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Abstract A substantial part of critically ill patients suffer from sepsis‐induced immunosuppression. Reversal of immunosuppression through PD‐1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD‐1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD‐1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7–10 days, prolonged PD‐1 inhibition may unnecessarily induce longer‐term immune‐related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD‐1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7–78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost‐effective pharmacotherapeutic intervention to treat sepsis‐induced immunosuppression.

Abstract Introduction Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour‐bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle‐specific alterations associated with human lung cancer cachexia. Methods Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour‐bearing group. Syngeneic lung epithelium‐derived adenocarcinoma cells (K‐rasG12D; p53R172HΔG) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis. Results Two‐third of the tumour‐bearing mice developed cachexia based on predefined criteria. Final body weight (−13.7 ± 5.7%; P

Abstract Aims Heart failure (HF) is an important health problem for which multidisciplinary care is recommended, yet few studies involve primary care practitioners in the multidisciplinary management of HF. We set up a multifaceted prospective observational trial, OSCAR‐HF, piloting audit and feedback, natriuretic peptide testing at the point of care, and the assistance of a specialist HF nurse in primary care. The aim was to optimize HF care in general practice. Methods and results This is an analysis at 6 month follow‐up of the study interventions of the OSCAR‐HF pilot study, a nonrandomized, noncontrolled prospective observational trial conducted in eight Belgian general practices [51 general practitioners (GPs)]. Patients who were assessed by their GP to have HF constituted the OSCAR‐HF study population. We used descriptive statistics and mixed‐effects modelling for the quantitative analysis and thematic analysis of the focus group interviews. There was a 10.2% increase in the registered HF population after 6 months of follow‐up (n = 593) compared with baseline (n = 538) and a 27% increase in objectified HF diagnoses (baseline n = 359 to 456 at T6 M). Natriuretic peptide testing (with or without referral) accounted for 54% (n = 60/111) of the newly registered HF diagnoses. There was no difference in the proportion of patients with HF with reduced ejection fraction who received their target dosage of renin‐angiotensin‐aldosterone system inhibitors or beta‐blockers at 6 months compared with baseline (P = 0.9). Patients who received an HF nurse intervention (n = 53) had significantly worse quality of life at baseline [difference in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score 9.2 points; 95% confidence interval (CI) 4.0, 14] and had a significantly greater improvement in quality‐of‐life scores at the 6 month follow‐up [change in MLHFQ score −9.8 points; 95% CI −15, −4.5] than patients without an HF nurse intervention. GPs found audit and feedback valuable but time intensive. Natriuretic peptides were useful, but the point‐of‐care test was impractical, and the assistance of an HF nurse was a useful addition to routine HF care. Conclusions The use of audit and feedback combined with natriuretic peptide testing was a successful strategy to increase the number of registered and objectified HF diagnoses at 6 months. GPs and HF nurses selected patients with worse quality‐of‐life scores at baseline for the HF nurse intervention, which led to a significantly greater improvement in quality‐of‐life scores at the 6 month follow‐up compared with patients without an HF nurse intervention. The interventions were deemed feasible and useful by the participating GPs with some specific remarks that can be used for optimization. Trial Registration: ClinicalTrials.gov (NCT02905786), registered on 14 September 2016 at https://clinicaltrials.gov/.

Abstract Background Cytochrome P450 4F3 (CYP4F3) is an ω‐hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease. We report a 26‐year‐old female with a complex immune phenotype, mainly marked by exhaustion, muscle weakness, and inflammation‐related conditions. The molecular cause is unknown, and symptoms have been aggravating over the years. Methods Whole exome sequencing was performed and validated; flow cytometry and enzyme‐linked immunosorbent assay were used to describe patient's phenotype. Function and impact of the mutation were investigated using molecular analysis: co‐immunoprecipitation, western blot, and enzyme‐linked immunosorbent assay. Capillary electrophoresis with ultraviolet detection was used to detect LTB4 and its metabolite and in silico modelling provided structural information. Results We present the first report of a patient with a heterozygous de novo missense mutation c.C1123 > G;p.L375V in CYP4F3 that severely impairs its activity by 50% (P 0.9 for both co‐immunoprecipitation with POR and Cytb5). In silico modelling of CYP4F3 in complex with POR and Cytb5 suggests that the loss of catalytic activity of the mutant CYP4F3 is explained by a disruption of an α‐helix that is crucial for the electron shuffling between the electron carriers and CYP4F3. Interestingly, zileuton still inhibits ex vivo LTB4 production in patient's whole blood to 2% of control (P

