Evaluation of Risk Stratification Markers and Models in Acute Pulmonary Embolism: Rationale and Design of the MARS-PE (Mainz Retrospective Study of Pulmonary Embolism) Study Programme.

An acute pulmonary embolism (PE) is a crucial event in patients' life and connected with serious morbidity and mortality. Regarding a high case-fatality rate, early and accurate risk-stratification is crucial. Risk for mortality and complications are closely related to hemodynamic stability and cardiac adaptations. The currently recommended risk-stratification approach is not overall simple to use and might delay the identification of those patients, who should be monitored more closely and may treated with more aggressive treatment strategies. Additionally, some risk-stratification criteria for the imaging procedures are still imprecise. Summarized, the search for the most effective risk-stratification tools is still ongoing and some diagnostic criteria might have to be refined. In the MAinz Retrospective Study of Pulmonary Embolism (MARS-PE), overall 182 consecutive patients with confirmed PE were retrospectively included over a 5-year period. Clinical, echocardiographic, functional and laboratory parameters were assessed. The study was designed to provide answers to some of the mentioned relevant questions.

D-Dimer and thrombus burden in acute pulmonary embolism.

BACKGROUND: Thrombus burden in pulmonary embolism (PE) is associated with higher D-Dimer-levels and poorer prognosis. We aimed to investigate i) the influence of right ventricular dysfunction (RVD), deep venous thrombosis (DVT), and high-risk PE-status on D-Dimer-levels and ii) effectiveness of D-Dimer to predict RVD in normotensive PE patients. METHODS: Overall, 161 PE patients were analyzed retrospectively, classified in 5 subgroups of thrombus burden according to clinical indications and compared regarding D-Dimer-levels. Linear regression models were computed to investigate the association between D-Dimer and the groups. In hemodynamically stable PE patients, a ROC curve was calculated to assess the effectiveness of D-Dimer for predicting RVD. RESULTS: Overall, 161 patients (60.9% females, 54.0% aged >70 years) were included in this analysis. The D-Dimer-level was associated with group-category in a univariate linear regression model (ß 0.050 (95%CI 0.002-0.099), P = .043). After adjustment for age, sex, cancer, and pneumonia in a multivariate model we observed an association between D-Dimer and group-category with borderline significance (ß 0.047 (95%CI 0.002-0.096), P = .058). The Kruskal-Wallis test demonstrated that D-Dimer increased significantly with higher group-category. In 129 normotensive patients, patients with RVD had significantly higher D-Dimer values compared to those without (1.73 (1.11/3.48) vs 1.17 (0.65/2.90) mg/l, P = .049). A ROC curve showed an AUC of 0.61, gender non-specific, with calculated optimal cut-off of 1.18 mg/l. Multi-variate logistic regression model confirmed an association between D-Dimer >1.18 mg/l and RVD (OR2.721 (95%CI 1.196-6.190), P = .017). CONCLUSIONS: Thrombus burden in PE is related to elevated D-Dimer levels, and D-Dimer values >1.18 mg/l were predictive for RVD in normotensive patients. D-Dimer levels were influenced by DVT, but not by cancer, pneumonia, age, or renal impairment.

Renal function as a cofactor for risk stratification and short-term outcome in acute pulmonary embolism.

