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Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment., (© 2024. The Author(s).)

Tumour-infiltrating lymphocytes (TILs) are considered crucial in anti-tumour immunity. Accordingly, the presence of TILs contains prognostic and predictive value. In 2011, we performed a systematic review and meta-analysis on the prognostic value of TILs across cancer types. Since then, the advent of immune checkpoint blockade (ICB) has renewed interest in the analysis of TILs. In this review, we first describe how our understanding of the prognostic value of TIL has changed over the last decade. New insights on novel TIL subsets are discussed and give a broader view on the prognostic effect of TILs in cancer. Apart from prognostic value, evidence on the predictive significance of TILs in the immune therapy era are discussed, as well as new techniques, such as machine learning that strive to incorporate these predictive capacities within clinical trials., (© 2022. The Author(s).)

Background: In patients receiving mechanical ventilation, spontaneous awakening trials reduce morbidity and mortality when paired with spontaneous breathing trials. However, spontaneous awakening trials are not performed every day they are indicated and little is known about spontaneous awakening trial protocol use in cardiac intensive care units., Local Problem: Spontaneous awakening trial completion rate at the study institution was low and no trial protocol was regularly used., Methods: A preintervention-postintervention retrospective cohort study was performed in adult patients with at least 24 hours of invasive mechanical ventilation in Michigan Medicine's cardiac intensive care unit. Patients with SARS-CoV-2 infection were excluded. Data included demographics, sedation, mechanical ventilation duration, and in-hospital mortality. A nurse-driven spontaneous awakening trial protocol modified for the cardiac intensive care unit was implemented in October 2020., Results: Compared with the preintervention cohort (n = 29, May through July 2020), the postintervention cohort (n = 27, October 2020 through February 2021) had a higher ratio of number of trials performed to number of days eligible for trial (0.91 vs 0.52; P < .01). Median continuous sedative infusion duration was shorter after intervention (2.3 vs 3.6 days; P = .02). Median mechanical ventilation duration (3.8 vs 4.7 days; P = .18) and mortality (41% vs 41%; P = .95) were similar between groups., Conclusions: Spontaneous awakening trial protocol implementation led to a higher trial completion rate and a shorter duration of continuous sedative infusion. Larger studies are needed to assess the impact of protocolized spontaneous awakening trials on cardiac intensive care unit patient outcomes., (©2022 American Association of Critical-Care Nurses.)

