Purpose Data suggest that DNA damage by poly (ADP-ribose) polymerase inhibition and/or reduced vascular endothelial growth factor signaling by vascular endothelial growth factor receptor inhibition may complement antitumor activity of immune checkpoint blockade. We hypothesize the programmed death-ligand 1 (PD-L1) inhibitor, durvalumab, olaparib, or cediranib combinations are tolerable and active in recurrent women's cancers. Patients and Methods This phase I study tested durvalumab doublets in parallel 3 + 3 dose escalations. Durvalumab was administered at 10 mg/kg every 2 weeks or 1,500 mg every 4 weeks with either olaparib tablets twice daily or cediranib on two schedules. The primary end point was the recommended phase II dose (RP2D). Response rate and pharmacokinetic analysis were secondary end points. Results Between June 2015 and May 2016, 26 women were enrolled. The RP2D was durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice a day, or cediranib 20 mg, 5 days on/2 days off. No dose-limiting toxicity was recorded with durvalumab plus olaparib. The cediranib intermittent schedule (n = 6) was examined because of recurrent grade 2 and non-dose-limiting toxicity grade 3 and 4 adverse events (AEs) on the daily schedule (n = 8). Treatment-emergent AEs included hypertension (two of eight), diarrhea (two of eight), pulmonary embolism (two of eight), pulmonary hypertension (one of eight), and lymphopenia (one of eight). Durvalumab plus intermittent cediranib grade 3 and 4 AEs were hypertension (one of six) and fatigue (one of six). Exposure to durvalumab increased cediranib area under the curve and maximum plasma concentration on the daily, but not intermittent, schedules. Two partial responses (≥15 months and ≥ 11 months) and eight stable diseases ≥ 4 months (median, 8 months [4 to 14.5 months]) were seen in patients who received durvalumab plus olaparib, yielding an 83% disease control rate. Six partial responses (≥ 5 to ≥ 8 months) and three stable diseases ≥ 4 months (4 to ≥ 8 months) were seen in 12 evaluable patients who received durvalumab plus cediranib, for a 50% response rate and a 75% disease control rate. Response to therapy was independent of PD-L1 expression. Conclusion To our knowledge, this is the first reported anti-PD-L1 plus olaparib or cediranib combination therapy. The RP2Ds of durvalumab plus olaparib and durvalumab plus intermittent cediranib are tolerable and active. Phase II studies with biomarker evaluation are ongoing.

Heart rate (HR), mean arterial blood pressure (MAP), and rate-pressure product (RPP) responses to submaximal isokinetic concentric (CON) and eccentric (ECC) knee extension exercise were compared at the same absolute torque output in 20 young (mean+/-SD=23.2+/-1.7 years) and 20 older (mean+/-SD=75.2+/-4.6 years) adults. After determination of peak CON and ECC torques, subjects performed separate, randomly ordered, 2-minute bouts of isokinetic CON and ECC exercise (90 degrees/s, exercise intensity: 50% of CON peak torque). CON exercise elicited greater changes in HR, MAP, and RPP than ECC exercise (p<.001) for both age groups. There were no age-related differences in HR, MAP, or RPP responses for either CON or ECC exercise. At the same absolute torque output, isokinetic CON knee extension exercise elicited significantly greater increases in cardiovascular stress than ECC exercise in both young and older adults. This result has implications for determining appropriate fitness and rehabilitation programs.

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Objectives: We investigated the relationship between low wall shear stress (WSS) and severe endothelial dysfunction (EDFx). Background: Local hemodynamic forces, such as WSS play an important role in atherogenesis through their effect on endothelial cells. We hypothesized that low WSS independently predicts severe EDFx in patients with coronary artery disease (CAD). Methods: Forty-four patients with CAD underwent coronary angiography, fractional flow reserve (FFR) and endothelial function testing. Segments with >10% vasoconstriction after acetylcholine (Ach) infusion were defined as having severe EDFx. WSS, calculated using 3D angiography, velocity measurements and computational fluid dynamics, was defined as low (< 1 Pa), intermediate (1–2.5 Pa) or high (> 2.5 Pa). Results: Median age was 52 years, 73% were females. Mean FFR was 0.94 ± 0.06. In 4,510 coronary segments, median WSS was 3.67 Pa. 24% had severe EDFx. A higher proportion of segments with low WSS had severe EDFx (71%) compared to intermediate WSS (22%) or high WSS (23%) (p < 0.001). Segments with low WSS demonstrated greater vasoconstriction in response to ACh than intermediate or high WSS segments (−10.7% vs. −2.5% vs. +1.3%, respectively, p < 0.001). In a multivariable logistic regression analysis, female sex (OR: 2.44, p = 0.04), diabetes (OR: 5.01, p = 0.007) and low WSS (OR: 9.14, p < 0.001) were independent predictors of severe EDFx. Conclusion: In patients with non-obstructive CAD, segments with low WSS demonstrated more vasoconstriction in response to ACh than intermediate or high WSS segments. Low WSS was independently associated with severe endothelial dysfunction.

In general, TPS even with advanced algorithms do not provide accurate dosimetry in the buildup region, as verified by EBT2 film for all treatment techniques. For all cases, TPS and measured doses were in agreement from 6 mm in depth but differed at shallower depths. Grid size plays an important role in dose calculation. For accurate dosimetry small grid size should be used where differences are lower between TPS and measurements.

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