Correction to: Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

Following publication of the original article [1], the authors reported the following errors in the article.

Relationship between tumor biomarkers and efficacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer.

BACKGROUND: The phase III EMILIA and TH3RESA trials demonstrated clinical benefits of trastuzumab emtansine (T-DM1) therapy in patients with previously treated HER2-positive metastatic breast cancer (MBC). Data from these and other trials showed that T-DM1-associated survival benefits were observed across biomarker subgroups tested in these trials. Prespecified, exploratory analyses of the phase III MARIANNE study examined the effects of HER2-related biomarkers on PFS in patients administered T-DM1 in the first-line MBC setting. METHODS: In MARIANNE, patients with previously untreated HER2-positive MBC were randomized (1:1:1) to trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. Biomarker subgroups included HER2 and HER3 mRNA expression levels (≤median vs. >median), HER2 staining intensity (IHC 3+ vs. 2+ vs. 0/1+), PIK3CA status (mutated vs. non-mutated), PTEN H-score (≤median vs. >median), and PTEN protein expression level (0 vs. 1+ vs. 2+ vs. 3+ vs. 4+). PFS was analyzed descriptively for each subgroup using Kaplan-Meier methodology. Additional exploratory post-hoc analyses evaluated the effects of HER2 heterogeneity. Multivariate analyses were also performed. RESULTS: Median PFS was numerically longer for patients with HER2 mRNA levels >median versus ≤median across treatment arms. In general, there were no predictive biomarkers of benefit for either T-DM1 treatment arm; most hazard ratios were close to 1 with wide confidence intervals that included the value 1. Focal HER2 expression (IHC 3+ or IHC 2+) was present in 3.8% of patients and was associated with numerically shorter PFS in the T-DM1-containing treatment arms versus trastuzumab plus taxane. Compared with non-mutated PIK3CA, mutated PIK3CA was associated with numerically shorter median PFS across treatment groups. Post-hoc multivariate analysis showed HER2 mRNA expression and mutated PIK3CA were prognostic for PFS (P ≤ 0.001 for both biomarkers). CONCLUSIONS: In MARIANNE, biomarkers related to the HER2 pathway did not have predictive value for PFS when comparing T-DM1 (with or without pertuzumab) with trastuzumab plus taxane. However, HER2 mRNA level and PIK3CA mutation status showed prognostic value. Evaluation of other potential biomarkers, including immune markers, is ongoing. TRIAL REGISTRATION: Registration number: NCT01120184 . Date of registration: April 28, 2010 (registered prospectively).

Evaluation of riproximin binding properties reveals a novel mechanism for cellular targeting.

Riproximin is a cytotoxic type II ribosome-inactivating protein showing high selectivity for tumor cell lines. Its binding to cell surface glycans is crucial for subsequent internalization and cytotoxicity. In this paper, we describe a unique mechanism of interaction and discuss its implications for the cellular targeting and cytotoxicity of riproximin. On a carbohydrate microarray, riproximin specifically bound to two types of asialo-glycans, namely to bi- and triantennary complex N-glycan structures (NA2/NA3) and to repetitive N-acetyl-D-galactosamine (GalNAc), the so-called clustered Tn antigen, a cancer-specific O-glycan on mucins. Two glycoproteins showing high riproximin binding, the NA3-presenting asialofetuin and the clustered Tn-rich asialo-bovine submaxillary mucin, were subsequently chosen as model glycoproteins to mimic the binding interactions of riproximin with the two types of glycans. ELISA analyses were used to relate the two binding specificities of riproximin to its two sugar binding sites. The ability of riproximin to cross-link the two model proteins revealed that binding of the two types of glycoconjugates occurs within different binding sites. The biological implications of these binding properties were analyzed in cellular assays. The cytotoxicity of riproximin was found to depend on its specific and concomitant interaction with the two glycoconjugates as well as on dynamic avidity effects typical for lectins binding to multivalent glycoproteins. The presence of definite, cancer-related structures on the cells to be targeted determines the therapeutic potency of riproximin. Due to its cross-linking ability, riproximin is expected to show a high degree of specificity for cells exposing both NA2/NA3 and clustered Tn structures.

Transcriptomic hepatotoxicity signature of chlorpromazine after short- and long-term exposure in primary human sandwich cultures.

