Citations

Increased infiltration of CD3 + and CD8 + T cells into ovarian cancer (OC) is linked to better prognosis, but the specific antigens involved are unclear. Recent reports suggest that HLA class I can present peptides from noncoding genomic regions, known as noncanonical or cryptic peptides, but their immunogenicity is underexplored. To address this, we used immunopeptidomic analysis and RNA sequencing on five metastatic OC samples, which identified 311 cryptic peptides (40 to 83 per patient). Despite comprising less than 1% of total peptides, cryptic peptides from noncoding transcripts emerged as the predominant antigen class when compared to the other major classes of known tumor-specific and tumor-associated antigens in OC samples. Notably, nearly 70% of the prioritized cryptic peptides elicited T cell activation, as evidenced by increased 4-1BB and IFN-γ expression in autologous CD8 + T cells. This study reveals noncoding cryptic peptides as an important class of immunogenic antigens in OC.

Cardiac amyloidosis is an underdiagnosed cause of infiltrative cardiomyopathy, leading to heart failure across the spectrum of ejection fractions. Although there are approved disease-modulating therapies for the transthyretin subtype (transthyretin amyloid cardiomyopathy [ATTR-CM]), the role of heart failure medications remains uncertain and challenging in clinical practice. Their effects on clinical outcomes, such as mortality and hospitalization, are unknown for ATTR-CM. This review aims to explore the use of these medications in ATTR-CM, considering the disease’s stage and patient-specific issues, such as fluid homeostasis, autonomic dysfunction, conduction disorders, low and fixed stroke volumes, and decreased functional capacity. As our understanding of this condition deepens, it is important to reassess the impact of contemporary heart failure medication in ATTR-CM. Finally, the relevance of guideline recommendations for heart failure drugs based on left ventricular ejection fraction should be reconsidered in the context of ATTR-CM.

AbstractAimAn estimated 5%–25% of women with endometriosis have colorectal involvement. Colorectal resection is the most suitable surgical management for cases with large bowel infiltration. However, this method is also associated with the highest rate of postoperative complications. Data focusing on surgeon speciality and surgical outcomes are currently limited. The aim of this work was to evaluate the surgical characteristics and short‐term postoperative outcomes following colorectal resection for endometriosis according to surgeon speciality.MethodUsing the National Surgical Quality Improvement Program (NSQIP) database, we included women who underwent colorectal resection for endometriosis between 2012 and 2020. Surgeries by general/colorectal surgeons were compared with those by gynaecological surgeons. The primary outcome was major complications according to the Clavien–Dindo classification.ResultsAmong 745 colorectal resections, 82.3% were performed by general/colorectal surgeons and 17.7% by gynaecologists. Racial and ethnic characteristics differed between groups, but other baseline characteristics were comparable. General/colorectal surgeons performed fewer minimally invasive surgeries (29.9% vs. 58.3%, p < 0.001). General/colorectal surgery cases had lower rates of any postoperative complications and minor complications (14.8% vs. 29.5%, p < 0.001; 10.1% vs. 23.5%, p < 0.001), while major complication rates were similar. Multivariable regression showed no association between major complications and surgical speciality. In a propensity score‐matched analysis, no significant differences were found between the two cohorts.ConclusionMost colorectal resections are performed by general/colorectal surgeons while a minimally invasive approach is more common among gynaecologists. There were no significant differences in outcomes between the two groups after adjusting for confounding variables. This suggests considering a multidisciplinary or dual surgery team approach to deep infiltrative endometriosis requiring bowel resection.

