Optimal Diagnostic Performance Research Articles

Diagnostic Accuracy of Transient Elastography for Detecting Liver Fibrosis After Liver Trannsplantation: A Specific Cut-Off Value Is Really Needed?

Liver transplant recipients often perform liver biopsy (LB), specially in the context of potentially recurring diseases, such as hepatitis C infection. However, the LB has risks of complications, despite being the gold standard. Transient elastography (TE) is a noninvasive method comparable to the LB to evaluate liver fibrosis in various settings, but its accuracy among transplant recipients is not fully understood. To determine the accuracy of TE in liver transplant recipients compared with LB to successfully predict liver fibrosis. Patients who underwent liver transplantation at Hospital Israelita Albert Einstein from 2010 to 2012 and presented with LB indication were also subjected to TE at the time of LB. The medium value of ten successful measurements was kept as a representative of the liver stiffness. The definition of cut-off points was made to ensure specificity of ≥90% for all fibrosis stages (F0-F4). LB was performed in 267 patients. TE was not analyzed in only 8 (3%) due to an elevated body mass index. The optimal liver stiffness cut-off value and diagnostic performance were 8.1kPa for F≥1, 12.3kPa for F≥2, 15.1 for F≥3, and 16.7 for F=4 for all patients and were 8.1kPa for F≥1, 12.3kPa for F≥2, 16.5 for F≥3, and 17.6 for F=4 for patients with hepatitis C. TE demonstrated good performance in defining cut-off points for fibrosis on liver histology observed in transplant recipients. The TE can be considered an alternative to LB in post-liver transplantation.

A cannabinoid link between mitochondria and memory

To evaluate the performance of the combination of diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) for differentiating radiologically indeterminate malignant from benign orbital masses.Sixty-five patients with orbital masses (36 benign and 29 malignant) underwent DW and DCE MRI examinations for pre-treatment evaluation. The apparent diffusion coefficient (ADC) was derived from DW imaging data using the mono-exponential model. The volume transfer constant (Ktrans), the flux rate constant between the extravascular extracellular space and the plasma (Kep), and the extravascular extracellular volume fraction (Ve) were calculated using modified Tofts model. Differences in quantitative metrics were tested using independent-samples t test. Receiver operating characteristic (ROC) curve analyses were used to determine and compare the diagnostic ability of each significant metric.The malignant group demonstrated significantly lower ADC (0.711±0.260 versus 1.187±0.389, p<0.001) and higher Kep values (1.265±0.637 versus 0.871±0.610, p=0.008) than the benign group. Optimal diagnostic performance (area under the ROC curve [AUC], 0.941; sensitivity, 0.966; specificity, 0.917) could be achieved using combined ADC and Kep values as the diagnostic index. The diagnostic performance of the combination of ADC and Kep was significantly better than Kep alone (p=0.006). Compared with ADC alone, combined ADC and Kep values also showed higher AUC (0.941 versus 0.898), although the difference did not reach statistical significance (p=0.220).Kep and ADC could help to differentiate radiologically indeterminate malignant from benign orbital masses. The combination of DW and DCE MRI might improve the differentiating performance.

Diagnostic values of red cell distribution width, platelet distribution width and neutrophil-lymphocyte count ratio for sepsis.

The aim of this study was to evaluate the diagnostic efficiency of red blood cell distribution width (RDW), platelet distribution width (PDW), the neutrophil-lymphocyte count ratio (NLCR), procalcitonin (PCT) and C-reactive protein (CRP) for the prediction of sepsis. A total of 120 consecutive patients who underwent blood culture testing were included. The PCT and CRP levels, and RDW, PDW and NLCR percentages were determined and compared between patients with positive blood cultures and those without. The PCT, CRP, RDW, PDW and NLCR values were significantly higher in patients with positive blood culture compared with those without. PCT and NLCR each had a high diagnostic performance for the prediction of sepsis, with an area under the curve (AUC) for sepsis of 0.829 and 0.718, respectively. A combination of RDW, PDW and NLCR also exhibited a good diagnostic performance for sepsis (AUC, 0.704). NLCR is easily obtained by automated hematological analysis. Moreover, NLCR was found to have a high diagnostic efficiency for the prediction of sepsis, with greater sensitivity and accuracy than CRP. In conclusion, PCT exhibited the optimal diagnostic performance among the tested markers. The combination of the three parameters of RDW, PDW and NLCR, demonstrated a high diagnostic performance similar to that of PCT.

