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Different immunohistochemical programmed death-ligand 1 (PD-L1) assays and scorings have been reported to yield variable results in triple-negative breast cancer (TNBC). We compared the analytical concordance and reproducibility of four clinically relevant PD-L1 assays assessing immune cell (IC) score, tumor proportion score (TPS), and combined positive score (CPS) in TNBC. Primary TNBC resection specimens (n = 104) were stained for PD-L1 using VENTANA SP142, VENTANA SP263, DAKO 22C3, and DAKO 28–8. PD-L1 expression was scored according to guidelines on virtual whole slide images by four trained readers. The mean PD-L1 positivity at IC-score ≥1% and CPS ≥1 ranged between 53% and 75% with the highest positivity for SP263 and comparable levels for 22C3, 28–8, and SP142. Inter-assay agreement was good between 28–8 and 22C3 across all scores and cut-offs (kappa 0.68–0.74) and for both assays with SP142 at IC-score ≥1% and CPS ≥1 (kappa 0.61–0.67). The agreement between SP263 and all other assays was substantially lower for all scores. Inter-reader agreement for each assay was good to excellent for IC-score ≥1% (kappa 0.73–0.78) and CPS ≥1 (kappa 0.68–0.74), fair to good for CPS ≥10 (kappa 0.52–0.67) and TPS ≥1% (kappa 0.53–0.72). The percentage of overlapping cases in the positive/negative category was >90% between IC-score ≥1% and CPS ≥1 but below when comparing IC-score ≥1% with CPS ≥10. We demonstrate an overall good inter-reader agreement for all PD-L1 assays in TNBC along with assay specific differences in positivity and concordances, which may aid to select the right test strategy in routine diagnostics., Highlights • Different PD-L1 IHC assays and scorings may show variable results in TNBC. • Overall good assay concordance between SP142, 22C3, and 28–8 at IC-score 1%. • Overall good assay concordance between SP142, 22C3, and 28–8 at CPS 1. • SP142 is less optimal for CPS assessment at higher cut-offs. • SP263 assay is not interchangeable with the other three PD-L1 assays.

Objectives The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs). Background The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined. Methods Patients (n = 4,012) were categorized into 3 groups: low eGFR ( Results Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted HR: 1.89; 95% CI: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding. Conclusions These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800 )

Background Lung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema. Methods We studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms. Results When relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees. Conclusions Selected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited. Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-021-01837-2.

BACKGROUND: Drug-coated balloons (DCB) and drug-eluting stents (DES) represent the currently recommended treatments for in-stent restenosis (ISR). Optical coherence tomography (OCT) allows detailed neointimal characterisation which can guide treatment strategies. AIMS: The aims of this study were first, to assess the relation between neointimal pattern and clinical outcomes following in-stent restenosis (ISR) treatment, and second, to explore a potential interaction between neointimal pattern and treatment modality relative to clinical outcomes. METHODS: Patients undergoing OCT-guided treatment (DCB or DES) of ISR in three European centres were included. Based on the median of distribution of non-homogeneous neointima quadrants, patients were categorised into low and high inhomogeneity groups. RESULTS: A total of 197 patients (low inhomogeneity=100 and high inhomogeneity=97) were included. There were no significant differences in terms of major adverse cardiac events (MACE) (p=0.939) or target lesion revascularisation (TLR) (p=0.732) between the two groups. The exploratory analysis showed a significant interaction between neointimal pattern and treatment modality regarding MACE (pint=0.006) and TLR (pint=0.022). DES showed a significant advantage over DCB in the high (MACE: HR 0.26 [0.10-0.65], p=0.004; TLR: HR 0.28 [0.11-0.69], p=0.006), but not in the low inhomogeneity group (MACE: p=0.917; TLR: p=0.797). CONCLUSIONS: In patients with ISR treated with DCB or DES, there were no significant differences in terms of MACE or TLR between the low and high inhomogeneity groups. A significant interaction was observed between treatment modality and neointimal pattern with an advantage of DES over DCB in the high and no difference in the low inhomogeneity group. This warrants confirmation from prospective dedicated studies.

Background: Data on the comparative efficacy and safety of ticagrelor versus prasugrel in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention are limited. We assessed the efficacy and safety of ticagrelor versus prasugrel in a head-to-head comparison in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention. Methods: In this prespecified subgroup analysis, we included 1653 patients with ST-segment–elevation myocardial infarction randomized to receive ticagrelor or prasugrel in the setting of the ISAR REACT-5 trial (Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5). The primary end point was the incidence of death, myocardial infarction, or stroke at 1 year after randomization. The secondary end point was the incidence of bleeding defined as BARC (Bleeding Academic Research Consortium) type 3 to 5 bleeding at 1 year after randomization. Results: The primary end point occurred in 83 patients (10.1%) in the ticagrelor group and in 64 patients (7.9%) in the prasugrel group (hazard ratio, 1.31 [95% CI, 0.95–1.82]; P =0.10). One-year incidence of all-cause death (4.9% versus 4.7%; P =0.83), stroke (1.3% versus 1.0%; P =0.46), and definite stent thrombosis (1.8% versus 1.0%; P =0.15) did not differ significantly in patients assigned to ticagrelor or prasugrel. One-year incidence of myocardial infarction (5.3% versus 2.8%; hazard ratio, 1.95 [95% CI, 1.18–3.23]; P =0.010) was higher with ticagrelor than with prasugrel. BARC type 3 to 5 bleeding occurred in 46 patients (6.1%) in the ticagrelor group and in 39 patients (5.1%) in the prasugrel group (hazard ratio, 1.22 [95% CI, 0.80–1.87]; P =0.36). Conclusions: In patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention, there was no significant difference in the primary end point between prasugrel and ticagrelor. Ticagrelor was associated with a significant increase in the risk for recurrent myocardial infarction. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01944800.

Background Current guidelines recommend intensified platelet inhibition by prasugrel or ticagrelor in patients with unstable angina (UA) or non-ST-segment elevation (NSTE) myocardial infarction (MI). Objectives This study sought to investigate the benefits and risks of ticagrelor as compared with prasugrel in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and planned invasive management. Methods This post hoc analysis combines the pre-specified subgroups of UA and NSTEMI of the randomized ISAR-REACT 5 trial. It included 1,179 patients assigned to ticagrelor and 1,186 assigned to prasugrel. Ticagrelor was started immediately after randomization and prasugrel after coronary angiography. The primary endpoint was a composite of death, MI, or stroke during 1-year follow-up, and the safety endpoint was Bleeding Academic Research Consortium class 3–5. Results The primary endpoint was reached in 101 (8.7%) patients in the ticagrelor and in 73 (6.3%) patients in the prasugrel group (hazard ratio [HR]: 1.41; 95% confidence interval [CI]: 1.04 to 1.90). The HR for all-cause death was 1.43 (95% CI: 0.93 to 2.21) and that for MI 1.43 (95% CI: 0.94 to 2.19). The safety endpoint occurred in 49 (5.2%) patients in the ticagrelor and in 41 (4.7%) patients in the prasugrel group (HR: 1.09; 95% CI: 0.72 to 1.65). Landmark analysis revealed persistence of the efficacy advantage with prasugrel after the first month. Conclusions In patients with NSTE-ACS, we found that prasugrel was superior to ticagrelor in reducing the combined 1-year risk of death, MI, and stroke without increasing the risk of bleeding. Due to the post hoc nature of the analysis, these findings need confirmation by further studies. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome; NCT01944800 )

Objectives The aim of this study was to assess the efficacy and safety of ticagrelor versus prasugrel in patients with diabetes mellitus (DM) presenting with acute coronary syndromes (ACS)...