Abstract Background: Age-related clonal hematopoiesis (ARCH) is a precursor state to blood cancers and is associated with epigenetic age acceleration (EpiAgeAccel). While ARCH is associated with increased all-cause mortality and cardiovascular disease, not much is known about these risks with therapy-related clonal hematopoiesis (t-CH) – CH occurring in the context of prior cytotoxic chemotherapy/radiation exposure. Methods: Patients were prospectively recruited for CH and EpiAge assessment from Mayo Clinic between 2022 and 2024. CH status was determined using error corrected sequencing on peripheral blood (PB) DNA (sensitivity 0.5% VAF). Patients with CH were classified as t-CH if they had received chemotherapy or radiation prior to CH detection. All other CH cases were classifed as ARCH. For EpiAge analysis, PB DNA was analyzed using the Illumina MethylationEPIC array. The resulting beta values were used to obtain epigentic age estimates using Horvath’s clock, Hannum’s Clock, PhenoAge, DunedinPACE, and estimated telomere lengths (DNAmTL). Results: 106 (62%) of 170 patients assessed were found to have CH. CH patients were classified into ARCH-63 (59%) and t-CH-43 (41%). While the median chronological age (69 vs 67 years) was similar between ARCH and t-CH, t-CH patients had lower Hgb [10.9g/dL vs. 13g/dL (p=0.0001)], lower platelet [146x109/L vs. 192x109/L (p=0.0132)] and lower WBC [4.4x109/L vs. 5.2x109/L (p=0.0345)]. The 3 most common ARCH mutations were TET2 (20%), DNMT3A (19%), and ASXL1 (14%), while PPM1D (27%), TET2 (18%), and DNMT3A (14%) were most frequent in t-CH. There was no significant difference in median EpiAge via Horvath (68 vs 67.5years p=0.2826), Hannum (65 vs 66 years p=0.9333), or PhenoAge (55 vs 56 years p=0.618) between ARCH and t-CH. However, DunedinPACE of aging was higher in t-CH (1.27 vs 1.18 bioyear/chronoyear p=0.0148) and median DNAmTL was shorter in t-CH (6.35 vs 6.49kb p=0.0247), compared to ARCH (Note patients with telomere biology disorders were excluded). Multivariable regression analysis adjusting for chronologic age, smoking status, and male sex showed that both ARCH and t-CH had EpiAgeAccel via Horvath(5.8years p=0.0001, 3.4 years p=0.051), Hannum(5years p=0.001, 4.5 years p=0.007), and PhenoAge (6.7years p=0.002, 7.6 years p=0.002) clocks. t-CH more than doubled DunedinPACE (0.2 bioyear/chronoyear, p&lt;0.001) of aging compared to ARCH (0.08 bioyear/chronoyear, p=0.026). t-CH also demonstrated a significant decrease in DNAmTL (0.34kb, p&lt;0.001) in comparison to ARCH (0.17kb, p=0.015). With a median follow-up of 20 months, t-CH was associated with worse overall survival in comparison to ARCH, and non-CH patients (p=0.013, 93% vs. 90% alive at 10 months, 87 vs. 72% alive at 20 months). Conclusion: Our prospective CH cohort study validates the association between CH and EpiAgeAccel using several different methylation clocks and for the first time highlights an increased pace of aging and shorter DNAmTL in the context of inferior survival outcomes in t-CH. Citation Format: Marissa Li, Jenna Fernandez, Kristina Kirschner, Tamir Chandra, Kristen McCullough, Sarah Aug, Terra Lasho, Christy Finke, James Foran, Cecilia Arana Yi, Yael Kusne, Talha Badar, Abhishek Mangaonkar, Naseema Gangat, Rachel Simon, Alejandro Ferrer, Mrinal Patnaik. A prospective cohort study of biological aging and epigenetic age acceleration in 106 patients with age and therapy-related clonal hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A015.

AbstractAn in-depth understanding of portal venous anatomy, particularly its variants, is essential for interventional radiologists performing complex hepatobiliary procedures such as transjugular intrahepatic portosystemic shunt (TIPS) creation. Anatomical variations in the portal venous system occur in approximately 35% of the population, and failure to identify these variants can result in significant procedural complications including vascular injury and postprocedural liver failure. This article discusses the most common (types I–V) portal vein variants and the importance of their preprocedural identification, their potential impact on procedural outcomes, and the role of advanced imaging techniques in mitigating risks associated with these anatomical variations.