The use of LDT may signify significant hemodynamic changes and left ventricular remodeling in severe aortic stenosis (AS). Therefore, we sought to determine whether loop diuretic therapy (LDT) is associated with adverse outcomes following transcatheter aortic valve implantation (TAVI) in patients with severe symptomatic AS. Subjects undergoing TAVI at a single institution from June 2008 to December 2017 were analyzed. LDT doses were normalized to oral furosemide daily equivalents. All outcomes were adjudicated using VARC2 criteria. Descriptive statistics, multivariate logistic regression, and propensity score matching were used. Of the 804 subjects studied, 48.3% were on pre-TAVI LDT with a mean dose of 51.1 mg furosemide dose-equivalents. Subjects on LDT were higher risk, frail patients with more co-morbidities including chronic kidney disease, coronary artery disease requiring prior bypass grafting, peripheral arterial disease, atrial fibrillation or flutter, and diabetes with more severe heart failure symptoms. Those on LDT also had worse left ventricular systolic function, lower transvalvular gradients, and markers of adverse left ventricular remodeling, including increased left ventricular mass index and higher rates of concentric and eccentric hypertrophy. On propensity-score matching, death within one year post-TAVI was borderline significantly higher in the pre-LDT as compared with no-LDT group (16.9% vs 10.4 %, p = 0.068). In conclusion, use of pre-TAVI LDT for severe symptomatic AS is associated with a trend towards worse 1-year mortality and is a marker of high-risk, frail individuals with advanced left ventricular remodeling., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Lipid profiles help estimate patient's short- and long-term atherosclerotic cardiovascular disease risk over the life course and inform treatment decisions. Advanced lipid testing can provide additional information in selected patients. New 2018 cholesterol guidelines suggest which patients may benefit from additional testing. In patients ages 40-75 years, calculation of a 10-year atherosclerotic cardiovascular disease risk score begins the clinician-patient risk discussion. In those at intermediate risk (10-year risk 7.5%-19.9%) for future events, inclusion of enhancing factors personalizes the risk decision. The guidelines identify enhancing factors that can support initiating statin therapy. Two advanced lipid tests may be used. Apolipoprotein B levels improve risk estimations and identify genetic disorders in hypertriglyceridemic patients. In patients with a family history of premature atherosclerotic cardiovascular disease, significantly elevated lipoprotein (a) levels may reclassify risk. The decision-making cascade of estimating 10-year risk, personalizing risk status with risk-enhancing factors, and, if appropriate, reclassifying risk with a coronary artery calcium score is advanced lipid thinking that can utilize advanced lipid testing to optimize atherosclerotic cardiovascular disease prevention., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Little is known about baseline diastolic dysfunction and changes in diastolic dysfunction grade after transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS) and its impact on overall outcomes. The aim of this study was to describe baseline diastolic dysfunction and changes in diastolic dysfunction grade that occur with TAVR and their relationship to mortality and rehospitalization., Methods: This was a single-center study evaluating all TAVRs from January 2012 to June 2014. We compared parameters of diastolic dysfunction grade on pre-TAVR and 1 month post-TAVR echocardiograms for all patients undergoing the procedure. Descriptive statistics, Kaplan-Meier time-to-event analysis, and multivariate logistic regression were used., Results: Of a sample size of 120 patients undergoing TAVR for symptomatic severe AS, 90 were included in the final analysis after excluding significant mitral valve disease. There were improvements in individual parameters of diastolic dysfunction grade such as lateral e' velocity, E/lateral e', and left atrial volume index (nonsignificant trend) in the setting of improvement in aortic valve area and gradients and functional class pre- and post-TAVR. Multivariate analysis revealed that baseline diastolic dysfunction grade, but not post-TAVR or changes in diastolic dysfunction grade, was associated with 1-year death (hazard ratio, 1.163; 95% CI, 1.049-1.277, P = .005) and combined death/cardiovascular hospitalization (hazard ratio, 1.174; 95% CI, 1.032-1.318; P = .018)., Conclusions: In this single-center retrospective study of patients with symptomatic severe AS who underwent TAVR, several diastolic function parameters improved on echocardiography, but baseline diastolic dysfunction grade remained the most important echocardiographic factor associated with adverse 1-year outcomes., (Copyright © 2017 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to determine the influence of inhospital and post-discharge worsening renal function (WRF) on prognosis after transcatheter aortic valve replacement (TAVR). Severe chronic kidney disease and inhospital WRF are both associated with poor outcomes after TAVR. There are no data available on post-discharge WRF and outcomes. This was a single-center study evaluating all TAVR from June 1, 2008, to June 31, 2014. WRF was defined as an increase in serum creatinine of ≥0.3 mg/dl. Inhospital WRF was measured from day 0 until discharge or day 7 if the hospitalization was >7 days. Post-discharge WRF was measured at 30 days after discharge. Descriptive statistics, Kaplan-Meier time-to-event analysis, and multivariate logistic regression were used. In a series of 208 patients who underwent TAVR, 204 with complete renal function data were used in the inhospital analysis and 168 who returned for the 30-day follow-up were used in the post-discharge analysis. Inhospital WRF was seen in 28%, whereas post-discharge WRF in 12%. Inhospital and post-discharge WRF were associated with lower rates of survival; however, after multivariate analysis, only post-discharge WRF remained a predictor of 1-year mortality (hazard ratio 1.18, p = 0.030 for every 1 mg/dl increase in serum creatinine). In conclusion, the rate of inhospital WRF is higher than the rate of post-discharge WRF after TAVR, and post-discharge WRF is more predictive of mortality than inhospital WRF., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The influence of elevated platelet concentration and recombinant factor VIIa (rFVIIa) on thrombin generation at 5 pM tissue factor (TF) in a synthetic mixture corresponding to hemophilia B (SHB) and "acquired" hemophilia B blood (AHBB) produced in vitro by an antifactor IX antibody was evaluated. (a) Thrombin generation in SHB and AHBB was delayed and reduced; (b) with 10 nM rFVIIa or 5x normal platelets (10 x 10(8)/mL) SHB and AHBB showed a slight increase in thrombin generation; (c) in the absence of TF, almost no thrombin generation was detected in SHB and AHBB in the presence of 10 nM rFVIIa and 10 x 10(8)/mL activated platelets (5x normal); (d) with TF, 10 nM rFVIIa and 3-5x normal nonactivated platelets (6-10 x 10(8)/mL), thrombin levels approaching normal values were attained. FVIIa appears to function effectively and locally by the combined effect of TF expression and platelet accumulation at the site of a vascular lesion.