Objectives The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their glomerular filtration rate (GFR). Background The outcomes of ticagrelor versus prasugrel in patients with ACS according to GFR have not been defined. Methods Patients (n=3985) with GFR available were categorized in three groups according to the tertiles of GFR. The primary endpoint was a composite of all-cause death, myocardial infarction and stroke at 1 year. Results The primary endpoint occurred significantly more often in patients with low GFR compared to high GFR as well as in patients with low GFR compared to intermediate GFR (picture 1). Patients in the lowest GFR group had significantly higher ischemic and bleeding risks than patients in the intermediate (hazard ratio [HR] 1.93 and 1.68) or high GFR groups (HR 3.52 and 2.96). In the group with low GFR, the primary endpoint occurred in 103 of 677 ticagrelor patients (15.4%) and in 72 of 652 prasugrel patients (11.2%; (HR=1.45, [1.07–1.96], p=.016, picture 2). In addition, each single component of the primary endpoint and stent thrombosis were numerically lower with prasugrel compared with ticagrelor. Occurrence of myocardial infarction was 3.7% with prasugrel compared to 6.6% with ticagrelor (p=0.019). BARC 3–5 bleeding events were similar with ticagrelor and prasugrel (8.8% versus 7.1%, p=0.278). In the intermediate and high GFR group the primary endpoint and bleeding events were similar between prasugrel and ticagrelor. Conclusions The incidence of a composite endpoint (all-cause death, myocardial infarction or stroke) occurred less frequently in patients who received prasugrel compared to patients who received ticagrelor in the low GFR population, whereas rate of bleeding events was similar. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Supported by a grant (FKZ 81X1600501) from the German Center for Cardiovascular Research and the Deutsches Herzzentrum München, Germany. Primary endpoint according to GFRLow GFR: Prasugrel versus Ticagrelor

Background: Complementary and alternative medicine (CAM) use is common among cancer patients. Data indicated that CAM use correlates with younger age, higher education levels, higher income, and less physician consultations. However, non-CAM use and predictors for non-CAM use are less clear among breast and gynecological cancer patients. Objectives: The purpose of this study was to determine the prevalence of non-CAM use and to investigate factors that might influence non-CAM use. Methods: The survey was conducted in breast cancer patients from January to May 2013 and in gynecological cancer patients from January to May 2014 with 2 pseudoanonymous questionnaires: one for CAM users (109 questions) and one for non-CAM users (85 questions). The survey was conducted via a telephone interview with 333 patients. Eligible participants were women with breast cancer (n = 285) and gynecological cancer (n = 291) who had undergone surgery at the Department of Gynecology and Obstetrics at the Technical University Munich, Germany, in the years 2012 (breast cancer) and 2011–2013 (gynecological cancer). Descriptive statistics were generated to determine patterns of non-CAM use. Univariable analysis was used to detect patient characteristics associated with noninterest in the different CAM therapies. Results: A total of 333 of 576 patients participated in the survey (58%). Fifty-eight percent (n = 192/333) were diagnosed with breast cancer and 42% (n = 141/333) with gynecological cancer. The overall prevalence of non-CAM use was 42% (n = 139/333). Eighty-one percent (n = 112/139) of the non-CAM users stated to have received no recommendation for CAM use, although 53% (n = 73/139) would have liked to receive information from their physician. As reasons for the nonuse of CAM therapies, 76% (n = 106/139) nonusers declared that they did not believe CAM use was necessary since the conventional therapy was considered sufficient, 44% (n = 61/139) reported a lack of information, 31% (n = 43/139) a fear of fraud, and 22% (n = 31/139) a fear of interactions and side effects of CAM. Sixty-eight percent (n = 95/139) of the patients stated that they would resort to CAM if the disease progressed while only 27% (n = 37/139) would still not use any CAM with progression of disease. Five percent (7/139) did not give any information regarding possible future CAM use with disease progression. Seventy-three percent (n = 102/139) would both welcome more physicians with qualifications in complementary medicine and supported an integration of CAM into our health care system. Furthermore, statistically significant correlations between patients’ sociodemographic characteristics and their nonuse of complementary therapies were identified. Conclusions: Our data demonstrate a high overall interest in CAM even in non-CAM users. Health care professionals should be aware of this in order to be able to better address patients’ needs. It is necessary to explore the use of CAM with cancer patients, educate them about potentially beneficial therapies even in the light of the limited available evidence, and work towards an integrated model of health care. Therefore, we implemented a counseling service as an outpatient program (ZIGG) for integrative medicine concepts and evidence-based complementary treatments to discuss integrative health approaches proactively with cancer patients in our cancer center in 2013.

Background The relative merits of ticagrelor as compared with prasugrel in patients with acute coronary syndromes for whom invasive evaluation is planned are uncertain. Methods In this mul...

Objectives The purpose of the study was to investigate the impact of oral anticoagulation (OAC) type on clinical outcomes 1 year after transcatheter aortic valve replacement (TAVR). Background Non–vitamin K oral anticoagulants (NOACs) are superior to vitamin K antagonists (VKAs) in nonvalvular atrial fibrillation (AF), while their comparative performance among patients in need of OAC undergoing TAVR is underinvestigated. Methods The study enrolled 962 consecutive patients who underwent TAVR in 4 tertiary European centers and were discharged on either NOACs (n = 326) or VKAs (n = 636). By using propensity scores for inverse probability of treatment weighting (IPTW), the comparison of treatment groups was adjusted to correct for potential confounding. Results Mean age and Society of Thoracic Surgeons score of the population were 81.3 ± 6.3 years and 4.5% (interquartile range: 3.0% to 7.3%); 52.5% were women and a balloon-expandable valve was used in 62.7% of cases. The primary outcome of interest, combined incidence of all-cause mortality, myocardial infarction, and any cerebrovascular event at 1-year after TAVR, was 21.2% with NOACs versus 15.0% with VKAs (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.00 to 2.07; p = 0.050, IPTW-adjusted). The 1-year incidence of any Bleeding Academic Research Consortium bleeds and all-cause mortality were comparable between the NOAC and VKA groups, 33.9% versus 34.1% (HR: 0.97; 95% CI: 0.74 to 1.26; p = 0.838, IPTW-adjusted) and 16.5% versus 12.2% (HR: 1.36; 95% CI: 0.90 to 2.06; p = 0.136, IPTW-adjusted), respectively. Conclusions Chronic use of both NOACs and VKAs among patients in need of OAC after TAVR are comparable regarding 1-year bleeding risk. The higher ischemic event rate observed with NOACs needs to be evaluated in large randomized trials.

BACKGROUND AND AIM In contrast to the first peak of multi-organ failure in acute pancreatitis, the second peak is mostly triggered by septic complications. Our aim was to analyze the spectrum of pathogens and antimicrobial resistance development in relation to the time-course of the disease and its clinical outcome. METHODS One hundred twenty-two patients with acute necrotizing pancreatitis undergoing pancreas puncture at two tertiary academic medical centers in Germany were retrospectively analyzed. RESULTS At species level, there was a change in spectrum from Enterococcus faecalis (∆d150 - d1 = 14.6% - 16.7% = -2.1%) to Enterococcus faecium (∆d150 - d1 = 93.1% - 16.3% = 76.8%) (P

Background and study aims Acute pancreatitis (AP) is one of the most common gastrointestinal disorders leading to hospitalization and the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP). Besides pharmaco-prophylaxis, pancreatic stenting has been demonstrated to protect from post-ERCP pancreatitis (PEP). However, it remains unclear which patients benefit from pancreatic stenting. We therefore hypothesized that in an unselected population, inadvertent cannulation of the pancreatic duct during first-time ERCP increases risk of PEP and that this risk can be significantly reduced by pancreatic stenting. Patients and methods This study was a multicenter, prospective, randomized controlled trial conducted at four European centers. A total of 167 patients undergoing first-time ERCP were enrolled in this trial. In the case of inadvertent cannulation of the pancreatic duct, patients were randomly assigned to receive either a 5 French plastic pancreatic stent of various length or no routine prophylactic intervention for PEP. Results A total of 167 patients were included in the final analysis. Prophylactic stent insertion significantly reduced the rate of PEP during first-time ERCP (odds ratio 0.43; 95% confidence interval 0.19 – 0.98; P = 0.04). The number needed to treat to prevent one case of PEP by prophylactic stent insertion after inadvertent cannulation of the pancreatic duct was 8.1 for the intention-to-treat population. Conclusion In an unselected patient population, inadvertent cannulation of the pancreatic duct during first-time ERCP is associated with a high risk for PEP. This risk can be significantly reduced by prophylactic pancreatic stenting, which is a safe and feasible procedure.