BACKGROUND: In addition to right ventricular dysfunction (RVD) and myocardial injury, impaired renal function is connected with poorer prognosis in pulmonary embolism (PE). We aimed to investigate renal function as a cofactor for risk stratification in PE. METHODS: Data from 182 patients with PE, treated between May 2006 and June 2011, were analysed retrospectively. PE patients with elevated creatinine were compared with those with normal values. Logistic regression models were calculated to investigate associations between creatinine and myocardial necrosis, RVD and in-hospital death. Prognostic performance of creatinine for prediction of myocardial necrosis and RVD were computed. RESULTS: Overall, 182 patients (61.5% females,aged 68.5±15.3years) with confirmed PE were included in this study; 142 patients(78.0%) showed normal creatinine, and 40(22.0%) had an elevated creatinine. Patients with elevated creatinine were older (75.9±10.7 vs. 66.5±15.7years, P=0.0003), more frequently female (77.5% vs. 57.0%,P=0.019), and had higher cardiac troponin I (0.19±0.23 vs. 0.11±0.29ng/ml,P=0.0004), systolic pulmonary artery pressure (43.18±16.69 vs. 30.83±17.53mmHG,P=0.0006) and percentage of RVD (77.1% vs. 54.1%,P=0.040). Creatinine was significantly and independently associated with myocardial necrosis (OR 10.192, 95%CI 2.850-36.452, P=0.0004), shock-index≥1.0 (OR 3.265, 95%CI 1.067-9.992, P=0.0381) and RVD (OR 5.172, 95%CI 1.387-19.295, P=0.014). Creatinine>1.25mg/dl indicated for myocardial necrosis (AUC 0.680) and RVD (AUC 0.663). CONCLUSIONS: Additionally, to RVD and myocardial necrosis, impaired renal function could give further information for risk stratification in PE. Cardio-pulmonary-renal interactions in PE seem to be multi-factorial.

[Short- and long-term results in operable pancreatic ductal adenocarcinomas from a cooperation between two departments gastroenterology-visceral surgery at non-university hospitals benchmarked to results of expert-centers]. / Kurz- und Langzeitergebnisse bei operablen duktalen Pankreasadenokarzinomen aus der Kooperation zwischen zwei Abteilungen Gastroenterologie-Viszeralchirurgie an nicht universitären Kliniken im Vergleich mit Resultaten aus Spitzenzentren.

The only curative approach in pancreatic ductal adenocarcinoma (PDAC) is resection, which is possible only in 15 - 30 % of patients. Local tumor spread or distant metastases are contraindications for resection in the majority of patients. Surgical-oncological quality with short- and long-term results are varying tremendously, so that "expertise/quality" are associated to hospital- or surgeon's volume and/or center formation. The treatment results also depend, to a great extent, on the medical diagnostic quality. With our retrospective study, we aim to compare the results-quality of cooperative pancreatic cancer treatment based on an extensive preoperative diagnostic procedure for staging and risk estimation in a specialized GI-medical department and visceral surgical-oncological expertise in pancreatic cancer surgery at a general hospital with the results-quality of expert centers. Fifty-three patients with PDAC had diagnosis and resection of their cancer between 1/2002 and 12/2009. The 30 day hospital-mortality was 3.8 % and the median survival time after demission from the hospital was 23.1 months. The 5-year-survival rate of R0-resected patients, all of whom had received adjuvant chemotherapy, was high with 31 %. The survival data and the extraordinarily high resection rate of 98.1 % in the patient group, whose primary tumor stage was pT3 in 81 %, reflects the excellent cooperation of high standards in medical diagnostic processes, visceral pancreatic surgery, and adjuvant medical chemotherapy. The results are well comparable to those of "high volume centers". The responsible heads of the two departments have been trained at university expert centers. Expertise in the treatment of pancreatic cancer patients may be successfully transferred from an expert center to a general hospital, if the team has high expertise.

Syncope and collapse in acute pulmonary embolism.