Background: Ventilator-associated pneumonia, common in critically ill patients, is associated with microaspiration of oropharyngeal secretions and may be related to suctioning and airway management practices., Objectives: To describe institutional policies and procedures related to closed-system suctioning and airway management of intubated patients, and to compare practices of registered nurses and respiratory therapists., Methods: A descriptive, comparative, multisite study of facilities that use closed-system suctioning devices on most intubated adults was conducted. Nurses and respiratory therapists who worked at the sites completed surveys related to their practices., Results: A total of 1665 nurses and respiratory therapists at 27 sites throughout the United States responded. The typical respondent had at least 6 years' experience with patients receiving mechanical ventilation (61%) and a baccalaureate degree or higher (54%). Most sites had policies for management of endotracheal tube cuffs (93%), hyperoxygenation (89%) and use of gloves (70%) with closed-system suctioning, and instillation of isotonic sodium chloride solution for thick secretions (74%). Only 48% of policies addressed oral care and 37% addressed oral suctioning. Nurses did more oral suctioning and oral care than respiratory therapists did, and respiratory therapists instilled sodium chloride solution more and rinsed the suctioning device more often than nurses did., Conclusions: Policies vary widely and do not always reflect current research. Consistent performance of practices such as wearing gloves for airway management and maintaining endotracheal cuff pressures must be evaluated. Collaborative, research-based policies and procedures must be developed and implemented to ensure best practices for intubated patients.

Background: The mechanism underlying decreased risk for myocardial infarction in carriers of the Leu34 polymorphism of the factor (F) XIII A-subunit is unclear. Given that acetylation of fibrinogen by aspirin can alter its clotting properties and the presence of fibrin stimulates thrombin-mediated activation of FXIII, we have tested the hypothesis that treatment with aspirin differentially modulates the influence of the FXIII Val34Leu polymorphism on its activation in vivo., Methods and Results: The rates of the disappearance of FXIIIA chain and the appearance of its activated form (FXIIIAa) in sequential 30-second blood samples collected at the site of microvascular injury were compared in 14 healthy carriers of the Leu34 allele and 23 Val34 homozygotes both before and after a 7-day aspirin ingestion (75 mg/d), with the use of quantitative Western blotting. The presence of the Leu34 allele was associated with a significant increase in the maximum rate of FXIII activation by thrombin. Although the Leu34-positive and -negative subjects were similar with respect to aspirin-related impairment of thrombin generation, aspirin led to a more pronounced inhibition of the activation of FXIII in the Leu34 carriers as compared with the Val34 homozygotes., Conclusions: Inhibition of FXIII activation by aspirin is enhanced in the Leu34 carriers in vivo, suggesting that these subjects might benefit more than the Leu34-negative subjects from the reduction in risk for myocardial infarction with low-dose aspirin.

The central event of the hemostatic process is the generation of thrombin through the tissue factor pathway. This is a highly regulated, dynamic process in which thrombin itself plays many roles, positively and negatively its production and destruction. The hemostatic process is essential to normal physiology and is also the Achilles heel of our aging population. The inappropriate generation of thrombin may lead to vascular occlusion with the consequence of myocardial infarction, stroke, pulmonary embolism, or venous thrombosis. In this review, we summarize our present views regarding the tissue factor pathway by which thrombin is generated and the roles played by extrinsic and intrinsic factor Xa generating complexes in hemostasis and the roles of the stoichiometric and dynamic inhibitors that regulate thrombin generation.