Background: The objective in epithelial ovarian cancer is to reach maximal cytoreduction with no visible residual tumor. Tumor detection during cytoreductive surgery depends on visual inspection, palpation, or blind biopsy, methods that lack reliability for identifying microscopic disease. Although the importance of microscopic disease in epithelial ovarian cancer is controversial, it may harbor chemoresistant cells and explain the high recurrence rates. Fluorescence-guided surgery (FGS) is an emerging approach. However, the potential in ovarian cancer remains underexplored; the majority of the existing evidence pertains to gastrointestinal tumors and a limited group of ovarian cancer patients. Their comparative effectiveness is still uncertain. Objective: To systematically review and evaluate the role of fluorescence-guided surgical techniques in detecting microscopic disease in ovarian cancer and compare their efficacy to total peritonectomy. Data Sources: A systematic search was made in three databases (PubMed, Web of Science, and Embase). The search was conducted from 1975 to 2024, including randomized controlled trials, observational studies, and conference abstracts in the last 25 years. Study Selection: Clinical studies published in English involving ovarian cancer patients undergoing FGS or total peritonectomy were included. Case reports, reviews, animal studies, and studies involving mixed cancer populations without ovarian cancer-specific data were excluded. Two independent reviewers screened 631 studies, yielding 12 eligible studies for final analysis. Data Extraction and Synthesis: Data were extracted and synthesized in accordance with PRISMA and MOOSE guidelines, using random-effects models for independent analysis. Sensitivity, specificity, positive predictive value (PPV), and odds ratios (ORs) were grouped, accompanied by subgroup analyses based on the fluorescence agent employed. For quality assessment, we utilized the NIH quality tool. Main Outcome(s) and Measure(s): The primary outcome was the rate of change in surgical management due to fluorescence guidance or total peritonectomy. Secondary outcomes comprised lesion-level sensitivity, specificity, and PPV. Safety outcomes included adverse events associated with fluorescence agents. Results: There were 12 studies involving 429 ovarian cancer patients. FGS improved the detection of microscopic disease compared to standard visualization methods, with a pooled sensitivity of 0.77. Folate receptor-targeted agents had high sensitivity (84%) but low specificity (26%). Aminolevulinic acid (5-ALA) showed superior diagnostic accuracy with a sensitivity of 84% and a specificity of 96%. Total peritonectomy showed no significant advantage over FGS for detecting microscopic disease. The adverse events were mild, with no serious events reported. We observed a high heterogeneity across studies and methodologies. Conclusions and Relevance: Fluorescence-guided surgery utilizing fluorescence tracers demonstrates potential in improving the detection of microscopic disease and may change surgical management in epithelial ovarian cancer, particularly with 5-ALA. Variability in performance and limited data on survival outcomes necessitates additional research. Total peritonectomy does not offer further advantage in the detection of microscopic disease. Future trials should focus on standardizing methodology and evaluating the effects of microscopic disease removal on survival outcomes. Registration: The study was registered to PROSPERO as CRD42024578274.

Background: The cumulative effect of repetitive subconcussive head impacts on neurocognitive function during youth contact sports remains largely unknown. There is a paucity of literature evaluating cumulative helmet forces over a season and their correlation with preseason and postseason cognitive performance tasks such as the King-Devick test (KDT). Hypothesis: Higher helmet forces recorded throughout a 10-week, 10-game youth football season would correlate with slower performance on postseason KDT. Study Design: Prospective cohort study. Level of Evidence: Level 3. Methods: A cohort of 58 youth football players (ages 9-13 years) underwent pre- and postseason KDT. Players wore SpeedFlex helmets (Riddell) fitted with InSite Impact Response System helmet accelerometers (Riddell) which recorded impacts of ≥15 g . Head impacts were tallied over a season and assigned a score of 1, 2, or 3 based on magnitude of g forces. Suspected concussions were correlated with KDT times and recorded instances of head impact. Pre- and postseason KDT scores were compared. Results: During the season, 2013 head impacts were recorded. Median (range) total cumulative force score was 24 (5-476); 6 players sustained head impacts concerning for concussion, and 4 were clinically diagnosed with concussions. Overall, postseason KDT times improved compared with preseason, with a median (range) change of −4.8 seconds (−7.6, −1.1). Analysis showed no correlation between changes in KDT time and total cumulative force score over the season. Conclusion: KDT times in youth football players did not change significantly based on head impact exposure over a single youth football season; most players’ KDT times improved from preseason to postseason. Clinical Relevance: Although our study did not show significant cognitive impact as measured by KDT over a single youth football season, the long-term effects of concussion on the immature brain and how it can impact cognitive development remains largely unknown and should be an area of ongoing study.

Abstract The prevalence of clonal hematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. We previously reported gene specific fitness effects in two longitudinal cohorts of aging. We now set out to define fitness effects across three longitudinal cohorts of aging in a total of 713 participants. We found that fitness correlates with timing of mutations, which needs to be taken into account when predicting health outcomes. We show that fitness and the time of mutations are superior predictors of outcomes such as all-cause mortality compared to the commonly used clone size (variant allele frequency). Our new predictor even outperforms age, the most important predictor for the onset of age-related disease thus far. In conclusion, the fitness landscape of mutations and their context in terms of clonal composition and timing of mutation acquisition are important parameters to bring CH predictors into the clinic.