Abstract Cartilage microtissues are promising tissue modules for bottom up biofabrication of implants leading to bone defect regeneration. Hitherto, most of the protocols for the development of these cartilaginous microtissues have been carried out in static setups, however, for achieving higher scales, dynamic process needs to be investigated. In the present study, we explored the impact of suspension culture on the cartilage microtissues in a novel stirred microbioreactor system. To study the effect of the process shear stress, experiments with three different impeller velocities were carried out. Moreover, we used mathematical modeling to estimate the magnitude of shear stress on the individual microtissues during dynamic culture. Identification of appropriate mixing intensity allowed dynamic bioreactor culture of the microtissues for up to 14 days maintaining microtissue suspension. Dynamic culture did not affect microtissue viability, although lower proliferation was observed as opposed to the statically cultured ones. However, when assessing cell differentiation, gene expression values showed significant upregulation of both Indian Hedgehog (IHH) and collagen type X (COLX), well known markers of chondrogenic hypertrophy, for the dynamically cultured microtissues. Exometabolomics analysis revealed similarly distinct metabolic profiles between static and dynamic conditions. Dynamic cultured microtissues showed a higher glycolytic profile compared with the statically cultured ones while several amino acids such as proline and aspartate exhibited significant differences. Furthermore, in vivo implantations proved that microtissues cultured in dynamic conditions are functional and able to undergo endochondral ossification. Our work demonstrated a suspension differentiation process for the production of cartilaginous microtissues, revealing that shear stress resulted to an acceleration of differentiation towards hypertrophic cartilage.

Abstract Aims The diagnosis of heart failure (HF) is an important problem in primary care. We previously demonstrated a 74% increase in registered HF diagnoses in primary care electronic health records (EHRs) following an extended audit procedure. What remains unclear is the accuracy of registered HF pre‐audit and which EHR variables are most important in the extended audit strategy. This study aims to describe the diagnostic HF classification sequence at different stages, assess general practitioner (GP) HF misclassification, and test the predictive performance of an optimized audit. Methods and results This is a secondary analysis of the OSCAR‐HF study, a prospective observational trial including 51 participating GPs. OSCAR used an extended audit based on typical HF risk factors, signs, symptoms, and medications in GPs' EHR. This resulted in a list of possible HF patients, which participating GPs had to classify as HF or non‐HF. We compared registered HF diagnoses before and after GPs' assessment. For our analysis of audit performance, we used GPs' assessment of HF as primary outcome and audit queries as dichotomous predictor variables for a gradient boosted machine (GBM) decision tree algorithm and logistic regression model. Of the 18 011 patients eligible for the audit intervention, 4678 (26.0%) were identified as possible HF patients and submitted for GPs' assessment in the audit stage. There were 310 patients with registered HF before GP assessment, of whom 146 (47.1%) were judged not to have HF by their GP (over‐registration). There were 538 patients with registered HF after GP assessment, of whom 374 (69.5%) did not have registered HF before GP assessment (under‐registration). The GBM and logistic regression model had a comparable predictive performance (area under the curve of 0.70 [95% confidence interval 0.65–0.77] and 0.69 [95% confidence interval 0.64–0.75], respectively). This was not significantly impacted by reducing the set of predictor variables to the 10 most important variables identified in the GBM model (free‐text and coded cardiomyopathy, ischaemic heart disease and atrial fibrillation, digoxin, mineralocorticoid receptor antagonists, and combinations of renin‐angiotensin system inhibitors and beta‐blockers with diuretics). This optimized query set was enough to identify 86% (n = 461/538) of GPs' self‐assessed HF population with a 33% reduction (n = 1537/4678) in screening caseload. Conclusions Diagnostic coding of HF in primary care health records is inaccurate with a high degree of under‐registration and over‐registration. An optimized query set enabled identification of more than 80% of GPs' self‐assessed HF population.

