Left Atrioventricular Transvalvular Pressure Gradients Derived from Intraoperative and Postoperative Echocardiograms following Atrioventricular Septal Defect Repair.

BACKGROUND: Left atrioventricular valve (LAVV) stenosis following an atrioventricular septal defect (AVSD) repair is a rare but potentially life-threatening complication. While echocardiographic quantification of diastolic transvalvular pressure gradients is paramount in the evaluation of a newly corrected valve function, it is hypothesized that these measured gradients are overestimated immediately following a cardiopulmonary bypass (CPB) due to the altered hemodynamics when compared to postoperative valve assessments using awake transthoracic echocardiography (TTE) upon recovery after surgery. METHODS: Out of the 72 patients screened for inclusion at a tertiary center, 39 patients undergoing an AVSD repair with both intraoperative transesophageal echocardiograms (TEE, performed immediately after a CPB) and an awake TTE (performed prior to hospital discharge) were retrospectively selected. The mean (MPGs) and peak pressure gradients (PPGs) were quantified using a Doppler echocardiography and other measures of interest were recorded (e.g., a non-invasive surrogate of the cardiac output and index (CI), left ventricular ejection fraction, blood pressures and airway pressures). The variables were analyzed using the paired Student's t-tests and Spearman's correlation coefficients. RESULTS: The MPGs were significantly higher in the intraoperative measurements when compared to the awake TTE (3.0 ± 1.2 vs. 2.3 ± 1.1 mmHg; p < 0.01); however, the PPGs did not significantly differ (6.6 ± 2.7 vs. 5.7 ± 2.8 mmHg; p = 0.06). Although the assessed intraoperative heart rates (HRs) were also higher (132 ± 17 vs. 114 ± 21 bpm; p < 0.001), there was no correlation found between the MPG and the HR, or any other parameter of interest, at either time-point. In a further analysis, a moderate to strong correlation was observed in the linear relationship between the CI and the MPG (r = 0.60; p < 0.001). During the in-hospital follow-up period, no patients died or required an intervention due to LAVV stenosis. CONCLUSIONS: The Doppler-based quantification of diastolic transvalvular LAVV mean pressure gradients using intraoperative transesophageal echocardiography seems to be prone to overestimation due to altered hemodynamics immediately after an AVSD repair. Thus, the current hemodynamic state should be taken into consideration during the intraoperative interpretation of these gradients.

Abdominal and Peripheral Tissue Oxygen Supply during Selective Lower Body Perfusion for the Surgical Repair of Congenital Heart Disease: A Pilot Study.

Background: Lower body perfusion (LBP) may be a strategy for maintaining organ perfusion during congenital heart disease surgery. It is hypothesized that renal and lower limb oxygen supply during LBP is superior to off-pump surgery and comparable to that of a standard cardiopulmonary bypass (CPB). Methods: in this prospective single-center study, patients aged <1 year were recruited if they were scheduled for a correction of aortic arch anomalies using antegrade cerebral perfusion and LBP (group 1), a repair of coarctation during aortic cross-clamping (group 2), or surgery under whole-body CPB (group 3). Renal (prefix "r") and peripheral (prefix "p") oxygen saturation (SO2), hemoglobin amount (Hb), blood velocity (Velo), and blood flow (Flow) were measured noninvasively. Results: A total of 23 patients were included (group 1, n = 9; group 2, n = 5; group 3, n = 9). Compared to the baseline values, rSO2 and pSO2 decreased significantly in group 2 compared to groups 1 and 3. Conversely, rHB significantly increased in group 2 compared to groups 1 and 3, reflecting abdominal venous stasis. Compared to group 3, group 1 showed a significantly lower pFlow during CPB; however, rFlow, pFlow, and pVelo did not differ. Conclusion: according to these observations, LBP results in an improved renal oxygen supply compared to off-pump surgery and may prove to be a promising alternative to conventional CPB.

Right ventricular volume-strain loops using 3D echocardiography-derived mesh models: proof-of-concept application on patients undergoing different types of open-heart surgery.