Diagnosis of pulmonary hypertension from magnetic resonance imaging-based computational models and decision tree analysis.

Accurately identifying patients with pulmonary hypertension (PH) using noninvasive methods is challenging, and right heart catheterization (RHC) is the gold standard. Magnetic resonance imaging (MRI) has been proposed as an alternative to echocardiography and RHC in the assessment of cardiac function and pulmonary hemodynamics in patients with suspected PH. The aim of this study was to assess whether machine learning using computational modeling techniques and image-based metrics of PH can improve the diagnostic accuracy of MRI in PH. Seventy-two patients with suspected PH attending a referral center underwent RHC and MRI within 48 hours. Fifty-seven patients were diagnosed with PH, and 15 had no PH. A number of functional and structural cardiac and cardiovascular markers derived from 2 mathematical models and also solely from MRI of the main pulmonary artery and heart were integrated into a classification algorithm to investigate the diagnostic utility of the combination of the individual markers. A physiological marker based on the quantification of wave reflection in the pulmonary artery was shown to perform best individually, but optimal diagnostic performance was found by the combination of several image-based markers. Classifier results, validated using leave-one-out cross validation, demonstrated that combining computation-derived metrics reflecting hemodynamic changes in the pulmonary vasculature with measurement of right ventricular morphology and function, in a decision support algorithm, provides a method to noninvasively diagnose PH with high accuracy (92%). The high diagnostic accuracy of these MRI-based model parameters may reduce the need for RHC in patients with suspected PH.

Global proteomic profiling in multistep hepatocarcinogenesis and identification of PARP1 as a novel molecular marker in hepatocellular carcinoma.

The more accurate biomarkers have long been desired for hepatocellular carcinoma (HCC). Here, we characterized global large-scale proteomics of multistep hepatocarcinogenesis in an attempt to identify novel biomarkers for HCC. Quantitative data of 37874 sequences and 3017 proteins during hepatocarcinogenesis were obtained in cohort 1 of 75 samples (5 pooled groups: normal livers, hepatitis livers, cirrhotic livers, peritumoral livers, and HCC tissues) by iTRAQ 2D LC-MS/MS. The diagnostic performance of the top six most upregulated proteins in HCC group and HSP70 as reference were subsequently validated in cohort 2 of 114 samples (hepatocarcinogenesis from normal livers to HCC) using immunohistochemistry. Of seven candidate protein markers, PARP1, GS and NDRG1 showed the optimal diagnostic performance for HCC. PARP1, as a novel marker, showed comparable diagnostic performance to that of classic markers GS and NDRG1 in HCC (AUCs = 0.872, 0.856 and 0.792, respectively). A significant higher AUC of 0.945 was achieved when three markers combined. For diagnosis of HCC, the sensitivity and specificity were 88.2% and 81.0% when at least two of the markers were positive. Similar diagnostic values of PARP1, GS and NDRG1 were confirmed by immunohistochemistry in cohort 3 of 180 HCC patients. Further analysis indicated that PARP1 and NDRG1 were associated with some clinicopathological features, and the independent prognostic factors for HCC patients. Overall, global large-scale proteomics on spectrum of multistep hepatocarcinogenesis are obtained. PARP1 is a novel promising diagnostic/prognostic marker for HCC, and the three-marker panel (PARP1, GS and NDRG1) with excellent diagnostic performance for HCC was established.

Transferring cut-off values between assays for cerebrospinal fluid Alzheimer's disease biomarkers.