Bladder urothelial cell carcinoma (UCC) incidence is about three times higher in men compared with women. There are several indications for the involvement of hormonal factors in the aetiology of UCC. Here, we provide evidence of androgen signalling in UCC progression. Microarray and qPCR analysis revealed that the androgen receptor (AR) mRNA level is upregulated in a subset of UCC cases. In an AR‐positive UCC‐derived cell line model, UM‐UC‐3‐AR, androgen treatment increased clonogenic capacity inducing the formation of big stem cell‐like holoclones, while AR knockdown or treatment with the AR antagonist enzalutamide abrogated this clonogenic advantage. Additionally, blockage of AR signalling reduced the cell migration potential of androgen‐stimulated UM‐UC‐3‐AR cells. These phenotypic changes were accompanied by a rewiring of the transcriptome with almost 300 genes being differentially regulated by androgens, some of which correlated with AR expression in UCC patients in two independent data sets. Our results demonstrate that AR signals in UCC favouring the development of an aggressive phenotype and highlights its potential as a therapeutic target for bladder cancer.

Abstract Background In vivo muscle protein synthesis rates are typically assessed by measuring the incorporation rate of stable isotope labelled amino acids in skeletal muscle tissue collected from vastus lateralis muscle. It remains to be established whether muscle protein synthesis rates in the vastus lateralis are representative of muscle protein synthesis rates of other muscle groups. We hypothesized that post‐absorptive muscle protein synthesis rates differ between vastus lateralis and rectus abdominis, pectoralis major, or temporalis muscle in vivo in humans. Methods Twenty‐four patients (62 ± 3 years, 42% female), scheduled to undergo surgery, participated in this study and underwent primed continuous intravenous infusions with l‐[ring‐13C6]‐phenylalanine. During the surgical procedures, serum samples were collected, and muscle tissue was obtained from the vastus lateralis as well as from the rectus abdominis, pectoralis major, or temporalis muscle. Fractional mixed muscle protein synthesis rates (%/h) were assessed by measuring the incorporation of l‐[ring‐13C6]‐phenylalanine into muscle tissue protein. Results Serum l‐[ring‐13C6]‐phenylalanine enrichments did not change throughout the infusion period. Post‐absorptive muscle protein synthesis rates calculated based upon serum l‐[ring‐13C6]‐phenylalanine enrichments did not differ between vastus lateralis and rectus abdominis (0.032 ± 0.004 vs. 0.038 ± 0.003%/h), vastus lateralis and pectoralis major, (0.025 ± 0.003 vs. 0.022 ± 0.005%/h) or vastus lateralis and temporalis (0.047 ± 0.005 vs. 0.043 ± 0.005%/h) muscle, respectively (P > 0.05). When fractional muscle protein synthesis rates were calculated based upon tissue‐free l‐[ring‐13C6]‐phenylalanine enrichments as the preferred precursor pool, muscle protein synthesis rates were significantly higher in rectus abdominis (0.089 ± 0.008%/h) compared with vastus lateralis (0.054 ± 0.005%/h) muscle (P

Abstract Multidisciplinary disease management programmes (DMPs) are a cornerstone of modern guideline‐recommended care for heart failure (HF). Few programmes are community initiated or involve primary care professionals, despite the importance of home‐based care for HF. We compared the outcomes of different multidisciplinary HF DMPs in relation to their recruitment setting and involvement of primary care health professionals. We conducted a systematic review and meta‐analysis of randomized controlled trials published in MEDLINE, Embase, and Cochrane between 2000 and 2020 using Cochrane Collaboration methodology. Our meta‐analysis included 19 randomized controlled trials (7577 patients), classified according to recruitment setting and involvement of primary care professionals. Thirteen studies recruited in the hospital (n = 5243 patients) and six in the community (n = 2334 patients). Only six studies involved primary care professionals (n = 3427 patients), with two of these recruited in the community (n = 225 patients). Multidisciplinary HF DMPs that recruited in the community had no significant effect on all‐cause and HF readmissions nor on mortality, irrespective of primary care involvement. Studies that recruited in the hospital demonstrated a significant reduction in mortality (relative risk 0.87, 95% confidence interval [CI] [0.76, 0.98]), HF readmissions (0.70, 95% CI [0.54, 0.89]), and all‐cause readmissions (0.72, 95% CI [0.60, 0.87]). However, the difference in effect size between recruitment setting and involvement of primary care was not significant in a meta‐regression analysis. Multidisciplinary HF DMPs that recruit in the community have no significant effect on mortality or hospital readmissions, unlike DMPs that recruit in the hospital, although the difference in effect size was not significant in a meta‐regression analysis. Only six multidisciplinary studies involved primary care professionals. Given demographic evolutions and the importance of integrated home‐based care for patients with HF, future multidisciplinary HF DMPs should consider integrating primary care professionals and evaluating the effectiveness of this model.