Background: The EndoPredict test is a clinico-molecular test that has been validated to predict the likelihood of distant metastases and late relapse inpatients (pts) with hormone receptor positive (HR+), HER2-negative (HER2-) early breast cancer and up to three positive lymph nodes. However, so far prospective outcome results of pts in whom decision on use of adjuvant chemotherapy (CTX) was based on Endopredict has not been available. Here we present three year outcome data of pts, whose adjuvant systemic therapy recommendation was based on EndoPredict test result. Methods: Pts with HR+, HER2- early breast cancer with 0-3 positive lymph nodes were enrolled at a single institution (Interdisciplinary Breast Center of Klinikum rechts der Isar, Munich, Germany). The Endopredict test was carried out on all tumor samples. Demographic, clinical and pathological data as well as EPclin risk class were assessed for each patient at baseline. Therapy recommendations were given during an interdisciplinary tumor board. Pts were evaluated for treatment compliance, local recurrence, distant metastases and survival (cut-off date of last follow up: July 31st 2017). Censored time-to-event outcomes were analysed by cox proportional hazards models. Additional estimates of the event-free-survival were given by the Kaplan-Meier method. Hypothesis testing was conducted on two-sided exploratory 5% significance levels. Results: A total of 373 consecutive pts were enrolled between March 2012 and March 2015. Median age was 59.9 (range: 29.1-88.9) years. In 39% of pts tumorsize was >2cm, 24% of pts were node positive, 16% had G3 tumors, in 21% of pts ki67 was ≥25% and in 13% progesterone receptor was Conclusion: These first prospective outcome results show, that EPclin in clinical routine is a valid clinico-molecular marker to predict DFS and guide decision of adjuvant CTX use in HR+, HER2- early breast cancer pts with 0-3 positive lymph nodes. Citation Format: Ettl J, Anders S, Hapfelmeier A, Noske A, Paepke S, Weichert W, Klein E, Kiechle M. First prospective outcome data for the clinico-molecular test Endopredict® in hormone receptor positive, HER2-negative early breast cancer in clinical routine [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-11.

Background The Cancer Genome Atlas (TCGA) consortium described EBV positivity(+), high microsatellite instability (MSI-H), genomic stability (GS) and chromosomal instability (CIN) as molecular subtypes in gastric carcinomas (GC). We investigated the predictive and prognostic value of these subtypes with emphasis on CIN in the context of neoadjuvant chemotherapy (CTx) in GC. Methods TCGA subgroups were determined for 612 resected adenocarcinomas of the stomach and gastro-oesophageal junction (291 without, 321 with CTx) and 143 biopsies before CTx. EBV and MSI-H were analysed by standard assays. CIN was detected by multiplex PCRs analysing 22 microsatellite markers. Besides the TCGA classification, CIN was divided into four CIN-subgroups: low, moderate, substantial, high. Mutation profiling was performed for 52 tumours by next-generation sequencing. Results EBV(+) (HR, 0.48; 95% CI, 0.23–1.02), MSI-H (HR, 0.56; 95% CI, 0.35–0.89) and GS (HR, 0.72; 95% CI, 0.45–1.13) were associated with increased survival compared to CIN in the resected tumours. Considering the extended CIN-classification, CIN-substantial was a negative prognostic factor in uni- and multivariable analysis in resected tumours with CTx (each p p = 0.026), but was not prognostically relevant. Conclusion A refined CIN classification reveals tumours with different biological characteristics and potential clinical implications.

Importance It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). Objective To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI. Design, Setting, and Participants A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle. Interventions Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization. Main Outcomes and Measures The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding. Results The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78;P = .005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34;P = .003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50;P = .54). Conclusions and Relevance Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings. Trial Registration ClinicalTrials.gov Identifier:NCT01944800

Background Risk factors of severe COVID-19 have mainly been investigated in the hospital setting. We investigated pre-defined risk factors for testing positive for SARS-CoV-2 infection and cardiovascular or pulmonary complications in the outpatient setting. Methods The present cohort study makes use of ambulatory claims data of statutory health insurance physicians in Bavaria, Germany, with polymerase chain reaction (PCR) test confirmed or excluded SARS-CoV-2 infection in first three quarters of 2020. Statistical modelling and machine learning were used for effect estimation and for hypothesis testing of risk factors, and for prognostic modelling of cardiovascular or pulmonary complications. Results A cohort of 99 811 participants with PCR test was identified. In a fully adjusted multivariable regression model, dementia (odds ratio (OR) = 1.36), type 2 diabetes (OR = 1.14) and obesity (OR = 1.08) were identified as significantly associated with a positive PCR test result. Significant risk factors for cardiovascular or pulmonary complications were coronary heart disease (CHD) (OR = 2.58), hypertension (OR = 1.65), tobacco consumption (OR = 1.56), chronic obstructive pulmonary disease (COPD) (OR = 1.53), previous pneumonia (OR = 1.53), chronic kidney disease (CKD) (OR = 1.25) and type 2 diabetes (OR = 1.23). Three simple decision rules derived from prognostic modelling based on age, hypertension, CKD, COPD and CHD were able to identify high risk patients with a sensitivity of 74.8% and a specificity of 80.0%. Conclusions The decision rules achieved a high prognostic accuracy non-inferior to complex machine learning methods. They might help to identify patients at risk, who should receive special attention and intensified protection in ambulatory care.

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2+) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells. We hypothesized that the chemokine CX3CL1 could improve both processes, as it is synthesized as a membrane-bound, adhesive form that is eventually cleaved into a soluble, chemotactic protein. Here, we show that CX3CL1 overexpression is a positive prognostic marker in breast cancer. CX3CL1 overexpression attracted tumor-suppressive lymphocytes, including NK cells, and inhibited tumor growth and lung metastasis in the syngeneic 4T1 breast cancer mouse model. In HER2+ SKBR3, MDA-MB-453, and HT-29 tumor cells, CX3CL1 overexpression increased NK cell–mediated cytotoxicity in vitro and acted synergistically with trastuzumab. Even though CX3CL1 did not further improve trastuzumab efficacy in vivo in the trastuzumab-sensitive MDA-MB-453 model, it compensated for NK-cell depletion and prolonged survival. In the HER2 low–expressing HT-29 model, however, CX3CL1 overexpression not only prolonged survival time but also overcame trastuzumab resistance in a partly NK cell–dependent manner. Taken together, these findings identify CX3CL1 as a feasible pharmacologic target to enable trastuzumab therapy in HER2 low–expressing cancers and render it a potential predictive biomarker to determine therapy responders.