Current technologies quantifying cerebrospinal fluid biomarkers to identify subjects with Alzheimer's disease pathology report different concentrations in function of technology and suffer from between-laboratory variability. Hence, lab- and technology-specific cut-off values are required. It is common practice to establish cut-off values on small datasets and, in the absence of well-characterized samples, to transfer the cut-offs to another assay format using 'side-by-side' testing of samples with both assays. We evaluated the uncertainty in cut-off estimation and the performance of two methods of cut-off transfer by using two clinical datasets and simulated data. The cut-off for the new assay was transferred by applying the commonly-used linear regression approach and a new Bayesian method, which consists of using prior information about the current assay for estimation of the biomarker's distributions for the new assay. Simulations show that cut-offs established with current sample sizes are insufficiently precise and also show the effect of increasing sample sizes on the cut-offs' precision. The Bayesian method results in unbiased and less variable cut-offs with substantially narrower 95% confidence intervals compared to the linear-regression transfer. For the BIODEM datasets, the transferred cut-offs for INNO-BIA Aβ1-42 are 167.5 pg/mL (95% credible interval [156.1, 178.0] and 172.8 pg/mL (95% CI [147.6, 179.6]) with Bayesian and linear regression methods, respectively. For the EUROIMMUN assay, the estimated cut-offs are 402.8 pg/mL (95% credible interval [348.0, 473.9]) and 364.4 pg/mL (95% CI [269.7, 426.8]). Sample sizes and statistical methods used to establish and transfer cut-off values have to be carefully considered to guarantee optimal diagnostic performance of biomarkers.

Comparative diagnostic performance of volumetric laser endomicroscopy and confocal laser endomicroscopy in the detection of dysplasia associated with Barrett’s esophagus

Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barrett's esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia. A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria. The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < .01). The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.

An Investigation of the Utility of the Addenbrooke's Cognitive Examination III in the Early Detection of Dementia in Memory Clinic Patients Aged over 75 Years

Background/Aims: To examine the validity of Addenbrooke's Cognitive Examination III (ACE-III) in detecting early dementia in UK memory clinic patients aged 75-85 years. Methods: The ACE-III was administered to 59 patients prior to diagnosis. The extent to which scores predicted the membership of the dementia or no-dementia group was explored using receiver operating characteristic curve analysis and other parameters of diagnostic performance. Thirty-three participants (55.9%) were diagnosed with dementia (Alzheimer's disease = 56.3%, Alzheimer's disease with cerebrovascular disease = 31.3%, and vascular dementia = 12.5%). Results: The optimal cut-off for detecting dementia was 81/100 (scores <81 indicating dementia with a sensitivity of 0.79, a specificity of 0.96, and a positive predictive value of 0.96), with superiority over published cut-offs (88/100 and 82/100) at medium and lower prevalence rates. The number of years of full-time education had a significant positive relationship to total ACE-III scores (r = 0.697, p < 0.001) for the no-dementia group. Exploratory analysis indicated that optimal cut-offs were different for higher versus lower education groups. Conclusions: The ACE-III has excellent accuracy for the detection of dementia in day-to-day clinical practice. Lower cut-offs than those specified in the index paper, and the consideration of the patients' years of full-time education may be necessary for optimal diagnostic performance.

The clinical value of dynamic contrast-enhanced MRI in differential diagnosis of malignant and benign ovarian lesions.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used in preoperative diagnosis of various tumors. We investigated the clinical value of DCE-MRI in differential diagnosis of malignant and benign ovarian lesions. The study involved 48 subjects with surgical pathology-confirmed ovarian tumors with solid components. Early dynamic phase enhancement performances of the ovarian lesions in patients were assessed, including the enhancement pattern, time-signal intensity curve (TIC), signal intensity rate at the initial 60 s (SI60), time to peak within 200 s (TTP200), and slope ratio. There were significant differences in enhancement patterns between benign and malignant ovarian tumors (P < .05). A total of 30 malignant tumors (30/31) displayed type I TIC, 8 benign tumors (8/13) showed type III TIC, and significant differences were found in TIC type between malignant and benign ovarian lesions (P < 0.01). Benign ovarian tumors showed lower SI60 (%) and slope ratio, as well as significantly prolonged TTP20, compared to malignant ovarian tumors (all P < 0.01). The microvessel count (MVC) of malignant tumors was significantly higher than that of benign tumors (P < 0.05). Receiver operating characteristic (ROC) curve analyses revealed that DCE-MRI provided an optimal diagnostic performance with threshold values of SI60 at 83.40 %, TTP200 at 77.65 s, and slope ratio at 4.12. These findings revealed that DCE-MRI provides critical information required for differential diagnosis of malignant and benign ovarian lesions.

