A Signature of Pre-Operative Biomarkers of Cellular Senescence to Predict Risk of Cardiac and Kidney Adverse Events after Cardiac Surgery.

Importance: Improved pre-operative risk stratification methods are needed for targeted risk mitigation and optimization of care pathways for cardiac patients. This is the first report demonstrating pre-operative, aging-related biomarkers of cellular senescence and immune system function can predict risk of common and serious cardiac surgery-related adverse events. Design: Multi-center 331-patient cohort study that enrolled patients undergoing coronary artery bypass grafing (CABG) surgery with 30-day follow-up. Included a quaternary care center and two community-based hospitals. Primary outcome was KDIGO-defined acute kidney injury (AKI). Secondary outcomes: decline in eGFR ≥25% at 30d and a composite of major adverse cardiac and kidney events at 30d (MACKE30). Biomarkers were assessed in blood samples collected prior to surgery. Results: A multivariate regression model of six senescence biomarkers (p16, p14, LAG3, CD244, CD28 and suPAR) identified patients at risk for AKI (NPV 86.6%, accuracy 78.6%), decline in eGFR (NPV 93.5%, accuracy 85.2%), and MACKE30 (NPV 91.4%, accuracy 79.9%). Patients in the top risk tertile had 7.8 (3.3-18.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d follow-up, and 5.7 (2.1-15.6) higher odds of developing MACKE30 versus patients in the bottom tertile. All models remained significant when adjusted for clinical variables. Conclusions: A network of senescence biomarkers, a fundamental mechanism of aging, can identify patients at risk for adverse kidney and cardiac events when measured pre-operatively. These findings lay the foundation to improve pre-surgical risk assessment with measures that capture heterogeneity of aging, thereby improving clinical outcomes and resource utilization in cardiac surgery.

Profiling an integrated network of cellular senescence and immune resilience measures in natural aging: a prospective multi-cohort study.

Background: Biological aging begins decades before the onset of age-related clinical conditions and is mediated by both cellular senescence and declining adaptive immune function. These processes are functionally related with the rate of senescent cell accumulation dependent upon a balance between induction and immune clearance. We previously showed that biomarkers in these domains can identify patients at-risk of surgery-related adverse events. Here, we describe evidence of clinical relevance in early aging and metabolic phenotypes in a general adult population. Methods: We enrolled a total of 482 participants (ages 25-90) into two prospective, cross-sectional healthy aging cohorts. Expression of biomarkers of adaptive immune function and cellular senescence (SapereX) was measured in CD3+ T cells isolated from peripheral blood. Findings: We established a network of biomarkers of adaptive immune function that correlate with cellular senescence and associate with early aging phenotypes. SapereX immune components associated with a decrease in CD4+ T cells, an increase in cytotoxic CD8+ T cells, and a loss of CD8+ naïve T cells (Pearson correlation 0.3-0.6). These components also associated with a metric of immune resilience, an ability to withstand antigen challenge and inflammation. In contrast, SapereX components were only weakly associated with GlycanAge (Pearson correlation 0.03-0.15) and commonly used DNA methylation clocks (Pearson correlation 0-0.25). Finally, SapereX biomarkers, in particular p16, were associated with chronic inflammation and metabolic dysregulation. Interpretation: Measurement of SapereX biomarkers may capture essential elements of the relationship between cellular senescence and dysregulated adaptive immune function and may provide a benchmark for clinically relevant health decisions.

A signature of pre-operative biomarkers of cellular senescence to predict risk of cardiac and kidney adverse events after cardiac surgery.