Abstract This review paper describes fault current interruption principles and various high‐voltage direct currrent (HVDC) circuit breaker technologies. First, fundamentals of HVDC fault current interruption and a generic set of requirements of HVDC circuit breakers are presented. The critical parameters during fault current interruption are assessed using a simplified mathematical model. Then, the state‐of‐the‐art of HVDC circuit breaker technologies and their application in actual HVDC multi‐terminal projects is highlighted. Several sub‐components of HVDC circuit breakers are standard components used in a non‐standard application and, hence, have to face non‐standard stresses. All of today's HVDC circuit breaker technologies consist of mechanical switching devices and metal‐oxide surge arresters, which are used in an unconventional way. A critical analysis of these stresses compared to the stresses in a conventional application is provided. Recommendations on testing supported with examples of actual full‐power ‘complete’ demonstration of HVDC circuit breakers up to 350 kV/20 kA are discussed. Finally, the actual status of standardisation activities is presented.

Abstract Aims Identifying heart failure (HF) patients in general practice is challenging, and little is known about the current quality of care. We implemented an extended audit from the electronic health records (EHRs) of general practitioners (GPs) to identify HF patients and investigate patient characteristics and quality of care. Methods and results This study describes the baseline results of the OSCAR‐HF pilot study in eight general practices (51 GPs) in Flanders, Belgium. This prospective trial ran for 6 months. Interventions included an extended audit, an N‐terminal pro‐B‐type natriuretic peptide point‐of‐care test, and assistance of a specialist HF nurse. The extended audit searched on risk factors for HF, HF symptoms, signs, and medication in the GPs' EHR to generate a list of possible HF patients. GPs determined which patients had HF. Those HF patients constituted the OSCAR‐HF study population. Each patient file was manually revised to extract biomarker measurements, echocardiography data, and quality indicators. An independent panel of experts assessed the validity of GPs' HF diagnoses. Feedback about the validity of the HF diagnosis was given to the GP. Out of 18 011 patients ≥ 40 years, we identified 310 patients with a registered HF diagnosis before the study start (HF prevalence: 1.7%). The extended audit led to a 74% increase in identified HF patients (n = 538, HF prevalence: 3.0%) with a mean age of 79 ± 11 years. The prevalence of HF with reduced ejection fraction (HFrEF) was 20% (n = 110). A high proportion of patients underwent echocardiography in the past 5 years (86%, n = 462). Natriuretic peptides were rarely available in patients' files (19%, n = 100). Medical specialists should improve communication about the HF diagnosis because a specialist diagnosis was present in only 225 patients (42%) while 67% (n = 359) of the HF diagnoses were judged objectified by a panel of experts. Assigning a diagnosis of HF was particularly difficult in HF patients with preserved EF (HFpEF). HFrEF treatment rates with renin–angiotensin–aldosterone system blockers (84%, n = 92) and beta‐blockers (86%, n = 94) were very good; however, target doses were hardly reached (34% and 14%, respectively). Conclusions This study highlighted the need to improve case finding for HF in general practice and showed that an extended audit in the GPs' EHR was a successful strategy to do so. To improve the quality of HF care in general practice, specific strategies are needed to diagnose HFpEF and to reach target doses of disease‐modifying drugs in HFrEF patients.