Cytokines and clinical predictors in distinguishing pulmonary transfusion reactions.

Pulmonary transfusion reactions are important complications of blood transfusion, yet differentiating these clinical syndromes is diagnostically challenging. We hypothesized that biologic markers of inflammation could be used in conjunction with clinical predictors to distinguish transfusion-related acute lung injury (TRALI), transfusion-associated circulatory overload (TACO), and possible TRALI. In a nested case-control study performed at the University of California at San Francisco and Mayo Clinic, Rochester, we evaluated clinical data and blood samples drawn before and after transfusion in patients with TRALI (n = 70), possible TRALI (n = 48), TACO (n = 29), and controls (n = 147). Cytokines measured included granulocyte-macrophage-colony-stimulating factor, interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-α. Logistic regression and receiver operating characteristics curve analyses were used to determine the accuracy of clinical predictors and laboratory markers in differentiating TACO, TRALI, and possible TRALI. Before and after transfusion, IL-6 and IL-8 were elevated in patients with TRALI and possible TRALI relative to controls, and IL-10 was elevated in patients with TACO and possible TRALI relative to that of TRALI and controls. For all pulmonary transfusion reactions, the combination of clinical variables and cytokine measurements displayed optimal diagnostic performance, and the model comparing TACO and TRALI correctly classified 92% of cases relative to expert panel diagnoses. Before transfusion, there is evidence of systemic inflammation in patients who develop TRALI and possible TRALI but not TACO. A predictive model incorporating readily available clinical and cytokine data effectively differentiated transfusion-related respiratory complications such as TRALI and TACO.

Evaluation of bioelectrical impedance analysis for identifying overweight individuals at increased cardiometabolic risk: a cross-sectional study.

ObjectiveTo investigate whether bioelectrical impedance analysis could be used to identify overweight individuals at increased cardiometabolic risk, defined as the presence of metabolic syndrome and/or diabetes.Design and MethodsCross-sectional study of a Scottish population including 1210 women and 788 men. The diagnostic performance of thresholds of percentage body fat measured by bioelectrical impedance analysis to identify people at increased cardiometabolic risk was assessed using receiver-operating characteristic curves. Odds ratios for increased cardiometabolic risk in body mass index categories associated with values above compared to below sex-specific percentage body fat thresholds with optimal diagnostic performance were calculated using multivariable logistic regression analyses. The validity of bioelectrical impedance analysis to measure percentage body fat in this population was tested by examining agreement between bioelectrical impedance analysis and dual-energy X-ray absorptiometry in a subgroup of individuals.ResultsParticipants were aged 16-91 years and the optimal bioelectrical impedance analysis cut-points for percentage body fat for identifying people at increased cardiometabolic risk were 25.9% for men and 37.1% for women. Stratifying by these percentage body fat cut-points, the prevalence of increased cardiometabolic risk was 48% and 38% above the threshold and 24% and 19% below these thresholds for men and women, respectively. By comparison, stratifying by percentage body fat category had little impact on identifying increased cardiometabolic risk in normal weight and obese individuals. Fully adjusted odds ratios of being at increased cardiometabolic risk among overweight people with percentage body fat ≥25.9/37.1% compared with percentage body fat <25.9/37.1% as a reference were 1.93 (95% confidence interval: 1.20–3.10) for men and 1.79 (1.10–2.92) for women.ConclusionPercentage body fat measured using bioelectrical impedance analysis above a sex-specific threshold could be used in overweight people to identify individuals at increased cardiometabolic risk, who could benefit from risk factor management.

Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator.

Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays. Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR. We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C. A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

Saline Contrast Echocardiography for the Detection of Patent Foramen Ovale in Hypoxia: A Validation Study Using Intracardiac Echocardiography

Although the "3 beat rule" is widely utiized to discriminate patent foramen ovale (PFO)-mediated right-to-left shunt (RTLS) from intrapulmonary RTLS using saline contrast transthoracic echocardiography (SCE), SCE diagnostic performance has yet to be validated using an invasive intracardiac standard. Percutaneous PFO occluder placement was recently shown to ameliorate hypoxia in patients with suspected PFO-mediated RTLS. We evaluated the ability of SCE to predict PFO presence and size using intracardiac echocardiography (ICE) as a gold standard in a hypoxic cohort. Sixty-three hypoxic patients with suspected PFO-mediated RTLS who underwent SCE at rest, with Valsalva maneuver, and with cough prior to ICE were evaluated retrospectively. PFO RTLS was defined by ICE findings including PFO anatomy, RTLS by saline contrast and color Doppler, and probe patency. SCE shunt severity and timing of left heart saline target appearance were compared to the presence of ICE-defined PFO RTLS. Forty-seven patients (75%) met criteria for PFO-mediated RTLS. A 4 beat cutoff for resting SCE provided optimal diagnostic performance for detection of PFO-mediated RTLS with a 71% sensitivity, 94% specificity, and 97% positive predictive value (PPV). Valsalva and cough maneuvers improved sensitivity compared to rest SCE (89% and 80%, respectively). Valsalva SCE shunt severity more accurately predicted PFO size than resting SCE. In contrast to the widely accepted "3 beat rule," resting SCE for the detection of PFO RTLS in a hypoxic population performs optimally using a 4-cycle cutoff with both excellent specificity and PPV.

Towards an optimal semiquantitative approach in giant cell arteritis: an 18F-FDG PET/CT case-control study

Giant cell arteritis (GCA) is the most common form of vasculitis in western countries. (18)F-FDG PET has been shown to be a valuable tool for the diagnosis of extracranial GCA, but results of studies are inconsistent due to a lack of standardized (18)F-FDG PET criteria. In this study, we compared different semiquantitative approaches using a controlled design to define the most efficient method. All patients with biopsy-proven GCA who had undergone an (18)F-FDG PET/CT scan in our PET unit were reviewed and matched with a control group based on age and sex. Different semiquantitative arterial (ascending and descending thoracic aorta and aortic arch) to background (liver, lung and venous blood pool) SUV ratios were blindly compared between GCA patients and matched controls. We included 11 patients with biopsy-proven GCA cases and 11 matched controls. There were no differences between the groups with regard to body weight, injected radioactivity, blood glucose level or CRP. The arterial to venous blood pool ratios discriminated the two groups better than other methods when applied to the aortic arch and the descending thoracic aorta (p<0.015). In particular, the highest aortic to highest blood pool SUVmax ratio, when applied to the aortic arch, provided optimal diagnostic performance (sensitivity 81.8 %, specificity 91 %, AUC 0.87; p<0.0001) using a cut-off value of 1.53. Among all tested (18)F-FDG PET/CT methods, the aortic to blood pool SUVmax ratio outperformed the liver and lung ratios. We suggest the use of this ratio for the assessment of aortic inflammation in GCA patients.

Performance comparison of immunodiffusion, enzyme-linked immunosorbent assay, immunochromatography and hemagglutination for serodiagnosis of human pythiosis

Pythiosis is a life-threatening infectious disease caused by the fungus-like organism Pythium insidiosum. Morbidity and mortality rates of pythiosis are high. The treatment of choice for pythiosis is surgical debridement of infected tissue. Early and accurate diagnosis is critical for effective treatment. In-house serodiagnostic tests, including immunodiffusion (ID), enzyme-linked immunosorbent assay (ELISA), immunochromatography (ICT) and hemagglutination (HA) have been developed to detect antibodies against P. insidiosum in sera. This study compares the diagnostic performance of ID, ELISA, ICT, and HA, using sera from 37 pythiosis patients and 248 control subjects. ICT and ELISA showed optimal diagnostic performance (100% sensitivity, specificity, positive predictive value and negative predictive value). ICT was both rapid and user-friendly. ELISA results were readily quantitated. ID is relatively insensitive. HA was rapid, but diagnostic performance was poor. Understanding the advantages offered by each assay facilitates selection of an assay that is circumstance-appropriate. This will promote earlier diagnoses and improved outcomes for patients with pythiosis.