Background: Right ventricular (RV) function can be quantified by right heart catheterization-derived pressure-volume loops. While this technique is invasive, echocardiography-based volume-strain loops (VSLs) potentially reflect a non-invasive alternative. In this study, an approach to generate VSLs from volume and multidimensional strain data of 3D echocardiography-derived RV mesh models is evaluated with regard to feasibility and reproducibility. Methods: In a retrospective cohort study design, 3D intraoperative transesophageal echocardiograms of twenty-three patients undergoing aortic valve surgery (AVS) and eighteen patients undergoing off-pump coronary artery bypass (OPCAB) grafting were available prior to sternotomy and after sternal closure. RV meshes were generated using 3D speckle-tracking. Custom-made software quantified the meshes' volumes, global longitudinal (RV-GLS) and global circumferential strain (RV-GCS) for VSL generation. Linear regression of systolic VSLs yielded slopes, intercepts and systolic areas. Polynomial regression of two orders was used to analyze systolic-diastolic coupling at 10% increments of the RV end-diastolic volume (RVEDV). Reproducibility was analyzed by fourfold double-measurements of four datasets. Results: VSL calculation was feasible from all included 3D datasets. RV-GLS remained unaltered, but RV-GCS worsened in AVS [abs. diff. (∆) 3.9%, P<0.01] and OPCAB patients (∆4.5%, P<0.001). While RV-GCS systolic areas were markedly reduced at the end of AVS (∆268mL%, P<0.01) and OPCAB (∆185mL%, P<0.001), RV-GCS slopes did not change. Systolic-diastolic uncoupling was not observed, but in trend, decreased diastolic RV-GCS after AVS (P=0.06) and increased diastolic RV-GCS after OPCAB (P=0.06) were observed. Intraclass correlation coefficients (0.84-0.98) and coefficients of variation (6.4-11.8%) indicated good reproducibility. Conclusions: RV VSL generation using 3D echocardiography-derived mesh models is feasible. Longitudinal and circumferential strain vectors yield intrinsically different VSL indices. In future investigations, VSLs of multidimensional strains could provide further insight into periprocedural changes of RV mechanics.

Regional Right Ventricular Function Assessed by Intraoperative Three-Dimensional Echocardiography Is Associated With Short-Term Outcomes of Patients Undergoing Cardiac Surgery.

Background: The assessment of right ventricular (RV) function in patients undergoing elective cardiac surgery is paramount for providing optimal perioperative care. The role of regional RV function assessment employing sophisticated state-of-the-art cardiac imaging modalities has not been investigated in this cohort. Hence, this study investigated the association of 3D echocardiography-based regional RV volumetry with short-term outcomes. Materials and Methods: In a retrospective single-center study, patients undergoing elective cardiac surgery were included if they underwent 3D transesophageal echocardiography prior to thoracotomy. A dedicated software quantified regional RV volumes of the inflow tract, apical body and RV outflow tract employing meshes derived from 3D speckle-tracking. Echocardiographic, clinical and laboratory data were entered into univariable and multivariable logistic regression analyses to determine association with the endpoint (in-hospital mortality or the need for extracorporeal circulatory support). Results: Out of 357 included patients, 25 (7%) reached the endpoint. Inflow RV ejection fraction (RVEF, 32 ± 8% vs. 37 ± 11%, p = 0.01) and relative stroke volume (rel. SV) were significantly lower in patients who reached the endpoint (44 ± 8 vs. 48 ± 9%, p = 0.02), while the rel. SV of the apex was higher (38 ± 10% vs. 33 ± 8%, p = 0.01). Global left and right ventricular function including RVEF and left ventricular global longitudinal strain did not differ. In univariable logistic regression, tricuspid regurgitation grade ≥ 2 [odds ratio (OR) 4.24 (1.66-10.84), p < 0.01], inflow RVEF [OR 0.95 (0.92-0.99), p = 0.01], inflow rel. SV [OR 0.94 (0.90-0.99), p = 0.02], apex rel. SV [OR 1.07 (1.02-1.13), p < 0.01] and apex to inflow rel. SV ratio [OR 5.81 (1.90-17.77), p < 0.01] were significantly associated with the endpoint. In a multivariable model, only the presence of tricuspid regurgitation [OR 4.24 (1.66-10.84), p < 0.01] and apex to inflow rel. SV ratio [OR 6.55 (2.09-20.60), p < 0.001] were independently associated with the endpoint. Conclusions: Regional RV function is associated with short-term outcomes in patients undergoing elective cardiac surgery and might be helpful for optimizing risk stratification.