BACKGROUND: Syncope and collapse (=presyncope) are 2 symptoms of pulmonary embolism (PE), which are suspected of being connected with poorer outcome, regardless of haemodynamic instability. However, pathomechanisms are not completely understood. We aimed to investigate these pathomechanisms in regard to blood pressure and heart rate of syncope/collapse in PE. METHODS: We performed a retrospective study of consecutive PE patients, who were treated in the Internal Medicine Department. Patients with and without syncope/collapse were compared. Regression models for associations between syncope/collapse and blood pressure, heart rate and shock index (SI) were computed. Moreover we calculated ROC analyses and Youden indices for effectiveness and cut-off-values of these parameters for the probability of syncope/collapse. RESULTS: 182 patients (mean-age 68.5±15.3years; 61.5% female) with confirmed PE were included in this study. 20 PE patients (11.0%) showed a syncope/collapse. PE patients with syncope/collapse were in median 7.5years older (78.5 (72.0/82.3) vs. 71.0 (61.0/80.0) years, P=.0575), had lower systolic (132.0 (108.8/154.0) vs. 145.5 (127.0/166.0) mmHg, P=.0845) and diastolic (70.0±27.0 vs. 78.4±18.4mmHg, P=.0740) blood pressure, whereas heart rate (103.5 (87.8/116.0) vs. 90.0 (76.0/102.0)beats/min, P=.0518), SI (0.78 (0.65/1.01) vs. 0.60(0.50/0.79), P=.0127) and frequency of right ventricular dysfunction (RVD) (88.2% vs. 55.8%, P=.0294) were higher in PE patients with syncope/collapse than in those without. Hypotension (systolic blood pressure<90mmHg), tachycardia and SI>1.0were connected with 6.4-fold, 2.5-fold and 5.8-fold higher probability of syncope/collapse, respectively. ROC analyses revealed cut-off values of ≤110mmHg, ≥107beats/min and >0.62 for systolic blood pressure, heart rate and SI with low AUC values, respectively. CONCLUSIONS: The pathomechanism of syncope/collapse in patients with acute PE seems to be connected with blood pressure fall, heart rate increase and RVD, in terms of cardiovascular syncope with reduced cardiac output and vasovagal reflex.

Right bundle branch block and SIQIII-type patterns for risk stratification in acute pulmonary embolism.

INTRODUCTION: Risk stratification in acute pulmonary embolism (PE) is crucial for identification of patients with poor prognosis. We aimed to investigate the ECG alterations of right bundle branch block (RBBB) and SIQIII-type patterns for risk stratification in acute PE. MATERIALS AND METHODS: Retrospective analysis of PE patients, treated in the Internal Medicine Department, was performed. Patients with RBBB and/or SIQIII-type were compared with those without both patterns. Logistic regression models for association between these ECG alterations and respectively right ventricular dysfunction (RVD), high-risk PE status and myocardial injury were computed. RESULTS: 175 patients were included for this retrospective analysis. Total study sample comprised 37 PE patients (21.1%) with RBBB and/or SIQIII-type patterns and 138 PE patients (78.9%) without both signs. Heart rate (97.4±17.2 vs. 93.2±26.8/min, P=0.021), cardiac troponin I values (0.19±0.38 vs. 0.11±0.24, P=0.003) and percentage of patients with RVD (83.9% vs. 52.7%, P=0.005) were significantly higher in PE patients with RBBB and/or SIQIII-type patterns compared to PE patients without both ECG alterations. Multi-variate logistic regression models adjusted for age and gender revealed significant associations between RBBB and RVD (OR3.942, 95% CI1.054-14.747, P=0.042) and between SIQIII-type patterns and RVD (OR5.667, 95% CI1.144-28.071, P=0.034). The association between RBBB and cardiac injury (cTnI>0.4ng/ml) (OR2.531, 95% CI 0.973-6.583, P=0.06) showed a borderline significance, while the association between SIQIII-type patterns and cardiac injury was significant (OR3.956, 95% CI1.309-11.947, P=0.015). CONCLUSIONS: RBBB and SIQIII-type patterns were both associated with RV overload and cardiac injury. RBBB and SIQIII-type patterns were connected with 3.9-fold and 5.7-fold elevated risk of RVD, respectively.

Typical symptoms for prediction of outcome and risk stratification in acute pulmonary embolism.