Abstract 9139: Inspiratory and Expiratory Main Pulmonary Artery Dimensions on Chest CT Exclude Pulmonary Hypertension in Chronic Obstructive Pulmonary Disease

Background: Pulmonary hypertension (PH) is present in 30-70% of chronic obstructive pulmonary disease (COPD) and is a strong predictor of morbidity and mortality. Although previous studies have demonstrated that a chest CT-determined main pulmonary artery diameter (MPAD) of ≥ 29 mm during inspiration is associated with PH, these have utilized small groups of heterogenous pulmonary disease. Consequently, the predictive value of MPAD in a pure COPD population remains unknown. In addition, previous studies have not evaluated the diagnostic utility of expiratory phase MPAD. Since variable inspiratory effort and loading of the pulmonary vasculature may confound efforts to predict PH, expiratory phase MPAD measurement may be a reliable indicator of PH. COPDGene is multicenter prospective study that correlates genotype with chest CT COPD phenotype. Using a large subgroup of the COPDGene cohort, we hypothesized that inspiratory MPAD (iMPAD) and expiratory MPAD (eMPAD) on chest CT accurately predict PH when defined by echocardiographic estimation of RVSP in a cohort of COPD patients. Methods: COPDGene subjects who completed both high-resolution chest CT as well as echocardiography were included for analysis. Cross-sectional iMPAD and eMPAD were measured at the widest dimension at the level of the aorta using the VIDA Pulmonary Workstation 2 software by 3 blinded readers. Based upon the previous World Health Organization definition of mild PH as 40-50 mmHg, a right ventricular systolic pressure (RVSP) ≥ 45 mmHg was classified as PH. Results: Multivariate regression analysis of 182 COPD subjects revealed significant correlations between RVSP and iMPAD (r .45, p &lt; .0001) as well as eMPAD (r .41, p &lt; .0001). Optimal diagnostic performance of iMPAD occurred at ≥ 28 mm with an AUC of .69 and a NPV of 88% but a PPV of only 38%. In comparison, optimal performance of eMPAD occurred at ≥ 31 mm with an equal AUC (69%) and nearly equivalent NPV (85%) and PPV (42%). Conclusions: Both iMPAD and eMPAD perform with excellent NPV but poor PPV for prediction of PH in a COPD cohort. In contrast to previous studies indicating good PPV in heterogenous pulmonary disease populations, the diagnostic utility of pulmonary artery diameter measurement in the COPD population may reside in its NPV for PH.

Heat Shock Protein 90 (Hsp90) Activity Status Is An Independent Prognostic Marker in Chronic Lymphocytic Leukemia (CLL) and Correlates with IgVH Mutational Status, ZAP-70 Expression and Time to First Treatment