IntroductionThe measurement of fractional exhaled nitric oxide (FeNO) is promising for diagnosing asthma and might substitute for bronchial provocation (BP) tests. To evaluate the diagnostic accuracy of FeNO within a confirmatory study, the following hypotheses will be tested: (1) A FeNO cut-off >50 ppb (parts per billion) is suitable for diagnosing asthma (sensitivity 35%, specificity 95%); (2) If the clinical symptoms ‘allergic rhinitis’ and ‘wheezing’ are present, asthma can be diagnosed at FeNO >33 ppb with a positive predictive value (PPV) >70% and (3) A FeNO >33 ppb can predict responsiveness to inhaled corticosteroid (ICS) with a PPV >70%.Methods and analysisA prospective diagnostic study will be conducted in three practices of pneumologists in Germany. 300 patients suspected of suffering from asthma will be included. As an index test, patients perform FeNO measurement with the device NIOX VERO. As reference a test, patients are examined with whole bodyplethysmography and BP, if necessary. After 3 months, patients with an asthma diagnosis will be examined again to verify the diagnosis and evaluate ICS responsiveness. Patients who did not receive an asthma diagnosis at the initial examination will be phoned after 3 months and asked about persistent respiratory symptoms to exclude false negative findings. As a primary target, sensitivity and specificity of FeNO >50 ppb will be determined. As a secondary target the PPV for asthma at FeNO >33 ppb, when the symptoms ‘allergic rhinitis’ and ‘wheezing’ are present, will be calculated. Regarding ICS responsiveness, the PPV of FeNO >33 ppb will be determined.Ethics and disseminationThe study was approved by the Ethical Committee of the Technical University of Munich (Reference number 122/20 S). The major results will be published in peer-reviewed academic journals and disseminated through conferences.Trial registration numberDRKS00021125.

OBJECTIVES: The objective of the study is to determine the impact of changing reference standards (RS), namely spirometry vs. whole-body plethysmography (WBP), on estimation of the diagnostic accuracy of fractional exhaled nitric oxide (FeNO) and clinical signs and symptoms (CSS) as index tests regarding asthma diagnosis. STUDY DESIGN AND SETTING: This was a diagnostic study conducted in 393 patients attending a private practice of pneumologists with complaints suspicious of asthma. First, the index tests were compared with the diagnostic results of spirometry in terms of forced expiratory volume in the first second (FEV1) responsiveness. Second, the index tests were compared with the results of WBP in terms of specific airway resistance and FEV1 responsiveness. Areas under the curve (AUC) were compared with a generalized estimating equation approach based on binary logistic regression. RESULTS: FeNO values and CSS 'wheezing' and 'allergic rhinitis' showed higher specificities (P

Aims Present society is constantly ageing and elderly frequently suffer from conditions that are difficult and/or costly to treat if detected late. Effective screening of the elderly is therefore needed so that those requiring detailed clinical work-up are identified early. We present a prospective validation of a screening strategy based on a Polyscore of seven predominantly autonomic, non-invasive risk markers. Methods and results Within a population-based survey in Germany (INVADE study), participants aged ≥60 years were enrolled between August 2013 and February 2015. Seven prospectively defined Polyscore components were obtained during 30-min continuous recordings of electrocardiogram, blood pressure, and respiration. Out of 1956 subjects, 168 were excluded due to atrial fibrillation, implanted pacemaker, or unsuitable recordings. All-cause mortality over a median 4-year follow-up was prospectively defined as the primary endpoint. The Polyscore divided the investigated population (n = 1788, median age: 72 years, females: 58%) into three predefined groups with low (n = 1405, 78.6%), intermediate (n = 326, 18.2%), and high risk (n = 57, 3.2%). During the follow-up, 82 (4.6%) participants died. Mortality in the Polyscore-defined risk groups was 3.4%, 7.4%, and 17.5%, respectively (P Conclusion The Polyscore-based mortality risk assessment from short-term non-invasive recordings is effective in the elderly general population, especially those aged 60–74 years. Implementation of a comprehensive Polyscore screening of this age group is proposed to advance preventive medical care.

Background The efficacy and safety of a reduced dose of prasugrel versus a standard dose of ticagrelor in elderly patients or those with a low body weight presenting with an acute coronary syndrome (ACS) are unknown. Objective To investigate the effect of an age- and weight-adapted dose of prasugrel versus a standard dose of ticagrelor in patients with ACS. (ClinicalTrials.gov: NCT01944800). Design Prespecified analysis of the multicenter, randomized ISAR-REACT 5 trial. Setting 23 centers in Germany and Italy. Patients 3997 patients with ACS planned for invasive management. Intervention Participants were randomly assigned to receive a standard dose of ticagrelor or prasugrel (reduced dose in the elderly or low-weight group and standard dose in the neither elderly nor low-weight group). Measurements The efficacy end point was a composite of death, myocardial infarction, or stroke, and the safety end point was bleeding, both at 12 months. Results In the elderly or low-weight group, the efficacy end point occurred in 12.7% of patients assigned to receive prasugrel and 14.6% of those assigned to receive ticagrelor (hazard ratio [HR], 0.82 [95% CI, 0.60 to 1.14]); in the neither elderly nor low-weight group, the efficacy end point occurred in 4.8% of patients assigned to receive prasugrel and 7.3% of those assigned to receive ticagrelor (HR, 0.65 [CI, 0.48 to 0.88]; P for interaction > 0.2). In the elderly or low-weight group, Bleeding Academic Research Consortium type 3 to 5 bleeding occurred in 8.1% of patients assigned to receive prasugrel and 10.6% of those assigned to receive ticagrelor (HR, 0.72 [0.46 to 1.12]), and in 3.7% and 3.8%, respectively, of patients in the neither elderly nor low-weight group (HR, 0.98 [CI, 0.65 to 1.47]; P for interaction > 0.2). Limitation The study is a subgroup analysis. Conclusion In elderly or low-weight patients with ACS, a reduced dose of prasugrel compared with the standard dose of ticagrelor is associated with maintained anti-ischemic efficacy while protecting these patients against the excess risk for bleeding. Primary funding source German Center for Cardiovascular Research and Deutsches Herzzentrum Munchen.

Introduction and aims. We aimed to explore the impact of infection diagnosed upon admission and of other clinical baseline parameters on mortality of cirrhotic patients with emergency admissions. Material and methods. We performed a prospective observational monocentric study in a tertiary care center. The association of clinical parameters and established scoring systems with short-term mortality up to 90 days was assessed by univariate and multivariable Cox regression analysis. Akaike’s Information Criterion (AIC) was used for automated variable selection. Statistical interaction effects with infection were also taken into account. Results. 218 patients were included. 71.2% were male, mean age was 61.1 ± 10.5 years. Mean MELD score was 16.2 ± 6.5, CLIF-consortium Acute on Chronic Liver Failure-score was 34 ± 11. At 28, 90 and 365 days, 9.6%, 26.0% and 40.6% of patients had died, respectively. In multivariable analysis, respiratory organ failure [Hazard Ratio (HR) = 0.15], albumin substitution (HR = 2.48), non-HCC-malignancy (HR = 4.93), CLIF-C-ACLF (HR = 1.10), HCC (HR = 3.70) and first episode of ascites (HR = 0.11) were significantly associated with 90-day mortality. Patients with infection had a significantly higher 90-day mortality (36.3 vs. 20.1%, p = 0.007). Cultures were positive in 32 patients with resistance to cephalosporins or quinolones in 10, to ampicillin/sulbactam in 14 and carbapenems in 6 patients. Conclusion. Infection is common in cirrhotic ED admissions and increases mortality. The proportion of resistant microorganisms is high. The predictive capacity of established scoring systems in this setting was low to moderate.