BACKGROUND: Clinical presentation of pulmonary embolism (PE) comprises a wide spectrum from asymptomatic incidental finding to typical symptoms with chest pain, dyspnea, hemoptysis and syncope/collapse. We aimed to investigate typical symptoms of PE and increasing number of these symptoms to predict outcome in acute PE. METHODS: Data of PE patients were analysed retrospectively. According to the typical symptoms patients were subdivided in groups with 0, 1, 2, or ≥3 symptoms, which were compared with Kruskal-Wallis-Test. Logistic regression models were computed to investigate the association between the symptoms as well as the groups with the outcome parameters in-hospital death, myocardial necrosis, Shock-Index ≥1.0 and (right ventricular dysfunction (RVD). ROC curves were calculated to test the effectiveness of increasing number of symptoms to predict the outcome parameters. RESULTS: One hundred eighty-two PE patients (61.5% female, mean age 68.5±15.3 years) were included in this study. 5 patients (2.7%) died in-hospital. Logistic regression models revealed associations between syncope/collapse and in-hospital death (OR 7.269, 95%CI 0.894-59.130, P=0.0636), myocardial necrosis (OR2.872, 0.904-9.130, P=0.0738), Shock-Index ≥1.0 (OR 4.906, 1.440-16.721, P=0.00110) and RVD (OR 5.265, 1.078-25.708, P=0.0401). Dyspnea and myocardial necrosis were also associated (OR 3.245, 1.127-9.348, P=0.0292). Increasing number of symptoms were not associated with in-hospital death, but absence of typical symptoms was associated with lower frequency of myocardial necrosis (OR 0.212, 0.046-0.976, P=0.0464). Effectiveness of increasing number of symptoms to predict myocardial necrosis was only moderate (AUC 0.608). CONCLUSIONS: The symptom syncope/collapse is connected with poorer outcome in acute PE. An increasing number of symptoms failed to be useful for outcome prediction and risk stratification in acute PE.

Impact of cancer on the effectiveness of cardiac Troponin I to predict right ventricular dysfunction in acute pulmonary embolism.

BACKGROUND: Deep vein thrombosis (DVT) and pulmonary embolism (PE) are connected with a poor outcome in cancer patients. We aimed to investigate the impact of cancer on the effectiveness of cardiac Troponin I (cTnI) to predict right ventricular dysfunction (RVD) in acute PE. METHODS: We retrospectively analyzed the data of 182 patients with confirmed PE. PE patients were subdivided into two groups: (i) with concomitant active cancer disease or history of cancer, and (ii) without known cancer. Receiver operating characteristic (ROC) curves with area under the curve (AUC) was calculated for cTnI predicting RVD and related cut-off levels for both groups. RESULTS: Thirty-seven PE patients (20.3%) had an active cancer disease or a history of cancer. In contrast, 145 (79.7%) of the included PE patients did not have a known cancer disease or a history of cancer. In the PE group with cancer, analysis of the ROC curve showed an AUC of 0.76 for cTnI predicting RVD with an optimal cut-off value of 0.04 ng/mL; the risk of misclassification was 25.0%. In the PE group without cancer, AUC was 0.81 for cTnI predicting RVD with an optimal cut-off value of 0.015 ng/mL; the risk of misclassification was 24.9%. CONCLUSIONS: cTnI is effective for predicting RVD in PE patients with and without cancer. However, the effectiveness of cTnI to predict RVD was higher in PE patients without cancer than in those with cancer or a history of cancer.

Blood pressure for outcome prediction and risk stratification in acute pulmonary embolism.

INTRODUCTION: Risk stratification of patients with acute pulmonary embolism (PE) is crucial in deciding appropriate therapy management. Blood pressure (BP) is rapidly available and a reliable parameter. We aimed to investigate BP for short-term outcome in acute PE. MATERIALS AND METHODS: Data of 182 patients with acute PE were analyzed retrospectively. Logistic regression models were calculated to investigate associations between BP and in-hospital-death as well as myocardial necrosis. Moreover, receiver operating characteristic (ROC) curves and cutoff values for systolic and diastolic BPs predicting in-hospital death and myocardial necrosis were computed. RESULTS: A total of 182 patients (61.5% female; mean age, 68.5 ± 15.3 years) with acute PE event were included in the study. Five patients (2.7%) died in the hospital. Logistic regression models showed a significant association between in-hospital death and systolic BP ≤ 120 mm Hg (odds ratio [OR], 22.222; 95% confidence interval [CI], 2.370-200.00; P = .00660), systolic BP ≤ 110 mm Hg (OR, 22.727; 95% CI, 3.378-142.857; P = .00130), systolic BP ≤ 100 mm Hg (OR, 16.129; 95% CI, 2.304-111.111; P = .00513), systolic BP ≤ 90 mm Hg (OR, 22.727; 95% CI, 3.086-166.667'; P = .00220), and diastolic BP ≤65 mm Hg (OR, 14.706; 95% CI, 1.572-142.857; P = .0184), respectively. Association between myocardial necrosis and systolic BP0 >100 mm Hg (OR, 5.444; 95% CI, 1.052-28.173; P = .0433) was also significant. Receiver operating characteristic analysis for systolic BP predicting in-hospital death revealed an area under the curve of 0.831 with a cutoff value of 119.5 mm Hg. Receiver operating characteristic analysis for diastolic BP predicting in-hospital death showed an area under the curve of 0.903 with a cutoff value of 66.5 mm Hg. CONCLUSIONS: Systolic and diastolic BPs are excellent prognosis predictors of patients with acute PE. Systolic BP of 120 mm Hg or less and diastolic BP of 65 mm Hg or less at admission are connected with elevated risk of in-hospital death.