Abstract 2544The clinical presentation of chronic lymphocytic leukemia (CLL) is variable and includes at least two distinct clinical subtypes: indolent or progressive disease. Several prognostic markers such as the mutational status of the IgVH genes or ZAP-70 expression identify patients that will have more aggressive clinical courses. We have previously reported that ZAP-70 expression in CLL requires the support and stability provided by the Hsp90 activated complex (Hsp90-AC) and that Hsp90 inhibitors induce apoptosis in CLL cells preferentially in patients with high–risk/rapid progressive disease.Hsp90 requires the conformation of a multimeric complex with other co-chaperones (Hop, p23) to become active and function as a chaperone for mutated, over-expressed, misfolded or constitutively activated proteins. However, to measure Hsp90-AC activity is challenging and requires protein assays that are semi-quantitative and not always can provide a functional read out. To address this problem we designed a test to measure Hsp90-AC by taking advantage of the higher avidity of this complex to bind Hsp90 inhibitors such as 17-AAG. We hypothesize that Hsp90-AC activity is an independent prognostic marker of disease progression in CLL and to test this we measured the ability of 17-AAG to inhibit Hsp90-AC and promote apoptosis in vitro in a cohort of previously untreated CLL patients. This evaluation was performed in samples collected at the time of diagnosis and the results were correlated with the time from diagnosis to first treatment (t-Tx1) as well as the presence of other known prognostic markers.Ninety-five previously untreated CLL patients were included in this cohort. In vitro sensitivity/apoptosis to Hsp90-AC inhibition using 17-AAG (1μg/ml) was measured by flow cytometry using DiOC6 and PI after 48 hours of incubation. Only samples with more than 60% viability were included and we selected a cut-point of ≥ 53% induction of apoptosis to determine if a sample was sensitive or not to Hsp90-AC inhibition (This cut-point was selected using a ROC analysis for optimal diagnostic performance).We found that 37 patients (39%) were sensitive to 17-AAG. These patient had a median time from diagnosis to first treatment (t-Tx1) of 7 years compared to 4.2 years in patients that were resistant to 17-AAG (p=0.04). In addition, 37 patients (39%) had unmutated IgVH genes with a median t-Tx1 of 8.7 years compared to 4.2 years in patients with mutated IgVH genes (p=0.02) and 41 patients (43%) had high levels of ZAP-70 expression (>20% by flow cytometry) and this group of patients had a median t-Tx1 of 7 years vs. 4.2 years in ZAP-70 negative patients (p=0.03). We evaluated the association between the degree of Hsp90-AC inhibition (17-AGG sensitivity) and IgVH mutational status and found a strong correlation between these two variables with shorter t-Tx1 in patients that were IgVH unmutated and sensitive to Hsp90 inhibitor (p=0.0003). We found a similar strong correlation between ZAP-70 expression and sensitivity to Hsp90-AC inhibitor (p=0.003). In our patient cohort, we saw that IgVH, ZAP-70 and Hsp90 inhibitor sensitivity are independent prognostic markers in CLL (Cox regression, p=0.002). We found that the sensibility and specificity of ZAP-70 test for high-risk CLL (sensitivity 81.1% [95% IC 67–95%] and specificity 77.6%[95% IC 65–90%]) was increased when the Hsp90-AC inhibitor sensitivity test was added (sensitivity 87% [95% IC 71–100%] and specificity 91%[95% IC 79–100%]).In conclusion, in vitro inhibition of Hsp90-AC in CLL using 17-AAG is an independent prognostic maker and strong predictor of the need for treatment. Hsp90-AC inhibition showed a high correlation with IgVH mutational status and ZAP-70 expression. Additionally, patients sensitive to 17-AAG whose leukemic cells also highly express ZAP-70 appear to have the worst prognosis with the shortest t-Tx1. Our data suggest that in vitro sensitivity to 17-AAG at the time of diagnosis serves as a quantitative surrogate marker for Hsp90-AC activity and correlates with disease progression in CLL. This is the first time that such correlation has been established in a cohort of cancer patients and shows the relevance of the Hsp90 chaperone system in cancer biology and disease progression. Disclosures:No relevant conflicts of interest to declare.

Acute Myocarditis: Diagnostic Value of Contrast-Enhanced Cine Steady-State Free Precession MRI Sequences

MRI has become the primary tool for assessment of myocardial inflammation in patients with suspected acute myocarditis. Optimal diagnostic performance is achieved with late gadolinium-enhanced sequences, but cine balanced steady-state free precession (SSFP) MRI sequences are routinely used to evaluate cardiac function. Our aim was to prospectively assess the diagnostic value of unenhanced and contrast-enhanced cine SSFP MRI sequences in comparison with late gadolinium-enhanced sequences for imaging of patients with strong evidence of acute myocarditis. Eighteen patients with strong evidence of acute myocarditis underwent 1.5-T cardiac MRI. Unenhanced and contrast-enhanced cine SSFP images and late gadolinium-enhanced images were obtained. The images were analyzed both qualitatively and quantitatively. Data were analyzed with analysis of variance and the Bonferroni test or paired Student t test. Areas of high signal intensity were detected in 28% (5/18), 94% (17/18), and 89% (16/18) of patients on unenhanced cine, contrast-enhanced cine, and late gadolinium-enhanced images. In one patient, contrast-enhanced cine images revealed subepicardial areas of high signal intensity that were not visible on late gadolinium-enhanced images. The location and transmural nature of involved segments matched on contrast-enhanced cine and late gadolinium-enhanced images (both, r = 0.91, p < 0.0001). The contrast-to-noise ratio was significantly higher on contrast-enhanced cine images than on late gadolinium-enhanced images (p < 0.05). Contrast-enhanced cine MRI is a valuable tool for detection of lesions of acute myocarditis and should be recommended for routine clinical MRI.