Aims We sought to determine the long-term outcome of high-risk patients who underwent transcatheter aortic valve replacement (TAVR) with first-generation devices with a focus on the identification of predictors for mortality and valve durability. Methods and results Consecutive patients in our prospective single-centre registry undergoing TAVR with first-generation devices (n=214 CoreValve; n=86 SAPIEN) between 06/2007 and 07/2009 were retrospectively analysed (n=300, mean age 81.43±6.55 years, mean STS score 6.5±4.5%). Kaplan-Meier estimates of survival and the Cox proportional hazards model were used to identify independent predictors of all-cause-mortality. At 1, 5, and 7 years, estimated survival rates were 76.0%, 40.2%, and 23.2%, respectively. Age-adjusted baseline predictors of mortality included atrial fibrillation, impaired kidney function, peripheral artery disease, and mitral regurgitation (≥moderate). Baseline risk-adjusted procedure-related predictors for all-cause mortality included acute kidney injury, neurological events, major vascular complications, and major/life-threatening bleeding. At both five and six years, 78.2% of surviving patients were in NYHA Class I or II. PVL was ≤mild in the majority of patients at discharge and throughout follow-up. At seven years, the overall crude cumulative incidence of structural valve deterioration according to the 2017 EAPCI/ESC/EACTS definition was 14.9% (CoreValve 11.8% vs. SAPIEN 22.6%; p=0.01). Conclusions Seven years after TAVR, 23.2% of high-risk patients were still alive. Independent predictors of all-cause mortality included both patient- and procedure-related factors. With a cumulative incidence of 14.9% at seven years, there is some suggestion that SVD post TAVR may become increasingly relevant during longer-term follow-up.

Pathogenic microbes may colonize the female genital tract via sexual transmission and cause health issues like inflammation or malignancy, summarized as sexually transmitted disease (STD). A major representative of such pathogens is Trichomonas vaginalis (T.v.), whose role in the etiology of cervical cancer remains elusive. Traditional morphologic screening of cervical smears is able to detect T.v., although its identification may be complicated by look-alikes such as degenerated granulocytes and basal cells. In addition, the parasite's endosymbiont Mycoplasma hominis (M.h.) cannot be detected in the Pap test. This investigation was aimed at designing a PCR-based method to detect specific pathogenic germs by using cervical cytology slides to overcome morphologic uncertainty and increase diagnostic accuracy. To test our molecular screening method on T.v., M.h., and HPV in archival smears, we elaborated a multiplex PCR approach based on microdissection. This assay was applied to a minute quantity of starting material which harbored or was suspected to harbor T.v.; the resulting isolated DNA was used for subsequent molecular analyses of T.v., M.h., and HPV. We clarified the diagnosis of genital T.v. infection in 88 and 1.8% of morphologically suspicious and T.v.-negative cases, respectively. We also revealed a tendency of M.h. co-infection in high-risk HPV cases. In conclusion, a microdissection-based approach to detect pathogenic microbes such as T.v., HPV, and M.h. is a molecular tool easy to implement and may help to better understand the interactivity of these germs with respect to pathogenesis.

Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo., Polarisation of metastasising cancer cells in circulation has not been investigated before. Here the authors identify single cell polarity as a distinct polarisation state of single cells in liquid phase, and show that perturbing single cell polarity affects attachment, adhesion, transmigration and metastasis in vitro and in vivo.

BACKGROUND AND AIM Mortality of cirrhotic patients after emergency care admission is high, and prognostic factors can help in prioritizing patients. The aim of our study was to assess the association between levels of cardiac troponin T (cTnT) and 1-year mortality in patients with liver cirrhosis without known cardiac disease, who were admitted to the emergency department (ED). METHODS All patients with cirrhosis presented to the ED from October 2009 until August 2015 who had an initial cTnT value measured with the first lab panel were retrospectively analyzed with a follow-up of 365 days. RESULTS Of a total of 237 cirrhotic ED patients, cTnT measurements were available for 87 (63% men, mean age 58.9 ± 11.0 years, and median Model for End-stage Liver Disease score was 15 [25th-75th percentile: 10-19]). Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C-ACLF) score was 33. Forty-three patients (49%) had cTnT values above the normal range (14 ng/L), of which 19 (22%) had values over 30 ng/L. Two patients were lost to follow-up. In multivariable analysis, both CLIF-C-ACLF (hazard ratio 1.072 per point increase; 95% confidence interval 1.029-1.117; P

The aim of this investigation was to identify patient's characteristics and periprocedural variables related to periprocedural transfusion in transfemoral Transcatheter Aortic Valve Implantation (tf-TAVI).Transfusion of allogenic red-blood cells (RBC) in tf-TAVI and the number of transfused units has been linked to an increased 30-day mortality. In line with the trend of minimization and cost-effectiveness, transfusion should be avoided, wherever possible.Between 2007 and 2015, 1,734 procedures were analyzed from our prospective registry for RBC-transfusion. Multiple logistic regression analysis was used to identify the dependent variables.Transfusion was considered necessary in 14% (n = 243) of the patients. Female gender (OR [95% CI]) (1.680 [1.014-2.783]) and preprocedural moderate (7.594 [4.404-13.095]) and severe anemia (8.202 [0.900-74.752]) according to WHO were the most important preprocedural variables. Periprocedural, pericardial effusion (12.109 [3.753-39.063]), emergency extracorporeal circulation (54.5288 [6.178-481.259]) and major vascular injury (2.647 [1.412-4.962]) were related to transfusion. The same applies to moderate (4.255 [1.859-9.740]) and severe anemia (31.567 [8.560-116.416]) as well as periprocedural experience (0.072 [0.035-0.149] - 0.141[0.079-0.251], P 0.001) CONCLUSION: Procedural experience, serious adverse events, low pre- and periprocedural Hb levels and female gender were the main variables relating to transfusion. Even in experienced high-volume centers, transfusion is still necessary in a considerable number of patients.

ObjectiveCancer cachexia is a paraneoplastic syndrome comprising involuntary weight loss and muscle depletion (sarcopenia). Although weight loss has been associated with poor clinical outcome, there is only limited information on the prevalence and prognostic impact of sarcopenia in ovarian cancer so far.MethodsTotal skeletal muscle mass was determined by computed tomography image analysis of the third lumbar skeletal muscle cross-sectional area in 128 patients with advanced serous ovarian cancer. Longitudinal change of muscle mass was studied in 209 consecutive computed tomography scans from 43 patients. Association with survival was determined using Cox proportional hazards model.ResultsThe prevalence of sarcopenia at first diagnosis was 11% (12/105; 95% confidence interval [CI], 6%–20%). Sarcopenic patients had a significantly reduced progression-free (hazard ratio, 2.64; 95% CI, 1.24–5.64;P= 0.012) and overall survival (hazard ratio, 3.17; 95% CI, 1.29–7.80;P= 0.012). On multivariable analysis, these prognostic effects remained significant after adjustment for age, International Federation of Gynecology and Obstetrics stage, and postsurgical residual disease. Longitudinal analyses identified both patients with loss and gain of muscle mass. However, change in muscle mass over time was not associated with survival.ConclusionsBaseline sarcopenia is a prognostic factor in advanced serous ovarian cancer. Identification of sarcopenic patients and early enrollment in physical or nutritional education programs might thus be a feasible way to improve outcome and should be further evaluated in prospective clinical trials.

BACKGROUND: Asthma education (AE) is associated with reduced hospitalization and disability. We compared the effectiveness of an electronic AE program (eAEP) with a conventional face-to-face AE program (presence-based AEP; pAEP) for asthma knowledge (AK) with regard to self-management. METHODS: A randomized controlled pilot study was conducted in a pulmonary reha- bilitation clinic. AK was determined by means of the Asthma Knowledge Test (AKT). The change in AKT score within each group was calculated with a paired t-test. Group differences were estimated with adjusted linear regression models. RESULTS: In the intervention group (n = 41), the AKT score increased from 41.57 (standard deviation 5.63) at baseline to 45.82 (3.84) after completion of the eAEP (p < 0.001), and again to 47.20 (3.78) after completion of the pAEP (p = 0.046). In the control group (n = 41), the score increased from 41.73 (4.74) at baseline to 45.72 (3.65) after completion of the pAEP (p < 0.001). There was no relevant differ- ence in knowledge gain between the eAEP and the pAEP group after completion of the corresponding educational sessions (p = 0.881). The AKT score was higher in the eAEP group after obligatory participation in pAEP than in the group that only completed the pAEP (p = 0.020). CONCLUSION: An internet-based AEP could help to reduce the knowledge deficits of a large proportion of patients with asthma.