Background: Age-related clonal hematopoiesis (ARCH) is a precursor state to blood cancers and is associated with epigenetic age acceleration (EpiAgeAccel) (Aging Cell, 2021). While ARCH in combination with AgeAccel has the highest risk for all cause mortality and cardiovascular disease, not much is known about context-relevant clonal hematopoiesis (CRCH) - CH occurring in the context of prior chemo/radiation, bone marrow failure and germline predisposition syndromes. CRCH has a unique mutational signature enriched in genes in DNA damage response and repair (TP53 and PPM1D). To answer this question, we assessed EpiAge in a prospective cohort of patients with both ARCH and CRCH. Methods: Patients were prospectively recruited for CH and EpiAge assessment from the Mayo Clinic CH clinic between 2022 and 2024. Demographic and clinical data including chronologic age, BMI, sex, blood counts, and medical history were recorded at the time of enrollment. CH status was determined using error corrected sequencing on peripheral blood (PB) DNA. All somatic variants with a variant allele frequency (VAF) ≥0.5% were considered as CH. For EpiAge analysis PB DNA was analyzed using the Illumina MethylationEPIC array. The resulting beta values were used to obtain epigenetic age estimates using Horvath's clock (Genome Biol., 2013), Hannum's Clock (Mol Cell., 2013), PhenoAge (Aging, 2018), DunedinPACE (eLife, 2022), and predicted telomere length (Aging, 2019). Results: 106 (62%) of 170 patients assessed were found to have CH, with the most frequent mutations being TET2 (19%), PPM1D (17%), DNMT3A (16%), ASXL1 (9%), and TP53 (6%); median VAF 9.5%. Except for a higher median chronologic age (68 vs 60 years, p&lt;0.001) in the CH group, baseline characteristics including BMI, comorbidities, baseline blood counts, sex and tobacco use history were similar between the two groups. The CH group demonstrated significant EpiAgeAccel by all three clocks: Horvath (p=0.001), Hannum (p&lt;0.001), and PhenoAge (p&lt;0.001); with an increase in biological age of 4.9 years (95% CI 2-7.7) by Horvath clock, 4.8 years (95% CI 2.2-7.5) by Hannum clock, and 7 years (95% CI 2.9-10.5) by PhenoAge, after adjusting for chronologic age, sex, smoking status, and cancer history. CH was also associated with increased DunedinPACE of aging by 0.13 biological year per chronologic year (bioyear/chronoyear) (95% CI 0.06-0.2, p&lt;0.001), and shortened telomere lengths by 0.24kb (95% CI 0.11-0.35, p&lt;0.001) after adjusting for chronologic age and excluding patients with telomere biology disorders. CH patients were then further classified into ARCH-63 (59%) and CRCH-43 (41%). While the median chronological age (69 vs 67 years) was similar between the 2 groups, CRCH patients had lower Hgb [10.9g/dL vs. 13g/dL (p=0.0001)] , lower platelet [146x109/L vs. 192x109/L (p=0.0132)] and lower WBC [4.4x109/L vs. 5.2x109/L (p=0.0345)]. The median BMI, comorbidities, and tobacco use history were similar between the 2 groups. The 3 most common ARCH mutations were TET2 (20%), DNMT3A (19%), and ASXL1 (14%), while, PPM1D (27%), TET2 (18%), and DNMT3A (14%) were frequent in CRCH. There was no significant difference found in median EpiAge via Horvath (68 vs 67.5years p=0.2826), Hannum (65 vs 66 years p=0.9333), or PhenoAge (55 vs 56 years p=0.618) between ARCH and CRCH. However, DunedinPACE of aging was higher in CRCH (1.27 vs 1.18 bioyear/chronoyear p=0.0148) and median telomere length was shorter in CRCH (6.35 vs 6.49kb p=0.0247), in comparison to ARCH. Multivariable regression analysis was completed for both ARCH and CRCH compared to non-CH, adjusting for chronologic age, smoking status, and male sex. While both ARCH and CRCH demonstrated EpiAgeAccel via Horvath(5.8years p=0.0001, 3.4 years p=0.051), Hannum(5years p=0.001, 4.5 years p=0.007), and PhenoAge (6.7years p=0.002, 7.6 years p=0.002) clocks, CRCH more than doubled DunedinPACE (0.2 bioyear/chronoyear, p&lt;0.001) of aging compared to ARCH (0.08 bioyear/chronoyear, p=0.026). CRCH also demonstrated double the decrease in telomere length (0.34kb, p&lt;0.001) compared to ARCH (0.17kb, p=0.015). Conclusion: Our prospective CH cohort study validates the association between CH and EpiAgeAccel using several different methylation clocks and for the first time, highlights increased pace of aging and shorter telomere lengths in CRCH versus ARCH. Correlations with cardiovascular disease and mortality outcomes are ongoing.