The sequence of coagulant reactions in vivo following vascular injury is poorly characterized. Using quantitative immunoassays, the time courses were evaluated for activation of prothrombin, factor (F)V, FXIII, fibrinogen (Fbg) cleavage, and FVa inactivation in bleeding-time blood collected at 30-second intervals from 12 healthy subjects both before and after aspirin ingestion. Prothrombin decreased at a maximum rate of 14.2 +/- 0.6 nM per second to 10% of initial values at the end of bleeding. Significant amounts of alpha-thrombin B chain appeared rapidly at 90 seconds of bleeding and increased at a maximum rate of 0.224 +/- 0.03 nM per second to a peak value of 38 nM. Kinetics of prethrombin 2 generation was almost identical. Prothrombinase concentration reached a peak value of 22 pM at 150 seconds and then decreased to 9 pM at the end of bleeding. Prothrombin fragment 1.2 (F1.2) was produced explosively (0.673 +/- 0.05 nM per second), whereas thrombin-antithrombin III (TAT) complexes were generated at a much slower rate (0.11 +/- 0.008 nM per second; P =.002). FVa light chain was detectable 30 seconds later than the heavy chain (150 seconds) and was produced at a slightly slower rate (0.027 +/- 0.001 nM per second) when compared with the heavy chain (0.032 +/- 0.002 nM per second; P =.041). The 30 000 fragment (residues 307-506) of FVa heavy chain produced by activated protein C appeared as early as at 90 seconds and increased with time. Fbg was removed from the blood shed with a high rate of 0.047 +/- 0.02 microM/s and became undetectable at approximately 180 seconds of bleeding. The velocity of FXIII activation correlated with thrombin B-chain formation. A 7-day aspirin administration (75 mg/d) resulted in significant reductions in maximum rates of (1) prothrombin removal (by 29%; P =.008); generation of alpha-thrombin B-chain (by 27.2%; P =.022), and prethrombin 2 (by 26%; P =.014); formation of F1.2 (by 31.4%; P =.009) and TAT (by 30.3%; P = 0.013); (2) release of FVa heavy chain (by 25%; P =.003) and FVa light chain (by 29.6%; P =.007); (3) Fbg depletion from solution (by 30.5%; P =.002); and (4) FXIII activation (by 28.6%; P =.003). Total amounts of the proteins studied, collected at every interval, also significantly decreased following aspirin ingestion. These results indicate that low-dose aspirin impairs thrombin generation and reactions catalyzed by this enzyme at the site of the injury.

Background: The mechanism of the antithrombotic action of statins is unclear. The aim of this study was to evaluate the effects of simvastatin on the coagulation process at sites of microvascular injury., Methods and Results: Tissue factor-initiated coagulation was assessed in blood samples collected every 30 seconds from bleeding-time wounds of 17 patients who had advanced coronary artery disease and total cholesterol levels of 224.6+/-11.8 mg/dL (mean+/-SEM). Quantitative Western blotting for time courses of fibrinogen depletion and activation of prothrombin, factor V, and factor XIII was performed before and after 3 months of simvastatin treatment (20 mg/d). Simvastatin induced reductions in total cholesterol (23%) and LDL-cholesterol (36%), which were accompanied by significant decreases in the rates of prothrombin activation (16.2+/-2.1%; P=0.004), formation of alpha-thrombin B-chain (27.4+/-1.8%; P=0.001), generation of factor Va heavy chain (29.7+/-3.1%; P=0.007) and factor Va light chain (18.9+/-1.2%; P=0.02), factor XIII activation (19.8+/-1.3%; P=0.001), and fibrinogen conversion to fibrin (72.2+/-3%; P=0.002). Posttreatment fibrinopeptides A and B concentrations, determined by using high-performance liquid chromatography, were reduced within the last 30 seconds of bleeding. The 30-kDa fragment of the factor Va heavy chain (residues 307 to 506), produced by activated protein C, and the 97-kDa fragment of the factor Va heavy chain (residues 1 to 643) were released more rapidly after simvastatin treatment. The antithrombotic actions of simvastatin showed no relationship to its cholesterol-lowering action., Conclusions: Simvastatin treatment depresses blood clotting, which leads to reduced rates of prothrombin activation, factor Va generation, fibrinogen cleavage, factor XIII activation, and an increased rate of factor Va inactivation. These effects are not related to cholesterol reduction.