Background. Regarding sustainability in the intensive care unit (ICU), there is increasing interest in reducing material waste and avoiding unnecessary procedures. Therapeutic drug monitoring (TDM) of vancomycin, using a dedicated tube, is standard clinical care during treatment with vancomycin. Furthermore, in the ICU, on a daily basis, arterial blood gas (ABG) tests are frequently performed throughout the day. After analysis, a variable volume of blood is discarded. Lithium heparin (LiHep) syringes for ABG tests differ from normally used dipotassium ethylenediaminetetraacetic acid (K2EDTA) tubes. The primary objective was to compare both containers and validate the use of LiHep syringes. Secondary objectives were to evaluate the potential impact on saving materials, nursing time, and costs when implementing vancomycin TDM via LiHep syringes. Methods. Vancomycin analysis from sampling in lithium heparin (LiHep) syringes for ABG tests was validated and compared with the concentrations from conventional sampling in K2EDTA tubes. For method comparison, a Bland–Altman plot and Deming regression analysis were performed. The method was validated for inter- and intra-day precision and accuracy. Vancomycin was analyzed by means of the validated method using a particle-enhanced turbidimetric inhibition immunoassay (PETINIA) autoanalyzer. Furthermore, an analysis was conducted to evaluate the potential impact of implementing vancomycin sampling via ABG tests on savings in materials, nursing time, and costs. Results. From 18 patients, 24 plasma samples in both K2EDTA tubes and LiHep syringes were obtained and compared. The mean relative difference between the two containers was −2.0% (−3.0 to −0.93%). Both the Deming regression analysis and the Bland–Altman plot met the acceptance criteria. Potentially, over 1000 blood draws and accompanying materials and packaging can be saved when vancomycin samples are obtained by means of scavenged LiHep syringes. The vancomycin analysis for LiHep syringes showed a total interday precision of 1.95% and an accuracy of 99.7%. The total intraday precision was 2.22%, and the accuracy was 99.2%. Accuracy and precision values were within the acceptance criteria of recovery 85 to 115% and ≤15%, respectively. Conclusion. No significant differences were found in vancomycin concentration between the two analyses, and the LiHep analysis was validated for further implementation in clinical care. Residual blood from ABG test samples can be used for TDM of vancomycin, resulting in a potential reduction of materials used and the number of blood draws. These results will contribute to a more sustainable TDM process with benefits for the patient.

Abstract Purpose It is usually assumed that the severity of varus osteoarthritis (OA) of the knee is correlated with the axis deviation of the limb. Despite this, there is currently no clear radiographic definition to define a so‐called ‘high degree’ varus knee, which is characterized by a pronounced lateral ligamentous laxity. The purpose of this study was to radiographically determine if the lateral joint line opening (LJLO) is an indicative parameter when defining so‐called high grade varus knees. Methods Two hundred forty Full length radiographs of patients with end‐stage varus osteoarthritis who were scheduled for Total knee arthroplasty (TKA) were evaluated. The Hip‐knee‐ankle‐angle (HKA‐angle), Joint‐line‐convergence‐angle (JLCA) and the lateral joint line opening were measured. The lateral joint line opening is the shortest distance between the lateral tibial plateau and the deepest point of the lateral femoral condyle. Linear regression models were used to investigate the relationships between the radiographic measurements. Results Hip‐knee‐angle‐angle, joint‐line‐conversion‐angle, and lateral joint line opening were all positively correlated (p

Abstract Focal eosinophilic infiltration (FEI) of the liver shares imaging characteristics with malignant hepatic lesions but should be suspected when concomitantly observing eosinophilia. While in itself benign, the cause of FEI should be sought and treated.

