Purpose/Objectives Moderate Deep Inspiration Breath-hold (mDIBH), utilizing an Active breathing Control (ABC) 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/Methods Ninety-nine patients with left sided breast cancer were evaluated for ABC treatment, of which, 87 patients were treated with mDIBH. Plans for both the free-breathing (FB) and mDIBH CT scans were evaluated. Dose volume histograms (DVHs) were analyzed for the heart and ipsilateral lung, comparing results for mDIBH vs FB plans. Results Eighty-seven patients are included for analysis. Of those, 66% received adjuvant chemotherapy with cardiotoxic agents. The mean dose to 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 Gy vs. 2.54 Gy; p<0.001), a relative reduction of 40%. As well, there were significant reductions in all other heart parameters evaluated (i.e 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 Gy 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.

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. p16 INK4a (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.

Objective: Measures that capture aging-related decline can identify patients at risk for cardiac surgery-associated adverse events to guide perioperative care and improve patient outcomes. We determined if a panel of biomarkers of cellular senescence, a fundamental aging mechanism, can predict risk of adverse kidney and cardiac events in patients undergoing CABG surgery. Methods: Patients to undergo CABG with or without valve repair or replacement were recruited into a pilot cohort of 66 patients and a development cohort of 331 patients. Blood samples were collected prior to surgery for assessment of expression of preselected biomarkers of senescence. Patients were followed through hospital stay and up to a 30d post-surgery. Daily post-op serum creatinine (sCR) was used to identify incidence of acute kidney injury (AKI) and sCr measures at 30 days were used to identify patients whose eGFR decreased 25% or more as compared to baseline (development cohort only). A composite of major adverse cardiac and kidney events (MACKE30) was used as another endpoint in development cohort only. Results: AKI occurred in 30.0% of patients in pilot study and 19.9% of development cohort. Persistent decline in kidney function at 30d occurred in 11.0%, and MACKE30 in 13.4% of patients. A panel 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). When compared between 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 Surprisingly, patients with kidney function decline and AKI were largely non-overlapping, and potentially of different etiology. Typical clinical factors that predispose to AKI (e.g., age, CKD, surgery type) associated with AKI but not the 30d decline endpoint. Instead, a new-onset atrial fibrillation associated with 30d kidney decline and not AKI. Conclusions: A 6-member panel of biomarkers of senescence, a fundamental mechanism of aging, can identify patients for risk of adverse kidney and cardiac events when measured pre-operatively.

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