Association of Three-Dimensional Mesh-Derived Right Ventricular Strain with Short-Term Outcomes in Patients Undergoing Cardiac Surgery.

BACKGROUND: Three-dimensional (3D) right ventricular (RV) strain analysis is not routinely performed perioperatively. Although 3D RV strain adds incrementally to outcome prediction in various cardiac diseases, its role in the perioperative setting is not sufficiently understood. The aim of this study was to investigate the association between 3D RV strain measured on RV meshes created from 3D transesophageal echocardiographic data and short-term outcomes among patients undergoing cardiac surgery. METHODS: A total of 496 patients undergoing cardiac surgery who underwent intraoperative 3D transesophageal echocardiography (under general anesthesia, before sternotomy) were retrospectively selected, and RV meshes were generated using commercially available speckle-tracking software. Custom-made software automatically quantified longitudinal and circumferential RV strains on the mesh surfaces. Echocardiographic and clinical parameters were entered into logistic regression models to determine their associations with the primary (in-hospital death or need for extracorporeal life support) and secondary (postoperative ventilation > 48 hours) end points. RESULTS: Mesh-derived RV strain analysis was feasible in 94% of patients and revealed distinct regional patterns with basal-apical gradients for both longitudinal and circumferential strain. Thirty-seven patients (7.6%) reached the primary end point, and 118 patients (23.8%) reached the secondary end point. In a multivariable logistic regression model, serum lactate (P < .01), an emergency indication for surgery (P < .01), tricuspid regurgitation (P < .001), and mesh-derived RV global longitudinal strain (RV-GLS; P < .01) were independently associated with the primary end point, while established measures of RV function (3D RV ejection fraction, fractional area change, tricuspid annular plane systolic excursion) and left ventricular (LV) function (3D-derived LV ejection fraction and LV-GLS) were not independently associated. Hematocrit (P < .01), serum lactate (P < .001), pulmonary hypertension (P = .04), tricuspid regurgitation (P < .01), emergency procedures (P = .02), LV-GLS (P = .02), and RV-GLS (P < .001) were associated with the secondary end point. CONCLUSIONS: RV-GLS measured on RV meshes derived from 3D transesophageal echocardiography was independently associated with short-term outcomes in patients undergoing cardiac surgery and might be helpful for identifying patients at risk for adverse postoperative events.

The impact of dissection membrane motility on mid-term aortic remodelling after thoracic endovascular repair.

OBJECTIVES: The aim of this study was to assess preoperative dissection flap motility and to evaluate its impact on the aortic remodelling and the development of distal stent-induced new entry after thoracic endovascular aneurysm repair (TEVAR)/frozen elephant trunk (FET). METHODS: Patients with primary or residual type B dissections were included in a retrospective study with transoesophageal echocardiography analysis of the preoperative dissection flap motility assessed by the true lumen (TL) strain. Three-dimensional computing tomography centreline reconstructions before TEVAR/FET and during the follow-up were conducted to measure aortic remodelling: false lumen thrombosis, TL expansion and aortic diameters at 10 and 20 cm downstream the left subclavian artery, at the coeliac trunk and in the infrarenal aorta. All continuous variables are reported as median with first and third quartiles. RESULTS: Fifty-six consecutive patients were treated with TEVAR (n = 45) or FET (n = 11) in the acute (n = 16), subacute (n = 16) and chronic (n = 24) dissection phase. At a median follow-up of 6 (3-12) months, they showed a favourable TL expansion in the descending aorta, significantly higher in the acute [+9 mm (5-12); P < 0.001] and subacute groups [+5 mm (3-8); P = 0.039] than in the chronic group [+2 mm (0-5)]. The dissection flap motility parameter TL strain was superior in the acute (P = 0.006) and subacute (P = 0.035) groups in comparison to the chronic group. The motile flap [TL strain >22.5% (median)] was associated with a higher TL expansion rate in the thoracic aorta (P = 0.009) and a comparable distal stent-induced new entry incidence (overall: 16%) in comparison to the immobile flap (P = 0.89). CONCLUSIONS: The intraoperative assessment and the inclusion of the dissection flap motility parameters in the decision-making during TEVAR/FET may refine the distal endograft sizing for an improved remodelling of the TL.