The risk factor age in normotensive patients with pulmonary embolism: Effectiveness of age in predicting submassive pulmonary embolism, cardiac injury, right ventricular dysfunction and elevated systolic pulmonary artery pressure in normotensive pulmonary embolism patients.

INTRODUCTION: Right ventricular dysfunction (RVD), submassive pulmonary embolism (PE), elevated systolic pulmonary artery pressure (sPAP), elevated cardiac troponin I (cTnI) and old age are well-known risk factors for poor outcome in acute normotensive PE. The aim of this analysis was to calculate age cut-off values to predict submassive PE, cardiac injury, RVD and elevated sPAP in normotensive PE patients. METHODS: Retrospective analysis of clinical, laboratory, radiological and echocardiographic data of normotensive PE patients (2006-2011) was performed. Receiver operating characteristic (ROC) curves and Youden indexes were used to test the effectiveness of using patients' ages at the PE event to predict a submassive PE, cardiac injury (elevated cTnI >0.1ng/ml), RVD and elevated sPAP (>30mmHg) in normotensive PE patients and to calculate optimal cut-off values. Patients >76years were compared to those aged ≤76years. RESULTS: 129 normotensive PE patients (59.7% women) met the inclusion criteria and were included in this analysis. The optimal cut-off value for patient ages to predict submassive PE, cardiac injury (elevated cTnI >0.1ng/ml), RVD and elevated sPAP (>30mmHg) was 76.5, 81.5, 66.5 and 66.5years, respectively, with moderate effectiveness (AUC 0.69, 0.58, 0.71 and 0.69, respectively). Patients >76years old had higher percentages of submassive PE (91.1% vs. 63.1%, P=0.000680), RVD (91.1% vs. 58.3%, P=0.000119), sPAP (42.64±16.70 vs. 29.24±17.56mmHg, P=0.000044) and cTnI (0.22±0.40 vs. 0.10±0.25ng/ml, P=0.00488). CONCLUSIONS: Age is an important prognostic factor in acute normotensive PE. In addition to cTn and RVD, age should be taken into account in determining the risk stratification for acute PE.

D-dimer for risk stratification in haemodynamically stable patients with acute pulmonary embolism.

PURPOSE: Patients with submassive pulmonary embolism (PE) have a higher short-term mortality than those with low-risk PE. Rapid identification of submassive PE is important for adequate treatment of non-massive PE. We aimed to investigate the utility of D-dimer for the prediction of submassive PE stadium in normotensive PE patients. PATIENTS AND METHODS: Normotensive PE patients were classified into submassive or low-risk PE groups. In addition to the comparison of the groups, area under the curve (AUC) and D-dimer cut-off for the prediction of submassive PE stadium, multi-variate logistic regression for association between D-dimer values above this cut-off and submassive PE stadium were also calculated. RESULTS: The data of 129 normotensive PE patients (59.7% women, mean age 70.0 years (60.7/81.0)) were analysed retrospectively. Patients with submassive PE were older (75.0 years (61.7/81.0) vs. 66.5 years (55.7/74.2), P=0.026) and more frequently female (63.6% vs. 53.8%, P=0.35). Heart rate (100.0beats/min (85.0/108.0) vs. 80.0beats/min (70.0/96.2), P<0.0001), systolic pulmonary-artery pressure (41.55±16.79mmHg vs. 22.62±14.81mmHg, P<0.0001), and D-dimer (2.00mg/l (1.09/3.98) vs. 1.21mg/l (0.75/1.99), P=0.011) were higher in patients with submassive PE. D-dimer values >1.32mg/l were indicative of submassive PE and shock-index ≥0.7. The effectiveness (AUC) of the test was 0.63 for submassive PE and 0.64 for shock-index ≥0.7. D-dimer values >1.32mg/l were associated with submassive PE stadium (OR 3.81 (95% CI: 1.74-8.35), P=0.00083) as well as with systolic blood pressure (OR 0.98 (95% CI: 0.97-0.99), P=0.033), heart rate (OR 1.02 (95% CI: 1.00-1.04), P=0.023) and shock-index value (OR 15.89 (95% CI: 1.94-130.08), P=0.0099). CONCLUSIONS: D-dimer values >1.32mg/l are indicative of submassive PE stadium and shock-index ≥0.7. Efficacy of D-dimer for predicting submassive PE stadium was only weak to moderate.