Abstract Background Living tissues maintain a fine balance between protein synthesis and protein breakdown rates. Animal studies indicate that protein synthesis rates are higher in organs when compared with skeletal muscle tissue. As such, organ and tumour protein synthesis could have major effects on whole‐body protein metabolism in wasting disorders such as cancer cachexia. We aimed to assess protein synthesis rates in pancreatic tumour tissue and healthy pancreas, liver, and skeletal muscle tissue in vivo in humans. Methods In eight patients with pancreatic cancer undergoing pancreaticoduodenectomy, primed continuous infusions with L‐[ring‐13C6]phenylalanine and L‐[3,5‐2H2]tyrosine were started prior to surgery and continued throughout the surgical procedures. During surgery, plasma samples and biopsies from the pancreas, pancreatic tumour, liver, and vastus lateralis muscle were taken. Post‐absorptive fractional protein synthesis rates were determined by measuring incorporation of labelled L‐[ring‐13C6]phenylalanine in tissue protein using the weighed plasma L‐[ring‐13C6]phenylalanine enrichments as the precursor pool. Results Five male patients and three female patients with a mean age of 67 ± 2 years were included into this study. Plasma L‐[ring‐13C6]phenylalanine enrichments (6–9 mole per cent excess) did not change during surgery (P = 0.60). Pancreatic tumour protein synthesis rates were 2.6‐fold lower than surrounding pancreatic tissue protein synthesis rates (0.268 ± 0.053 vs. 0.694 ± 0.228%/h, respectively; P = 0.028) and 1.7‐fold lower than liver protein synthesis rates (0.268 ± 0.053 vs. 0.448 ± 0.043%/h, respectively; P = 0.046). Among healthy organ samples, protein synthesis rates were 20‐fold and 13‐fold higher in pancreas and liver, respectively, compared with skeletal muscle tissue (0.694 ± 0.228 and 0.448 ± 0.043 vs. 0.035 ± 0.005%/h, respectively; P

Background In cardiac arrest, computerized analysis of the ventricular fibrillation (VF) waveform provides prognostic information, while its diagnostic potential is subject of study. Animal studies suggest that VF morphology is affected by prior myocardial infarction (MI), and even more by acute MI. This experimental in‐human study reports on the discriminative value of VF waveform analysis to identify a prior MI. Outcomes may provide support for in‐field studies on acute MI. Methods and Results We conducted a prospective registry of implantable cardioverter defibrillator recipients with defibrillation testing (2010–2014). From 12‐lead surface ECG VF recordings, we calculated 10 VF waveform characteristics. First, we studied detection of prior MI with lead II, using one key VF characteristic (amplitude spectrum area [AMSA]). Subsequently, we constructed diagnostic machine learning models: model A, lead II, all VF characteristics; model B, 12‐lead, AMSA only; and model C, 12‐lead, all VF characteristics. Prior MI was present in 58% (119/206) of patients. The approach using the AMSA of lead II demonstrated a C‐statistic of 0.61 (95% CI, 0.54–0.68). Model A performance was not significantly better: 0.66 (95% CI, 0.59–0.73), P=0.09 versus AMSA lead II. Model B yielded a higher C‐statistic: 0.75 (95% CI, 0.68–0.81), P

Abstract Objectives Aging is associated with altered immune function and chronic low‐grade inflammation, referred to as immunosenescence. As breast cancer is an age‐related disease, the impact of aging on tumor immune responses may have important consequences. However, effects of immunosenescence on breast tumor immune infiltration remain largely unknown. Methods This exploratory study investigated a broad panel of immune/senescence markers in peripheral blood and in the tumor microenvironment of young, middle‐aged and old patients diagnosed with early invasive luminal (hormone‐sensitive, HER2‐negative) breast cancer. In the old group, G8‐scores were computed as a correlate for clinical frailty. Results Significant age‐related changes in plasma levels of several inflammatory mediators (IL‐1α, IP‐10, IL‐8, MCP‐1, CRP), immune checkpoint markers (Gal‐9, sCD25, TIM‐3, PD‐L1), IGF‐1 and circulating miRs (miR‐18a, miR‐19b, miR‐20, miR‐155, miR‐195 and miR‐326) were observed. Shifts were observed in distinct peripheral blood mononuclear cell populations, particularly naive CD8+ T‐cells. At the tumor level, aging was associated with lower total lymphocytic infiltration, together with decreased abundance of several immune cell markers, especially CD8. The relative fractions of cell subsets in the immune infiltrate were also altered. Clinical frailty was associated with higher frequencies of exhausted/senescent (CD27−CD28− and/or CD57+) terminally differentiated CD8+ cells in the blood and with increased tumor infiltration by FOXP3+ cells. Conclusion Aging and frailty are associated with profound changes of the blood and tumor immune profile in luminal breast cancer, pointing to a different interplay between tumor cells, immune cells and inflammatory mediators at higher age.