[Vasopressors: Physiology, Pharmacology and Clinical Applications]. / Vasopressoren: Physiologie, Pharmakologie und klinischer Einsatz.

Vasopressors are widely used in anaesthesiology and critical care medicine, to treat harmless (e.g. anaesthesia-induced hypotension) as well as life-threatening conditions (e.g. septic shock). Some clinically used vasopressors resemble endogenous substances - such as norepinephrine - while others have been artificially synthesized (e.g. phenylephrine). Most of the substances used in different clinical scenarios have various effects except for vasoconstriction alone. Therefore, a thorough understanding of the pharmacology and clinical profile of every single substance is of highest importance prior to practical usage. Furthermore, the fundamentals of vascular physiology and vasotonic regulation are mandatory to safely provide vasopressor-based therapies. This article covers the essentials of physiology and pharmacology of vasopressors, and the clinical settings they are used in (e.g. septic shock, vasoplegic shock after cardiac surgery, trauma-induced hypotension).

Acute changes of global and longitudinal right ventricular function: an exploratory analysis in patients undergoing open-chest mitral valve surgery, percutaneous mitral valve repair and off-pump coronary artery bypass grafting.

BACKGROUND: Right ventricular (RV) function is an important prognostic indicator. The acute effects of cardiac interventions or cardiac surgery on global and longitudinal RV function are not entirely understood. In this study, acute changes of RV function during mitral valve surgery (MVS), percutaneous mitral valve repair (PMVR) and off-pump coronary artery bypass surgery (OPCAB) were investigated employing 3D echocardiography. METHODS: Twenty patients scheduled for MVS, 23 patients scheduled for PMVR and 25 patients scheduled for OPCAB were included retrospectively if patients had received 3D transesophageal echocardiography before and immediately after MVS, PMVR or OPCAB, respectively. RV global and longitudinal function was assessed using a 3D multiparameter set consisting of global right ventricular ejection fraction (RVEF), tricuspid annular plane systolic excursion (TAPSE), longitudinal contribution to RVEF (RVEFlong) and free wall longitudinal strain (FWLS). RESULTS: Longitudinal RV function was significantly depressed immediately after MVS, as reflected by all parameters (RVEFlong: 20 ± 5% vs. 13 ± 6%, p <  0.001, TAPSE: 13.1 ± 5.1 mm vs. 11.0 ± 3.5 mm, p = 0.04 and FWLS: -20.1 ± 7.1% vs. -15.4 ± 5.1%, p <  0.001, respectively). The global RVEF was slightly impaired, but the difference did not reach significance (37 ± 13% vs. 32 ± 9%, p = 0.15). In the PMVR group, both global and longitudinal RV function parameters were unaltered, whereas the OPCAB group showed a slight reduction of RVEFlong only (18 ± 7% vs. 14 ± 5%, p <  0.01). RVEFlong yielded moderate case-to-case but good overall reproducibility. CONCLUSIONS: TAPSE, FWLS and RVEFlong reflect the depression of longitudinal compared to global RV function initially after MVS. PMVR alone had no impact, while OPCAB had a slight impact on longitudinal RV function. The prognostic implications of these phenomena remain unclear and require further investigation.