Objective: To evaluate the incidence of cancer within the first 15 years of life in children who underwent cardiac catheterization under the age of one year. Methods: In this retrospective, single center study, 2770 infants (7.8% with trisomy 21) were studied. All infants underwent cardiac catheterization under one year of age between January 1980 and December 1998. Newly diagnosed cancer in the first 15 years of life was assessed through record linkage to the German Childhood Cancer Registry (GCCR). Cancer risk in study patients was compared to the GCCR population of children less than 15 years. Patients with trisomy 21 were compared to the Danish Cytogenic Register for trisomy 21. Effective radiation doses were calculated for each tumor patient and 60 randomly selected patients who did not develop cancer. Results: In total, 24,472.5 person-years were analyzed. Sixteen children developed cancer, while 3.64 were expected (standardized incidence ratio (SIR) = 4.4, 95% confidence interval (CI): 2.5&ndash, 7.2, p &lt, 0.001). There was no preferred cancer type. The observed incidence of leukemia and solid tumors in trisomy 21 was only slightly higher (1 in 476 py) than expected (1 in 609 py, p = 0.64). There was no direct relationship between the radiation dose and the incidence of cancer. Conclusion: Cardiac catherization in the first year of life was associated with a significantly increased cancer risk in a population with congenital heart disease.

Background and Purpose: To identify factors associated with prior stroke at presentation in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO). Methods: We studied cross-sectional data from the International PFO Consortium Study (NCT00859885). Patients with first-ever stroke and those with prior stroke at baseline were analyzed for an association with PFO-related (right-to-left shunt at rest, atrial septal aneurysm, deep venous thrombosis, pulmonary embolism, and Valsalva maneuver) and PFO-unrelated factors (age, gender, BMI, hypertension, diabetes mellitus, hypercholesterolemia, smoking, migraine, coronary artery disease, aortic plaque). A multivariable analysis was used to adjust effect estimation for confounding, e.g., owing to the age-dependent definition of study groups in this cross-sectional study design. Results: We identified 635 patients with first-ever and 53 patients with prior stroke. Age, BMI, hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and right-to-left shunt (RLS) at rest were significantly associated with prior stroke. Using a pre-specified multivariable logistic regression model, age (Odds Ratio 1.06), BMI (OR 1.06), hypercholesterolemia (OR 1.90) and RLS at rest (OR 1.88) were strongly associated with prior stroke.Based on these factors, we developed a nomogram to illustrate the strength of the relation of individual factors to prior stroke. Conclusion: In patients with CS and PFO, the likelihood of prior stroke is associated with both, PFO-related and PFO-unrelated factors. CA extern

Purpose Prospectively collected outcome data of patients (pts) whose adjuvant systemic therapy recommendation was based on the clinico-molecular test EndoPredict® (EP) are presented. Methods Pts with ER-positive, HER2-negative early breast cancer with 0–3 positive lymph nodes were enrolled. The EP was carried out on all tumor samples. Pts were evaluated for treatment compliance, local recurrence, distant metastases and overall survival. Censored time-to-event outcomes were analysed by Cox proportional hazards models. Additional estimates of the event-free-survival were calculated by the Kaplan–Meier method. Hypothesis testing was conducted on two-sided exploratory 5% significance levels. Results 373 consecutive pts were enrolled. EP classified 238 pts (63.8%) as low risk and 135 pts (36.2%) as high risk. Median follow-up was 41.6 months. Risk for disease recurrence or death in EPclin high-risk patients was twofold higher in comparison with EPclin low-risk patients (hazard ratio (HR) 2.05 (95% CI 0.85–4.96; p = 0.110). Patients with EPclin high risk were at significant higher risk of distant metastases than patients with EPclin low risk (HR 5.18; 95% CI 1.04–25.74; p = 0.0443). EPclin high-risk patients who actually underwent adjuvant CTX had a 3-year-DFS of 96.3% (95% CI 92.2–100) in contrast to EPclin high-risk patients without CTX (3-year-DFS: 91.5% (95% CI 82.7–100%); HR 0.32; 95% CI 0.10–1.05; p = 0.061). Conclusion These first prospective outcome results show that EP, in clinical routine, is a valid clinico-molecular test, to predict DFS and to guide decision of adjuvant CTX use in ER-positive, HER2-negative early breast cancer pts with 0–3 positive lymph nodes. Adjuvant CTX seems to be beneficial for EPclin high-risk patients.

Objectives Adjuvant chemotherapy decision in patients with hormone receptor positive, HER2 negative breast cancer (BC) is challenging. Ki-67 is widely used for adjuvant therapy decision in BC. The multigene assay EndoPredict (EP) has shown to provide valid and additional information about the risk of recurrence compared to traditional pathological factors. In this study, we compared Ki-67 with EP assay generated risk groups. Methods We analyzed the results from prospective EP testing (n = 373) and tumor proliferation assessed by Ki-67 staining in luminal breast cancer. We statistically investigated the association of both parameters and probed for equivalence in risk stratification. Results Evaluation of Ki-67 was feasible in 307 (82%) BC specimens with known EP test results. The EPscore (now called 12-gene molecular score) delineated 140 low and 167 high scores. After combining the EPscore with pathological tumor stage and nodal status, we received 203 EPclin low-risk and 104 EPclin high-risk classifications. EPscore and EPclin were significantly associated with Ki-67 indices and tumor grade (p, Highlights • Comparison of prospective EndoPredict tests with Ki-67 in a large breast cancer cohort. • EPscore and EPclin were significantly associated with Ki-67 indices. • Ki-67 values above 25% partly overlap with high-risk EP test results. • Ki-67 less than 25% was not reliable in predicting a low-risk EP profile. • EP testing is useful, particularly in breast cancer with low and intermediate Ki-67 levels.

OBJECTIVES Cryoballoon pulmonary vein isolation (cPVI) in patients with atrial fibrillation requires fluoroscopic guidance, causing a relevant amount of radiation exposure. Strategies to reduce radiation exposure in electrophysiologic procedures and specifically cPVI are of great importance. The aim of this study was to evaluate a possible reduction of radiation dose using the novel Azurion 7 F12 x-ray system compared with its predecessor Allura FD10. METHODS In February 2017, the Philips Azurion angiography system was introduced, combining the Allura Clarity radiation dose reduction technology with a more powerful generator, improved image resolution, and a large screen display. In 173 patients undergoing cPVI by a single experienced operator in our institution between December 2016 and April 2018, dose area products (cGy×cm) and image quality were compared using Azurion 7 F12 or Allura FD10 angiography system. RESULTS A significant reduction in total radiation dose expressed as a dose area products of 524 (332; 821) cGy×cm on the Allura system compared with 309 (224; 432) cGy×cm on the Azurion system was observed (P

ObjectiveTo investigate whether immune cell composition and content of neutrophil extracellular traps (NETs) in relation to clinical outcome are different between acute ischemic stroke (AIS) and acute myocardial infarction (AMI), we performed histologic analysis and correlated results with clinical and procedural parameters.MethodsWe retrieved thrombi from patients with AIS (n = 71) and AMI (n = 72) during endovascular arterial recanalization and analyzed their immune cell composition and NET content by immunohistology. We then associated thrombus composition with procedural parameters and outcome in AIS and with cardiac function in patients with AMI. Furthermore, we compared AIS thrombi with AMI thrombi and differentiated Trial of Org 10172 in Acute Stroke Treatment classifications to address potential differences in thrombus pathogenesis.ResultsAmounts of leukocytes (p = 0.133) and neutrophils (p = 0.56) were similar between AIS and AMI thrombi. Monocytes (p = 0.0052), eosinophils (p < 0.0001), B cells (p < 0.0001), and T cells (p < 0.0001) were more abundant in stroke compared with AMI thrombi. NETs were present in 100% of patients with AIS and 20.8% of patients with AMI. Their abundance in thrombi was associated with poor outcome scores in patients with AIS and with reduced ejection fraction in patients with AMI.ConclusionIn our detailed histologic analysis of arterial thrombi, thrombus composition and especially abundance of leukocyte subsets differed between patients with AIS and AMI. The presence and amount of NETs were associated with patients' outcome after AIS and AMI, supporting a critical impact of NETs on thrombus stability in both conditions.