Heart rate in pulmonary embolism.

Heart rate is a rapidly available risk stratification parameter in acute pulmonary embolism (PE). We aimed to investigate the effectiveness of heart rate in predicting the outcome in acute PE. Data of 182 patients with acute PE were analysed retrospectively. Logistic regression models were calculated to investigate the associations between heart rate and in-hospital death, myocardial necrosis, PE status and presence of right ventricular dysfunction (RVD), respectively. ROC curve and cut-off values for heart rate predicting RVD as well as intermediate risk PE status in normotensive PE patients and for heart rate predicting in-hospital death and myocardial necrosis in all PE patients were calculated. ROC analysis for heart rate predicting RVD and intermediate risk PE were 0.706 and 0.718, respectively, with cut-off value of 86 beats/min. Regression models showed associations between heart rate >85 beats/min and both RVD (OR 4.871, 95 % CI 2.256-10.515, P = 0.000055) and intermediate risk PE (OR 5.244, 95 % CI 2.418-11.377, P = 0.000027). In hemodynamically stable and unstable PE patients, logistic regression models showed a borderline significant association between tachycardia and in-hospital death (OR 7.066, 95 % CI 0.764-65.292, P = 0.0849) and a significant association between heart rate and myocardial necrosis (OR 0.975, 95 % CI 0.959-0.991, P = 0.00203). ROC analysis for heart rate predicting in-hospital death and myocardial necrosis revealed AUC of 0.655 and 0.703 with heart rate cut-off values of 99.5 beats/min and 92.5 beats/min, respectively. An elevated heart rate in acute PE is connected with a worse outcome. Effectiveness in the prediction of RVD, intermediate PE status, cardiac injury and in-hospital death is acceptable. The cut-off value for the prediction of RVD and intermediate risk PE status in normotensive PE is 86 beats/min, while tachycardia predicts in-hospital death.

Impact of advanced age on the severity of normotensive pulmonary embolism.

The prevalence of pulmonary embolism (PE) increases progressively with age. Less data about the impact of increasing age on the severity of PE are available. The objectives of this study were to investigate the impact of increasing age on the severity of normotensive PE. Retrospective analysis of clinical, laboratory, radiological and echocardiagraphic data of normotensive patients with PE was performed. According to patients' age at the moment of acute PE event, the total number of 129 normotensive PE patients was subdivided into 4 age groups. In age groups 18-59, 60-69, 70-79 and 80-94 years were, respectively, a number of 30, 31, 33 and 35 patients included. Percentage of women in age groups increased with advanced age (P = 0.021). Systolic pulmonary artery pressure (PAP) (P < 0.0001) and frequency of incomplete or complete right bundle-branch block (RBBB) (P = 0.019), of right ventricular dysfunction (RVD) (P = 0.00031) and of submassive PE stadium with intermediate risk (P = 0.0016) increased significantly with growing age. Multivariable regression model confirmed an association between age and submassive PE [OR (per year) 1.04; 95 % CI, 1.02-1.07, P = 0.0020] as well as female gender and submassive PE (OR 2.45; 95 % CI, 1.10-5.50, P = 0.029) and tachycardia and submassive PE (OR 15.33; 95 % CI, 3.45-68.24, P = 0.00034). Advanced age, female gender and tachycardia are risk factors for a submassive PE with intermediate risk in normotensive PE patients. The percentage of PE patients with submassive PE, right ventricular overload, RVD, RBBB, elevated systolic PAP increases with advanced age.