Objective: Understand the potential for pre-operative biomarkers of cellular senescence, a primary aging mechanism, to predict risk of cardiac surgery-associated adverse events. Methods: Biomarkers of senescence were assessed in blood samples collected prior to surgery in 331 patients undergoing CABG +/-valve repair or replacement. Patients were followed throughout the hospital stay and at a 30-day follow-up visit. Logistic regression models for pre-operative risk prediction were built for age-related clinical outcomes with high incidence including KDIGO-defined acute kidney injury (AKI), decline in eGFR ≥25% between pre-op and 30 days, and MACKE30, a composite endpoint of major adverse cardiac and kidney events at 30d. Results: AKI occurred in 19.9% of patients, persistent decline in kidney function at 30d occurred in 11.0%, and MACKE30 occurred in 13.4%. A network of six biomarkers of senescence (p16, p14, LAG3, CD244, CD28 and suPAR) were able to identify patients at risk for AKI (AUC 0.76), kidney decline at 30d (AUC 0.73), and MACKE30 (AUC 0.71). Comparing the top and bottom tertiles of senescence-based risk models, patients in the top tertile had 7.8 (3.3-8.4) higher odds of developing AKI, 4.5 (1.6-12.6) higher odds of developing renal decline at 30d, and 5.7 (2.1-15.6) higher odds of developing MACKE30. All models remained significant when adjusted for clinical variables. Patients with kidney function decline at 30d were largely non-overlapping and clinically distinct from those who experienced AKI, suggesting a different etiology. Typical clinical factors that predispose to AKI (e.g., age, CKD, surgery type) associated with AKI but not the 30d decline endpoint which was instead associated with new-onset atrial fibrillation. Conclusions: A six-member network of biomarkers of senescence, a fundamental mechanism of aging, can identify patients for risk of adverse kidney and cardiac events when measured pre-operatively.

p16 a biomarker of aging and tolerance for cancer therapy.

There is great variability in life-expectancy, physical, cognitive, and functional domains in cancer patients of similar chronologic age. Nowhere is this more apparent than among middle-aged and older patients. However, even in younger patients of similar age, extensive exposure to environmental stressors can cause great variability in health status. A biomarker that would reflect biologic age and any and all health deficits in a cancer patient at a distinct point in time might help predict long term outcomes related to treatment, especially toxicity and overall survival. p16INK4a (hereafter referred to as p16) expression represents an ideal biomarker that reflects both cellular senescence and biologic aging. In murine models, p16 expression reflects biologic aging in almost all organs. Preliminary findings in patients with cancer support p16 measurement as a marker of physiologic aging and predictor of toxicity in patients treated with chemotherapy. This review describes the role of p16 in cell senescence, the methodology of p16 measurement in humans, preliminary studies of p16 in humans, and the potential clinical utility of p16 in guiding treatment for cancer patients.

Six-year experience routinely using moderate deep inspiration breath-hold for the reduction of cardiac dose in left-sided breast irradiation for patients with early-stage or locally advanced breast cancer.

PURPOSE: Moderate deep inspiration breath-hold (mDIBH), using an Active Breathing Control device, has been used in our clinic since 2002 to reduce cardiac dose for patients receiving left-sided breast irradiation. We report our routine use of the mDIBH technique in clinically localized breast cancer, treated to the intact breast, reconstructed breast, or chest wall. MATERIALS AND METHODS: Ninety-nine patients with left-sided breast cancer were evaluated for Active Breathing Control treatment, of which, 87 patients were treated with mDIBH. Plans for both the free-breathing (FB) and mDIBH computed tomography scans were evaluated. Dose-volume histograms (DVHs) were analyzed for the heart and ipsilateral lung, comparing results for mDIBH versus FB plans. RESULTS: Eighty-seven patients were included for analysis. Of those, 66% received adjuvant chemotherapy with cardiotoxic agents. The mean dose for the whole breast was 47.6 Gy. There was a statistically significant decrease in all DVH parameters evaluated, favoring the delivery of mDIBH over FB plans. mDIBH plans significantly reduced cardiac mean dose (4.23 vs. 2.54 Gy; P<0.001), a relative reduction of 40%. In addition, there were significant reductions in all other heart parameters evaluated (ie, volume of heart treated, V30, V25, V20, V15, V10, and V5). mDIBH also significantly reduced lung dose, including a reduction of the left lung mean dose (9.08 vs. 7.86 Gy; P<0.001), a relative reduction of 13%, as well as significant reduction of all lung DVH parameters evaluated. CONCLUSIONS: To date, this series represents the largest experience utilizing mDIBH to reduce cardiac irradiation during left-sided breast cancer treatment. Statistically significant reductions in all heart and lung DVH parameters were achieved with mDIBH over FB plans. mDIBH, for the treatment of left-sided breast cancer, is a proven technique for reducing cardiac dose that may lead to reduced cardiotoxicity and can be routinely integrated into the clinic.