Background and aims We aimed at studying the association of three major human monocyte subsets after percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. Methods We prospectively studied 67 sequential patients (40 male, 27 female; mean age 71 ± 11 years) treated with femoropopliteal angioplasty. Multi-color flow cytometry characterized monocyte subsets from venous blood for expression of CD14 and CD16 and intracellular myeloperoxidase (MPO) prior to, and 3, 6 and 12 months post PTA. Analyses tested associations between monocyte subsets and risk for restenosis. Results 16/67 patients (24%) developed restenosis within 12 months after PTA. Patients with hyperlipidemia had increased risk for restenosis (HR = 1.7, 95% CI 0.7–2.9, p = 0.001). Increased baseline monocytes associated with an increased risk of late restenosis (HR = 4.9, 95% CI: 1.3–18.6, p = 0.047). CD14 ++ CD16 ++ ‘intermediate' monocytes assessed at baseline, and after 3, 6, and 12 months significantly associated with the risk for subsequent restenosis: HR = 3.9 (95% CI: 2.4–6.5, p = 0.029), HR = 5.7 (95% CI = 0.7–44.7, p = 0.013), HR = 6.5 (95% CI: 2.5–16.9, p = 0.001) and HR = 1.5 (95% CI = 1.4–15.5 p = 0.001), respectively. Moreover, the probability for freedom of restenosis decreased with increased levels of intermediate subsets at 12 months after PTA. Additionally, intracellular MPO expression in CD14 ++ CD16 ++ measured at 3, 6 and 12 months associated with an increased restenosis risk (HR = 1.5, 95% CI: 0.8–2.1, p = 0.214, HR = 1.9, 95% CI: 1.0–2.3 p = 0.051 and HR = 1.4, 95% CI: 1.0–1.8, p = 0.052). Conclusions Our results imply altered innate immunity after angioplasty. Elevated CD14 ++ CD16 ++ intermediate monocyte frequencies and increased MPO expression may identify individuals at heightened risk for restenosis.

Volumetric-modulated arc therapy (VMAT) achieves high conformity to the planned target volume (PTV) and good sparing of organs at risk (OAR). This study compares dosimetric parameters and toxicity in esophageal cancer (EC) patients treated with VMAT and 3D conformal radiotherapy (3D-CRT). Between 2007 and 2014, 17 SC patients received neoadjuvant chemoradiation (CRT) with VMAT. Dose–volume histograms and toxicity were compared between these patients and 20 treated with 3D-CRT. All patients were irradiated with a total dose of 45 Gy. All VMAT patients received simultaneous chemotherapy with cisplatin and 5‑fluorouracil (5-FU) in treatment weeks 1 and 5. Of 20 patients treated with 3D-CRT, 13 (65 %) also received CRT with cisplatin and 5‑FU, whereas 6 patients (30 %) received CRT with weekly oxaliplatin and cetuximab, and a continuous infusion of 5‑FU (OE-7). There were no differences in baseline characteristics between the treatment groups. For the lungs, VMAT was associated with a higher V5 (median 90.1 % vs. 79.7 %; p = 0.013) and V10 (68.2 % vs. 56.6 %; p = 0.014), but with a lower V30 (median 6.6 % vs. 11.0 %; p = 0.030). Regarding heart parameters, VMAT was associated with a higher V5 (median 100.0 % vs. 91.0 %; p = 0.043), V10 (92.0 % vs. 79.2 %; p = 0.047), and Dmax (47.5 Gy vs. 46.3 Gy; p = 0.003), but with a lower median dose (18.7 Gy vs. 30.0 Gy; p = 0.026) and V30 (17.7 % vs. 50.4 %; p = 0.015). Complete resection was achieved in 16 VMAT and 19 3D-CRT patients. Due to systemic progression, 2 patients did not undergo surgery. The most frequent postoperative complication was anastomosis insufficiency, occurring in 1 VMAT (6.7 %) and 5 3D-CRT patients (27.8 %; p = 0.180). Postoperative pneumonia was seen in 2 patients of each group (p = 1.000). There was no significant difference in 3‑year overall (65 % VMAT vs. 45 % 3D-CRT; p = 0.493) or 3‑year progression-free survival (53 % VMAT vs. 35 % 3D-CRT; p = 0.453). Although dosimetric differences in lung and heart exposure were observed, no clinically relevant impact was detected in either patient group. In a real-life patient cohort, VMAT enables reduction of lung and heart V30 compared to 3D-CRT, which may contribute to reduced toxicity.

The life expectancy of HIV-infected patients has recently been increasing. Although the mortality and morbidity associated with AIDS is decreasing, those associated with cardiovascular diseases and percutaneous coronary intervention (PCI) are receiving greater attention. Only limited data regarding coronary restenosis are available in these patients.In this prospective, systematic angiographic follow-up study, we enrolled HIV patients who underwent PCI for de-novo lesions and subsequent routine angiographic follow-up for 6-8 months. Angiographic restenosis was defined as stenosis of at least 50% of the in-segment area.Univariate and multivariate analyses were performed to evaluate restenosis and its predictors.Between May 2002 and March 2014, 47 patients with HIV underwent PCI in two high-volume centers in Munich, Germany. Of these patients, 41 with 131 de-novo lesions underwent invasive surveillance. One-quarter of the lesions treated subsequently presented with restenosis. Univariate analysis indicated that CD8 T-cell levels (P = 0.006), serum cholesterol (P = 0.042) and low-density lipoprotein-cholesterol (P = 0.042) levels at baseline, total number of stents (P = 0.047), and C-reactive protein level (P = 0.001) at follow-up were associated with restenosis. Multivariate analysis indicated that CD8 T-cell levels (P = 0.006) and persistent C-reactive protein elevation at 6-month follow-up (P = 0.00013) were independent predictors of restenosis.Inflammation, represented by CD8 T-cell levels, and persistent C-reactive protein elevation are independent predictors of angiographic restenosis and should therefore be closely monitored in HIV patients undergoing PCI.

Introduction: Integrative medicine is becoming increasingly relevant to modern oncology. The present study aims to assess the demand for integrative therapeutic approaches including complementary and alternative medicine (CAM), body and mind practices, nutritional counseling, and psychological assistance among breast and gynecological cancer patients. Methods: From April to July 2017, a pseudo-anonymous questionnaire was distributed to cancer patients at the Department of Gynecology and Obstetrics, Technical University of Munich. Patterns of CAM use and demand for integrative health approaches were investigated by generating descriptive statistics. Results: 182 (90%) of 203 patients participated in the survey. 59% indicated the use of CAM practices in general, and 41% specifically in relation to their oncological disease. Most frequently used modalities were herbal supplements (32%), homeopathy (29%), vitamins (28%), and selenium (21%). Integrative health approaches that patients would have desired alongside conventional oncological treatment were CAM (54%), relaxation therapies (44%), and dietary counseling (43%). Conclusion: There is a considerable demand for integrative medicine among breast and gynecological cancer patients. Our results underline the need for the implementation of evidence-based integrative treatments in cancer care in order to meet the standards of modern oncology.