Right ventricular dysfunction in hemodynamically stable patients with acute pulmonary embolism.

BACKGROUND: Echocardiography for risk stratification in hemodynamically stable patients with pulmonary embolism (PE) is well-established. Right ventricular dysfunction (RVD) is associated with an elevated mortality and adverse outcome. The aim of our study was to compare RVD criteria and investigate the role of elevated systolic pulmonary artery pressure (sPAP) in the diagnosis of RVD. METHODS: We retrospectively analyzed the echocardiographic and laboratory data of all hemodynamically stable patients with confirmed PE (2006-2011). The data were compared with three different definitions of RVD: Definition 1: RV dilatation, abnormal motion of interventricular septum, RV hypokinesis or tricuspid regurgitation. Definition 2: as with definition 1 but including elevated sPAP (>30mmHg). Definition 3: elevated sPAP (>30mmHg) as single RVD criterion. RESULTS: A total number of 129 patients (59.7% women, age 70.0years (60.7/81.0)) were included in this study. Median Troponin I level was measured as 0.02ng/ml (0/0.14); mean sPAP 33.9±18.5mmHg. The troponin cut-off levels for predicting a RVD of the 3 RVD definitions were in definition 1-3: >0.01ng/ml, >0.01ng/ml and >0.00ng/ml. Analysis of the ROC curve showed an AUC for RVD definitions 1-3: 0.790, 0.796 and 0.635. CONCLUSIONS: The combination of commonly used RVD criteria with added elevated sPAP improves the diagnosis of RVD in acute PE. Troponin I values of >0.01ng/ml in acute PE point to an RVD.

A 56-year-old man with co-prevalence of Leriche syndrome and dilated cardiomyopathy: case report and review.

We report about a 56-year-old man with dyspnoea and leg pain diagnosed with Leriche syndrome and chronic heart failure caused by dilated cardiomyopathy (DCM) with acute cardiac decompensation. Optimising of chronic heart failure therapy with diuretic and antihypertensive drugs leaded to recompensation. A defibrillator was implanted, and afterwards surgical therapy of Leriche syndrome was planned.Leriche syndrome is an uncommon variant of atherosclerotic occlusive disease characterised by total occlusion in abdominal aorta and/or both iliac arteries. If aortic stenosis develops slowly, collateral vascular circulation can be found frequently. Typical symptoms are claudication, symptoms related to an arterial insufficiency of the lower extremities, erectile dysfunction and weight loss. Risk factors of Leriche syndrome are diabetes mellitus, hypertension, hyperlipaemia and smoking. Further it is often associated with chronic renal failure and coronary artery disease. Diagnosis is normally made by computed tomography (CT) or magnetic resonance imaging (MRI). Standard therapy is surgical revascularisation.DCM is a common cause of a congestive heart failure, which could be induced by coronary artery disease, hypertension, toxic, metabolic, inflammatory and infectious agents, and inherited gene defects.

Cyclic vomiting syndrome in adults.

Cyclic vomiting syndrome (CVS) is a functional disorder that can occur in all age groups. It is characterized by recurrent stereotypic episodes of nausea and vomiting. Between these episodes are nausea-free intervals. Lack of awareness leads often to delay in making the correct diagnosis. A specific test to identify patients with CVS is still missing. The correct diagnosis is based on the typical anamnestic report and the exclusion of other disorders that are associated with recurrent vomiting. Treatment of acute vomiting episode comprises antiemetic, antimigraine and sedative therapy. For prophylaxis of vomiting episodes, amitriptyline and propranolol are frequently used.

Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes.