The effects of anesthesia induction and positive pressure ventilation on right-ventricular function: an echocardiography-based prospective observational study.

BACKGROUND: General anesthesia induction with the initiation of positive pressure ventilation creates a vulnerable phase for patients. The impact of positive intrathoracic pressure on cardiac performance has been studied but remains controversial. 3D echocardiography is a valid and MRI-validated bed-side tool to evaluate the right ventricle (RV). The aim of this study was to assess the impact of anesthesia induction (using midazolam, sufentanil and rocuronium, followed by sevoflurane) with positive pressure ventilation (PEEP 5, tidal volume 6-8 ml/kg) on 2D and 3D echocardiography derived parameters of RV function. METHODS: A prospective observational study on fifty-three patients undergoing elective cardiac surgery in a tertiary care university hospital was designed. Transthoracic echocardiography exams were performed before and immediately after anesthesia induction and were recorded together with hemodynamic parameters and ventilator settings. RESULTS: After anesthesia induction TAPSE (mean difference - 1.6 mm (95% CI - 2.6 mm to - 0.7 mm; p = 0.0013) as well as the Tissue Doppler derived tricuspid annulus peak velocity (TDITVs') were significantly reduced (mean difference - 1.9% (95% CI: - 2.6 to - 1.2; p < 0.0001), but global right ventricular ejection fraction (RVEF; p = 0.1607) and right ventricular stroke volume (RVSV; p = 0.1838) did not change. CONCLUSIONS: This data shows a preserved right ventricular ejection fraction and right ventricular stroke volume after anesthesia induction and initiation of positive pressure ventilation. However, the baso-apical right ventricular function is significantly reduced. Larger studies are needed in order to determine the clinical impact of these findings especially in patients presenting with impaired right ventricular function before anesthesia induction. TRIAL REGISTRATION: Retrospecitvely registered, 6th June 2016, ClinicalTrials.gov Identifier NCT02820727 .

Novel mesh-derived right ventricular free wall longitudinal strain analysis by intraoperative three-dimensional transoesophageal speckle-tracking echocardiography: a comparison with conventional parameters.

Longitudinal right ventricular (RV) function is substantial and might be reflected by free wall longitudinal strain (FWLS). Software solutions for FWLS analysis by two-dimensional (2D) and three-dimensional (3D) transesophageal echocardiography (TEE) are available, but data on validation are sparse. In this study, a novel method for FWLS analysis on 3D meshes ("mesh surface", MS-FWLS,) was tested for feasibility and compared to available parameters. 80 patients undergoing left-sided cardiac valve surgery with intraoperative TEE were included retrospectively. 2D-FWLS, 3D-derived (3Dd)-FWLS (assessed in optimized four-chamber views after volume analysis) and MS-FWLS were measured and compared to conventional parameters (3Dd-TAPSE, FAC and RVEF). The mean FWLS values did not differ significantly between methods (- 19.0 ± 6.1%, - 20.0 ± 7.3%, - 19.5 ± 7.3% for 2D-, 3Dd- and MS-FWLS, respectively). No significant differences in the mean FWLS between patients with normal or increased pulmonary artery pressures as well as normal or reduced left ventricular ejection fraction were observed. Agreement was best between 3Dd- and MS-FWLS (r = 0.89, bias = - 1.0%, LOA ± 6.9%). Conventional echocardiographic parameters yielded poorer intermodality agreement. In patients with discrepant results between 2D- and 3Dd-FWLS, 3Dd-FWLS and MS-FWLS yielded similar results (r = 0.82, bias = - 0.3%, LOA ± 8.6%), while 2D-FWLS and MS-FWLS did not. Intra- and interobserver variabilities of strain analyses were low. MS-FWLS might represent a promising method to overcome artefacts associated with 2D analysis. Its prognostic relevance needs to be investigated in prospective studies.

Regional Right Ventricular Volume and Function Analysis Using Intraoperative 3-Dimensional Echocardiography-Derived Mesh Models.