MDCT Bolus Tracking Data as an Adjunct for Predicting the Diagnosis of Pulmonary Hypertension and Concomitant Right-Heart Failure

The purpose of this study was to investigate the utility of bolus-triggering data from pulmonary CT angiography for predicting the diagnosis of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) and to test its performance against previously established CT signs of PH. Automated bolus-triggering data from pulmonary CT angiograms of 101 patients were correlated with echocardiographic findings and a variety of CT-derived indexes of PH and RVD, including right and left ventricular minor axis diameter; pulmonary artery (PA), aortic, and superior vena caval diameters; right ventricular thickness; contrast reflux; and configuration of the interventricular septum. For bolus triggering, a region of interest was placed in the main PA. Time to threshold, defined as the time from the beginning of contrast injection to the time attenuation exceeded the threshold (100 HU), was measured. On the basis of results of two consecutive echocardiographic studies, subjects were divided into control and PH groups. The latter group was subdivided into PH without RVD and PH with RVD. Time to threshold values were compared between groups and correlated with standard CT-derived parameters. Significant differences between groups were found in time to threshold, PA and right ventricular diameters, and PA-to-aorta and right ventricular-to-left ventricular ratios. Time to threshold had an incremental pattern from the control group (6.6 ± 1.0 seconds) to PH without RVD (9.2 ± 2.4 seconds) and PH with RVD (12.1 ± 3.4 seconds) (p < 0.001). The optimal diagnostic performance of time to threshold for revealing the presence of PH and RVD was at cutoff values of 7.75 and 8.75 seconds, respectively. Time to threshold had a strong direct correlation with PA diameter. In multivariable analyses, time to threshold was identified as a significant predictor of PH and RVD. The specificity of time to threshold and PA diameter together was higher than that of PA diameter alone. Measurement of time to threshold of contrast enhancement derived from bolus-timing data at MDCT may be a useful adjunctive tool for diagnosing PH and consequent RVD.

MRI and “Tenderness Guided” transvaginal ultrasonography in the diagnosis of recto‐sigmoid endometriosis

To compare the diagnostic accuracy of MRI and "tenderness-guided" transvaginal ultrasonography (tg-TVUS) in the identification of recto-sigmoid endometriosis. Institutional Review Board approval for this study was obtained, and written informed consent was given by all patients. This study is compliant with the STARD (Standards for Reporting of Diagnostic Accuracy) method. Fifty-nine patients (mean age, 33 years; range, 21-44 years) with clinical suspicion of deep pelvic endometriosis were prospectively enrolled. They underwent tg-TVUS and MRI before surgery. The characteristics of the MRI signal were analyzed. Mapping of recto-sigmoid endometriosis was performed and tg-TVUS and MR imaging results were compared with surgical and pathological findings. Sensitivity, specificity, and the positive and negative likelihood ratio (LR+ and LR-) were calculated. Inter-technique concordance was assessed using the Cohen statistic, and receiver operating characteristic (ROC) curves were obtained. Logistic regression analysis was performed. The prevalence of recto-sigmoid endometriosis was 51%. The specificity, sensitivity, and LR+ and LR- were 90%, 73%, 7.089 and 0.297, respectively, for MRI and 86%, 73%, 5.317 and 0.309, respectively, for tg-TVUS. The presence of a high T1 signal spot was an excellent specific finding (100%) but was associated with a low sensitivity (30%). Inter-technique concordance using the Cohen statistic indicated a kappa value of 0.658 (± 0.098 SD). According to the logistic regression equation obtained, the use of both tg-TVUS and MRI allows optimal diagnostic performance. MRI and tg-TVUS show similar results in the identification of recto-sigmoid endometriosis. The Cohen kappa value suggests that these methods may have complementary roles in the identification of recto-sigmoid endometriosis, depending on the site affected.