex (p = 0.02), body mass index of ≥30 kg/m 2 (p = 0.009), and femoral head chondromalacia (p < 0.001). Conclusions: This study demonstrates that FAI surgery yielded durable 10-year THA-free survivorship of 90.6%. Older age at surgery, obesity, male sex, and femoral head chondromalacia were key predictors of conversion to THA. Level of Evidence: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

PURPOSE Approximately three quarters of patients with sarcoma report financial toxicity, defined as the psychosocial and economic burden of cancer care. The Comprehensive Score for Financial Toxicity (COST) is a screening questionnaire validated in patients with cancer. However, its use is not widespread in sarcoma care, likely in part due to its complexity. This study aimed to characterize financial toxicity in patients with sarcoma and evaluate whether shorter screening tools can identify high-risk patients. METHODS We conducted a survey and retrospective cohort study of patients treated for sarcoma at a large, academic sarcoma center in 2016-2024. Patients completed the COST questionnaire (11 graded questions, each scored on a five-point Likert scale from 0 to 4) and the shorter, four-question Worry about Affording Healthcare Scale (WAHS). We obtained clinical information from the electronic health record. We used descriptive statistics to summarize responses to COST, Pearson's correlation coefficient to assess the association between WAHS and COST, and stepwise Spearman correlations to evaluate whether an abbreviated (1-4 question) version of COST correlated highly with total COST score. RESULTS Among 205 participants, the mean COST score was 20/44 (standard deviation = 6; lower scores indicate greater financial toxicity). Respondents worried most about job loss (mean COST: 0.99) and family finances (mean COST: 1.11). WAHS was weakly correlated with COST (r = 0.47, P < .01). A four-item abbreviated COST tool was strongly correlated with the total COST (ρ = 0.906, P < .0001) and demonstrated high sensitivity (96%) and moderate specificity (75%). CONCLUSION An abbreviated four-item COST tool could act as a clinically feasible, accurate screening tool after external validation. Routine financial toxicity screening could facilitate timely detection and referral to essential financial navigation resources.

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.

Abstract Introduction Revascularization to prevent limb loss is not feasible or represents a very high risk in a significant proportion of patients with chronic limb-threatening ischaemia (CLTI). No standard definition currently exists to define this population of patients. The aim of this study was to develop a consensus-based, multidomain definition to improve clinical assessment and reporting of studies in people with ‘no option’ (NO) or ‘poor option’ (PO) CLTI. Methods A modified Delphi process was conducted with 164 specialists from 30 countries. Two iterative survey rounds were used to reach consensus, defined as ≥70% agreement with a score of ≥7 on a nine-point scale. Results Some 164 international vascular specialists participated in the study, averaging 19 years of experience. A multidomain framework including arterial disease anatomy, biology, risk, function, and context (ABRFC) achieved 83% consensus. A ‘desert foot’ was defined as the absence of distal arterial revascularization targets on advanced non-invasive imaging, invasive digital subtraction angiography, and at least one failed endovascular revascularization attempt (81.6% agreement). Inadequate autogenous bypass conduit was defined as the lack of usable autologous vein across all four limbs (85% agreement). Patients were classified as NO for revascularization if they present with ‘desert foot’, prohibitive medical risk, a non-functional limb, or in those patients who refused arterial revascularization. PO revascularization patients combined factors such as severe infection, lack of autologous vein, or treatment non-compliance (72.1% agreement). Conclusion This consensus study established a structured, expert-validated definition of no option or poor option for revascularisation of patients with CLTI. The multidomain ABRFC framework provides a foundation for standardized clinical assessment, trial design, and future guideline development.

A bstract Alzheimer’s disease (AD) presents with substantial clinical and anatomical heterogeneity, including both typical amnestic and atypical variants such as posterior cortical atrophy and logopenic primary progressive aphasia. Although neurofibrillary tangle (NFT) burden is a defining pathological feature of AD, its regional distribution varies across clinical phenotypes, suggesting that selective neuronal vulnerability may shape disease presentation. However, the cellular and molecular determinants underlying this vulnerability remain incompletely understood. Here, we profiled single-nucleus transcriptomes across multiple brain regions, including hippocampal (CA1) and neocortical (superior temporal gyrus and occipital cortex) regions, from individuals with typical and atypical AD and healthy controls. Integrative analysis identified major cell classes and resolved diverse excitatory and inhibitory neuronal subpopulations that were reproducibly observed across regions and individuals. Using quasi-binomial regression models to assess compositional changes, we quantified subtype-specific vulnerability associated with AD pathology. We identified a distinct excitatory neuronal subpopulation characterized by NRGN and BEX1 expression, which showed reproducible depletion across multiple regions, with the strongest evidence in amnestic AD and in neocortical regions in lvPPA. This vulnerable population showed concordance with previously reported AD-associated excitatory neuron signatures, supporting a conserved transcriptional program of susceptibility. Genes enriched in this population were associated with chemical synaptic transmission and regulation of synaptic plasticity and formed interconnected networks in protein-protein interaction analyses. These findings suggest that intrinsic properties related to synaptic function may predispose specific neuronal populations to degeneration in AD. Together, our results define a conserved, transcriptionally distinct excitatory neuron subpopulation that is selectively vulnerable across AD phenotypes and brain regions. This work provides a framework for linking regional pathology to cell-type-specific susceptibility and highlights synaptic regulatory pathways as potential contributors to neuronal degeneration in Alzheimer’s disease.

ABSTRACT We report on the 2025 International ICU Diary Conference that provided a comprehensive update on current knowledge, innovations and global practices related to ICU diaries. Held in a 6‐week online format, the event featured 23 speakers and was attended by mean 69.7 (SD 20.5) participants per session. Topics included development of ICU diaries, use in special settings, digital diaries, survivors' and families' experiences, Post‐Intensive‐Care Syndrome and follow‐up and implementation projects. Highlights were innovative solutions for digital diaries and the report of persons with lived and living experiences with diaries, changing the focus on humanising critical care. Relevance for Practice ICU diaries support patient‐ and family‐centred care and should be implemented more widely across healthcare systems. Their successful adoption requires contextual adaptation and policy support, with future development likely to be shaped by the increasing use of digital ICU diaries.