OBJECTIVES: In daily echocardiographic practice, the right ventricle (RV) is assessed using mostly 2-dimensional (2D) echocardiography. Parameters measuring longitudinal shortening (eg, tricuspid annular plane systolic excursion) or changes in areas (eg, fractional area change) are used as surrogates for right ventricular function. Three-dimensional (3D) echocardiography-based techniques allow for cardiac magnetic resonance imaging-validated assessment of the RV. Depiction of regional right ventricular function is of increasing clinical interest. This study aimed to calculate regional volumetric changes in the right ventricular inlet, apical section, and outflow tract. Correlations between traditional parameters and regional right ventricular function were studied. DESIGN: Retrospective cohort study on patients scheduled for cardiac surgery. SETTING: Tertiary care university hospital. PARTICIPANTS: The study comprised 80 patients scheduled for cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Based on 3D echocardiographic datasets, mesh models of the RV were generated on a vendor-independent platform. The meshes were further cut into the following 3 regions: the inlet part, the apical section, and the outflow tract. The regional volumes and ejection fractions were compared with the global right ventricular and left ventricular functions. Regional volumes were correlated linearly with the global end-diastolic volume. The right ventricular outflow tract demonstrated a significantly lower ejection fraction than the inlet part (34% ± 11% v 28% ± 11%; p = 0.0054). The function in the right ventricular outflow tract was reduced significantly compared with the global right ventricular function in patients with severely reduced left ventricular ejection fraction (<20%). CONCLUSION: The different parts of the RV seem to have different ejection fractions. Different regions of the RV are affected differently by reduced left ventricular ejection fraction. Regional right ventricular analyses could help clinicians better understand pathologic states of the RV.

Comparison of immunohistochemistry with PCR for assessment of ER, PR, and Ki-67 and prediction of pathological complete response in breast cancer.

BACKGROUND: Proliferation may predict response to neoadjuvant therapy of breast cancer and is commonly assessed by manual scoring of slides stained by immunohistochemistry (IHC) for Ki-67 similar to ER and PgR. This method carries significant intra- and inter-observer variability. Automatic scoring of Ki-67 with digital image analysis (qIHC) or assessment of MKI67 gene expression with RT-qPCR may improve diagnostic accuracy. METHODS: Ki-67 IHC visual assessment was compared to the IHC nuclear tool (AperioTM) on core biopsies from a randomized neoadjuvant clinical trial. Expression of ESR1, PGR and MKI67 by RT-qPCR was performed on RNA extracted from the same formalin-fixed paraffin-embedded tissue. Concordance between the three methods (vIHC, qIHC and RT-qPCR) was assessed for all 3 markers. The potential of Ki-67 IHC and RT-qPCR to predict pathological complete response (pCR) was evaluated using ROC analysis and non-parametric Mann-Whitney Test. RESULTS: Correlation between methods (qIHC versus RT-qPCR) was high for ER and PgR (spearman´s r = 0.82, p < 0.0001 and r = 0.86, p < 0.0001, respectively) resulting in high levels of concordance using predefined cut-offs. When comparing qIHC of ER and PgR with RT-qPCR of ESR1 and PGR the overall agreement was 96.6 and 91.4%, respectively, while overall agreement of visual IHC with RT-qPCR was slightly lower for ER/ESR1 and PR/PGR (91.2 and 92.9%, respectively). In contrast, only a moderate correlation was observed between qIHC and RT-qPCR continuous data for Ki-67/MKI67 (Spearman's r = 0.50, p = 0.0001). Up to now no predictive cut-off for Ki-67 assessment by IHC has been established to predict response to neoadjuvant chemotherapy. Setting the desired sensitivity at 100%, specificity for the prediction of pCR (ypT0ypN0) was significantly higher for mRNA than for protein (68.9% vs. 22.2%). Moreover, the proliferation levels in patients achieving a pCR versus not differed significantly using MKI67 RNA expression (Mann-Whitney p = 0.002), but not with qIHC of Ki-67 (Mann-Whitney p = 0.097) or vIHC of Ki-67 (p = 0.131). CONCLUSION: Digital image analysis can successfully be implemented for assessing ER, PR and Ki-67. IHC for ER and PR reveals high concordance with RT-qPCR. However, RT-qPCR displays a broader dynamic range and higher sensitivity than IHC. Moreover, correlation between Ki-67 qIHC and RT-qPCR is only moderate and RT-qPCR with MammaTyper® outperforms qIHC in predicting pCR. Both methods yield improvements to error-prone manual scoring of Ki-67. However, RT-qPCR was significantly more specific.