Colorectal cancers (CRCs) develop on the basis of a deficient DNA mismatch repair (MMR) system in about 15% of cases. MMR-deficient CRC lesions show high-level microsatellite instability (MSI-H) and accumulate numerous mutations located at coding microsatellite loci that lead to the generation of immunogenic neopeptides. Consequently, the host's antitumoral immune response is of high importance for the course of the disease in MSI-H CRC patients. Accordingly, immune evasion mediated by impairment of HLA class I antigen presentation is frequently observed in these cancers. In this study, we aimed at a systematic analysis of alterations affecting HLA class II antigen expression in MSI-H CRC. HLA class II antigens are expressed by only two-thirds of MSI-H CRCs. The mechanisms underlying the lack of HLA class II antigens in a subset of MSI-H CRCs remain unknown. We here screened HLA class II regulatory genes for the presence of coding microsatellites and identified mutations of the essential regulator genes RFX5 in 9 (26.9%) out of 34 and CIITA in 1 (2.9%) out of 34 MSI-H CRCs. RFX5 mutations were related to lack of or faint HLA class II antigen expression (p = 0.006, Fisher's exact test). Transfection with wild-type RFX5 was sufficient to restore interferon gamma-inducible HLA class II antigen expression in the RFX5-mutant cell line HDC108. We conclude that somatic mutations of the RFX5 gene represent a novel mechanism of loss of HLA class II antigen expression in tumor cells, potentially contributing to immune evasion in MSI-H CRCs.

Beta2-microglobulin mutations in microsatellite unstable colorectal tumors.

Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI-H) phenotype. MSI-H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI-H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI-H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the beta2-microglobulin (beta2m) gene. To examine the implications of beta2m mutations during MSI-H colorectal tumor development, we analyzed the prevalence of beta2m mutations in MSI-H colorectal adenomas (n=38) and carcinomas (n=104) of different stages. Mutations were observed in 6/38 (15.8%) MSI-H adenomas and 29/104 (27.9%) MSI-H CRCs. A higher frequency of beta2m mutations was observed in MSI-H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of beta2m mutations in HNPCC-associated MSI-H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI-H cancers. beta2m mutations were positively related to stage in tumors without distant metastases (UICC I-III), suggesting that loss of beta2m expression may promote local progression of colorectal MSI-H tumors. However, no beta2m mutations were observed in metastasized CRCs (UICC stage IV, p=0.04). These results suggest that functional beta2m may be necessary for distant metastasis formation in CRC patients.

T25 repeat in the 3' untranslated region of the CASP2 gene: a sensitive and specific marker for microsatellite instability in colorectal cancer.

DNA mismatch repair deficiency is observed in about 10% to 15% of all colorectal carcinomas and in up to 90% of hereditary nonpolyposis colorectal cancer (HNPCC) patients. Tumors with mismatch repair defects acquire mutations in short repetitive DNA sequences, a phenomenon termed high-level microsatellite instability (MSI-H). The diagnosis of MSI-H in colon cancer is of increasing relevance, because MSI-H is an independent prognostic factor in colorectal cancer, seems to influence the efficacy of adjuvant chemotherapy, and is the most important molecular screening tool to identify HNPCC patients. To make MSI typing feasible for the routine pathology laboratory, highly reproducible and cost effective laboratory tests are required. Here, we describe a novel T25 mononucleotide marker in the 3'untranslated region of the CASP2 gene (CAT25) that displayed a quasimonomorphic repeat pattern in normal tissue of 200 unrelated individuals of Caucasian origin. In addition, CAT25 was monomorphic also in all tested donors of African and Asian origin (n = 102 and n = 79, respectively) and thus differs from the most commonly used markers BAT25 and BAT26. Without the analysis of corresponding normal tissue, CAT25 correctly detected 56 of 57 colorectal cancer specimens classified as MSI-H by using the standard National Cancer Institute/International Collaborative Group-HNPCC marker panel. Combined with the standard markers BAT25 and BAT26 in a multiplex PCR, all MSI-H colorectal cancer samples were typed correctly. No false-positive results were obtained in 60 non-MSI-H control colorectal cancer specimens. These data suggest that CAT25 should be included into novel marker panels for microsatellite testing thus allowing for a significant reduction of the complexity and costs of MSI typing. Moreover, CAT25 represents a highly promising marker for early detection of colorectal cancer in HNPCC germ line mutation carriers.