Transcatheter aortic valve implantation (TAVI) is a treatment strategy for patients with severe aortic stenosis. Although general anaesthesia (TAVI-GA) and sedation (TAVI-S) have previously been described for TAVI, the difference in safety and efficacy of both methods has not been studied in a randomized trial.The INSERT trial was a single centre, controlled parallel-group trial with balanced randomization. Sixty-six patients (68-94 yr) with acquired aortic stenosis undergoing transfemoral CoreValve™ were assigned to TAVI-GA or TAVI-S. Comparable operative risk was determined from risk-scores (EUROscore, STS-Score). Monitoring and anaesthetic drugs were standardized. Near-Infrared-Spectroscopy was used to monitor cerebral-oxymetry blinded. Primary outcome was the perioperative cumulative cerebral desaturation. As secondary outcomes, changes in neurocognitive function and respiratory and haemodynamic adverse events were evaluated.Of 66 included patients, 62 (TAVI-GA: n=31, TAVI-S: n=31) were finally analysed. Baseline characteristics were comparable. In 24 patients (39%) cerebral desaturation was observed. Cumulative cerebral desaturation was comparable (TAVI-GA:(median [IQR]) (0[0/1308] s%) vs. TAVI-S:(0[0/276] s%); P=0.505) between the groups. Neurocognitive function did not change within and between groups. Adverse events were more frequently observed in TAVI-S patients (P0.001). Bradypnoea (n=16, 52%) and the need for airway manoeuvres (n=11, 36%) or bag-mask-ventilation (n=6, 19%) were the most common respiratory adverse events.Cerebral desaturation occurred in both patient groups, but there was no significant difference between the two groups. Based on primary outcome, both methods were shown to be comparable. Neurocognitive outcome was similar. The higher incidence of adverse events in the sedation group suggests a potential advantage of general anaesthesia.NCT 01251328.

Impaired bone structure poses a challenge for the treatment of osteoporotic tibial plateau fractures. As knowledge of region-specific structural bone alterations is a prerequisite to achieving successful long-term fixation, the aim of the current study was to characterize tibial plateau bone structure in patients with osteoporosis and the elderly.Histomorphometric parameters were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 21 proximal tibiae from females with postmenopausal osteoporosis (mean age: 84.3 ± 4.9 years) and eight female healthy controls (45.5 ± 6.9 years). To visualize region-specific structural bony alterations with age, the bone mineral density (Hounsfield units) was additionally analyzed in 168 human proximal tibiae. Statistical analysis was based on evolutionary learning using globally optimal regression trees.Bone structure deterioration of the tibial plateau due to osteoporosis was region-specific. Compared to healthy controls (20.5 ± 4.7%) the greatest decrease in bone volume fraction was found in the medio-medial segments (9.2 ± 3.5%, p 0.001). The lowest bone volume was found in central segments (tibial spine). Trabecular connectivity was severely reduced. Importantly, in the anterior and posterior 25% of the lateral and medial tibial plateaux, trabecular support and subchondral cortical bone thickness itself were also reduced.Thinning of subchondral cortical bone and marked bone loss in the anterior and posterior 25% of the tibial plateau should require special attention when osteoporotic patients require fracture fixation of the posterior segments. This knowledge may help to improve the long-term, fracture-specific fixation of complex tibial plateau fractures in osteoporosis.

Perioperative chemotherapy is an established treatment of advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients.We analyzed 626 carcinomas of the stomach and of the gastro-esophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of 11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analyzing 50 tumor areas from 10 patients.A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathologic type suggested two groups with a significant difference in OS [hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.17-0.52]. The risk score was successfully validated in an independent cohort (HR 0.32; 95% CI 0.21-0.51; P 0.001) as well as in subgroups of primarily resected (HR 0.30; 95% CI 0.17-0.54; P 0.001) and pre-/perioperatively treated patients (HR 0.37; 95% CI 0.17-0.81; P = 0.009). A significant difference in OS of high- and low-risk patients was also found in primarily resected patients with intestinal (HR 0.45; 95% CI 0.23-0.90; P = 0.020) and nonintestinal-type carcinomas (HR 0.1; 95% CI 0.02-0.42; P 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies.The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.

Neurovascular coupling can be directly assessed by retinal vessel response to flickering light using optical imaging methods. The response is altered in a number of ocular and cardiovascular diseases. Whether it is altered in Alzheimer’s disease (AD) is investigated. Retinal vessel reaction to monochromatic flicker stimulation was examined by Dynamic Vessel Analyzer independent of the commercial software in elderly subjects: 15 patients with mild-to-moderate dementia due to AD (ADD); 24 patients with mild cognitive impairment due to AD (MCI); 15 cognitively healthy controls (HC). Retinal vessels in ADD showed a more emphasized and delayed reactive dilation as compared to HC. In MCI, these aspects still differed from those seen in ADD. Maximal arterial reaction was increased and dilation was delayed in ADD as compared to HC (p = 0.004 and p

Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations.

The sickest-first principle in donor-liver allocation can be implemented by allocating organs to patients with cirrhosis with the highest Model for End-Stage Liver Disease (MELD) scores. For patients with other risk factors, standard exceptions (SEs) and nonstandard exceptions (NSEs) have been developed. We investigated whether this system of matched MELD scores achieves similar outcomes on the liver transplant waiting list for various diagnostic groups in Eurotransplant (ET) countries with MELD-based individual allocation (Belgium, the Netherlands, and Germany). A retrospective analysis of the ET wait-list outflow from December 2006 until December 2015 was conducted to investigate the relation of the unified MELD-based allocation to the risk of a negative wait-list outcome (death on the waiting list or delisting as too sick) as opposed to a positive wait-list outcome (transplantation or delisting as recovered). A total of 16,926 patients left the waiting list with a positive (11,580) or negative (5346) outcome; 3548 patients had a SE, and 330 had a NSE. A negative outcome was more common among patients without a SE or NSE (34.3%) than among patients with a SE (22.6%) or NSE (18.6%; P < 0.001). Analysis by model-based recursive partitioning detected 5 risk groups with different relations of matched MELD to a negative outcome. In Germany, we found the following: (1) no SE or NSE, SE for biliary sepsis (BS); (2) SE for hepatocellular carcinoma (HCC), hepatopulmonary syndrome (HPS), or portopulmonary hypertension (PPH); and (3) SE for primary sclerosing cholangitis (PSC) or polycystic liver disease (PcLD). In Belgium and the Netherlands, we found the following: (4) SE or NSE, or SE for HPS or PPH; and (5) SE for BS, HCC, PcLD, or PSC. In conclusion, SEs and NSEs do not even out risks across different diagnostic groups. Patients with SEs or NSEs appear advantaged toward patients with cirrhosis without SEs or NSEs. Liver Transplantation 23 1256-1265 2017 AASLD.

Background We recently reported that nocturnal respiratory rate (NRR) predicts non-sudden cardiac death in survivors of myocardial infarction (MI). Here, we present the details of the technique deriving NRR from ECG recordings. Methods Continuous ECG and respiratory chest excursions were simultaneously recorded in 941 MI survivors who were followed-up for 5-years. Mean respiratory rate was derived from the ECG based on RR intervals, QRS amplitudes, and QRS vectors and compared to chest belt measurements. NRR was calculated from Holter-ECGs accordingly using the same ECG processing. Results Directly-measured and ECG-derived respiratory rates were in good agreement. Areas under the ROC curve for 10-min-ECG- and Holter-derived respiratory rate were well in the confidence intervals of that of the chest belt measurement. The optimum dichotomy of NRR for the prediction of mortality was ≥ 18.6 breaths per minute. Conclusions The mean respiratory rate can be precisely derived from continuous ECGs.