WHO grade related expression of TRAIL-receptors and apoptosis regulators in meningioma.

BACKGROUND AND AIMS: The expression of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and key regulators of the extrinsic apoptosis pathway correlate with clinical features and the WHO grade of malignancy in some tumor entities. Expression of pro-apoptotic TRAIL receptors and executioners of apoptosis are a prerequisite for TRAIL-based therapies as a promising future targeted therapy. METHODS: Human meningioma tissues (n=24 WHO grade I, n=7 WHO grade II, n=6 WHO grade III) were immunohistochemically analyzed for the expression of TRAIL-R1, TRAIL-R2, TRAIL-R3, TRAIL-R4, caspase-8, cFLIP, Bcl-2, Bcl-XL, Mcl-1, Bax, and Bak. Staining intensities were quantified by an automated software-based algorithm. RESULTS: While TRAIL-R1 and TRAIL-R3 were nearly absent in meningiomas, TRAIL-R2 and TRAIL-R4 were abundantly expressed. However, only TRAIL-R4 expression correlated with the WHO grade of malignancy. Bcl-2 showed a non-significant upregulation in WHO grade III meningiomas. Bcl-XL and Mcl-1 expression was significantly higher in WHO grade II compared to grade I. Bcl-XL and TRAIL-R4 expression correlated with the mitotic activity (Ki67) of the tumor. Furthermore, TRAIL-R2 expression correlated with TRAIL-R4. Bak expression correlated with both, Bcl-XL and Mcl-1 expression. The expression patterns did neither correlate with the progression-free nor with the overall survival of the meningioma patients. CONCLUSIONS: Apoptosis-inducing TRAIL-R2 and all key executioners of the extrinsic apoptosis pathway are abundantly expressed in meningioma. For some regulators of apoptosis with opposite functions, the expression of the pro-apoptotic protein significantly correlated with the expression level of the respective anti-apoptotic binding partner, possibly resulting in a steady-state of apoptosis. TRAIL-R2 might serve as a novel therapeutic target in meningioma.

T1 mapping in dilated cardiomyopathy with cardiac magnetic resonance: quantification of diffuse myocardial fibrosis and comparison with endomyocardial biopsy.

AIM: The aim of this study was to determine the value of extracellular volume fraction (ECV) for the non-invasive assessment of diffuse myocardial fibrosis (MF) in different stages of systolic left ventricular (LV) dysfunction in dilated cardiomyopathy (DCM) in comparison with endomyocardial biopsy. BACKGROUND: Non-invasive ECV assessment using cardiovascular magnetic resonance (CMR) T1 mapping reflects diffuse MF in patients with severe DCM, but earlier stages of DCM with mild LV functional impairment have not been investigated yet. METHODS: Forty-five subjects with mild functional impairment and LV dilation ['early DCM', ejection fraction (EF) 45-55%], 29 with LV dysfunction and volume dilatation ('DCM', EF <45%) and 56 healthy volunteers (controls) underwent standard CMR imaging, late gadolinium enhancement (LGE) and T1 mapping for the calculation of ECV. The collagen volume fraction (CVF) was quantified histologically from endomyocardial biopsies of 24 DCM patients out of the study cohort. RESULTS: The ECV between 'early DCM' (25 ± 4%), 'DCM' (27 ± 4%), and controls (23 ± 3; P < 0.05 for all) differed significantly. There was a weak inverse correlation between ECV and EF (r = -0.35; P < 0.01). A strong correlation between ECV and CVF could be detected (r = 0.85; P = 0.01). The cut-off value for ECV to differentiate between healthy myocardium and DCM was 26% (specificity 91.1%, sensitivity 62.1%, area under the curve 0.8, P < 0.0001). ECV is already elevated at early stages of functional impairment, whereby an overlap between early DCM and controls is present. But 31% of the early DCM patients had an ECV fraction above the mean ±2 SD ECV of controls. CONCLUSIONS: ECV measurement with CMR reflects myocardial collagen content in DCM. Therefore, CMR-based assessment of ECV may have the potential to serve as a non-invasive tool for the quantification of diffuse MF in order to monitor therapy response and aid risk stratification in different stages of DCM.

Bortezomib sensitizes primary meningioma cells to TRAIL-induced apoptosis by enhancing formation of the death-inducing signaling complex.

A meningioma is the most common primary intracranial tumor in adults. Here, we investigated the therapeutic potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in 37 meningiomas. Freshly isolated primary meningioma cells were treated with TRAIL with or without different sensitizing protocols, and apoptotic cell death was then quantified. Mechanisms of TRAIL sensitization were determined by a combination of Western blotting, flow cytometry, receptor complex immunoprecipitation, and siRNA-mediated knockdown experiments. Tumor necrosis factor-related apoptosis-inducing ligand receptor expression was analyzed using immunohistochemistry and quantified by an automated software-based algorithm. Primary tumor cells from 11 (29.7%) tumor samples were sensitive to TRAIL-induced apoptosis, 12 (32.4%) were intermediate TRAIL resistant, and 14 (37.8%) were completely TRAIL resistant. We tested synergistic apoptosis-inducing cotreatment strategies and determined that only the proteasome inhibitor bortezomib potently enhanced expression of the TRAIL receptors TRAIL-R1 and/or TRAIL-R2, the formation of the TRAIL death-inducing signaling complex, and activation of caspases; this treatment resulted in sensitization of all TRAIL-resistant meningioma samples to TRAIL-induced apoptosis. Bortezomib pretreatment induced NOXA expression and downregulated c-FLIP, neither of which caused the TRAIL-sensitizing effect. Native TRAIL receptor expression could not predict primary TRAIL sensitivity. This first report on TRAIL sensitivity of primary meningioma cells demonstrates that TRAIL/bortezomib cotreatment may represent a novel therapeutic option for meningiomas.

Interobserver agreement of proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids.

Evaluation of proliferative activity is a cornerstone in the classification of endocrine tumors; in pulmonary carcinoids, the mitotic count delineates typical carcinoid (TC) from atypical carcinoid (AC). Data on the reproducibility of manual mitotic counting and other methods of proliferation index evaluation in this tumor entity are sparse. Nine experienced pulmonary pathologists evaluated 20 carcinoid tumors for mitotic count (hematoxylin and eosin) and Ki-67 index. In addition, Ki-67 index was automatically evaluated with a software-based algorithm. Results were compared with respect to correlation coefficients (CC) and kappa values for clinically relevant grouping algorithms. Evaluation of mitotic activity resulted in a low interobserver agreement with a median CC of 0.196 and a median kappa of 0.213 for the delineation of TC from AC. The median CC for hotspot (0.658) and overall (0.746) Ki-67 evaluation was considerably higher. However, kappa values for grouped comparisons of overall Ki-67 were only fair (median 0.323). The agreement of manual and automated Ki-67 evaluation was good (median CC 0.851, median kappa 0.805) and was further increased when more than one participant evaluated a given case. Ki-67 staining clearly outperforms mitotic count with respect to interobserver agreement in pulmonary carcinoids, with the latter having an unacceptable low performance status. Manual evaluation of Ki-67 is reliable, and consistency further increases with more than one evaluator per case. Although the prognostic value needs further validation, Ki-67 might perspectively be considered a helpful diagnostic parameter to optimize the separation of TC from AC.