Drug-induced liver injury is the most frequent reason for market withdrawal of approved drugs, and is difficult to predict in animal models. Here, we analyzed transcriptomic data derived from short- and long-term cultured primary human hepatocytes (PHH) exposed to the well known human hepatotoxin chlorpromazine (CPZ). Samples were collected from five PHH cultures after short-term (1 and 3 days) and long-term (14 days) repeat daily treatment with 0.1 or 0.2 µM CPZ, corresponding to C(max). Two PHH cultures were additionally treated with 1 µM CPZ, and the three others with 0.02 µM CPZ. Differences in the total number of gene changes were seen between donors and throughout treatment. Specific transcriptomic hepatotoxicity signatures were created for CPZ and consisted of inflammation/hepatitis, cholestasis, and liver proliferation in all five donors, as well as fibrosis and steatosis, which were observed in four of five donors. Necrosis was present in three of five donors, and an indicative signature of cirrhosis was observed after long-term 14-day repeat treatment, also in three of five donors. The inter-donor variability in the inflammatory response to CPZ treatment was associated with variability in the strength of the response of the transcriptomic hepatotoxicity signatures, suggesting that features of inflammation could be related to the idiosyncratic hepatotoxic effects of CPZ in humans.

Semiautomated versus manual evaluation of liver metastases treated by radiofrequency ablation.

PURPOSE: To determine the accuracy of semiautomated volume and density measurements of liver metastases from colorectal and breast cancer before and after radiofrequency (RF) ablation compared with manual evaluation. MATERIALS AND METHODS: Twenty-five patients (mean age, 63.2 years +/- 10.7) with 50 known liver metastases from underlying primary breast (n = 15) or colorectal cancer (n = 35) underwent triphasic contrast-enhanced multidetector computed tomography (CT) to evaluate hepatic tumor load and localization before RF ablation and for postinterventional follow-up. Each lesion was quantified in terms of volume and CT value (in HU) with a semiautomated software tool and manually by an experienced radiologist before and 4 months after RF ablation. RESULTS: Before RF ablation, all 50 liver metastases, and after ablation, 49 of 50 ablation zones (98%), were correctly evaluated by the software. Mean lesion volumes before and after the intervention were 5.5 cm(3) and 22.4 cm(3), respectively. Corresponding concordance correlation coefficients between measurement techniques were 0.98 and 0.99, respectively, for volume; and 0.90 and 0.76, respectively, for CT value. CONCLUSIONS: Compared with manual measurements, semiautomated volumetric assessment of liver metastases before and after RF ablation demonstrated a high degree of correlation. Agreement of attenuation was slightly worse, particularly when assessing the postinterventional multidetector CT examination, probably because of the different regions of interest used for manual and semiautomated assessment of CT values.

Association of fetuin-A levels with the progression of aortic valve calcification in non-dialyzed patients.

AIMS: Fetuin-A has been identified as a potent circulating inhibitor of ectopic calcification. We investigated the relationship between baseline fetuin-A serum levels and the rate of progression of aortic valve calcification (AVC) in non-dialyzed patients with aortic valve disease (AVD). METHODS AND RESULTS: Seventy-seven patients (mean age 70 +/- 8 years) with echocardiographically proven AVD were collected. In all patients, serum fetuin-A levels, creatinine, calcium, lipid parameters, and C-reactive protein were measured at baseline. For quantification of AVC progression, all patients underwent multislice spiral computed tomography examinations at baseline and after a mean follow-up of 12.6 +/- 1.4 months (range 7-18 months). In a multifactorial analysis of covariance including fetuin-A levels, baseline AVC score, the covariables sex, age, body mass index, C-reactive protein, glomerular filtration rate, serum lipids, diabetes, smoking status, and hypertension, only serum fetuin-A levels significantly predict the progression of AVC (P < 0.001). Post hoc analysis demonstrated that patients with baseline fetuin-A levels lower than the median of the cohort (0.72 g/L) showed a significantly higher increase of AVC scores (34.6 +/- 31.4%) than patients with fetuin-A levels larger than the median (10.0 +/- 11.2%, P < 0.001) despite comparable baseline AVC scores. In addition, fetuin-A levels were associated with major adverse clinical events (MACE; P = 0.03). CONCLUSION: Serum levels of the calcification inhibitor fetuin-A are associated with the progression of AVC and MACE, independent of the renal function and inflammation.

Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification.

Matrix-Gla Protein (MGP) is a vitamin K-dependent protein acting as a local inhibitor of vascular calcification. Vitamin K-antagonists (oral anticoagulant; OAC) inhibit the activation of MGP by blocking vitamin K-metabolism. The aim of this study was to investigate the effect of long-term OAC treatment on circulating MGP levels in humans and on MGP expression in mice. Additionally, we tested the association between circulating inactive MGP (ucMGP) levels and the presence and severity of AVC in patients with aortic valve disease (AVD). We analysed circulating ucMGP levels in 191 consecutive patients with echocardiographically proven calcific AVD and 35 control subjects. The extent of AVC in the patients was assessed by multislice spiral computed tomography. Circulating ucMGP levels were significantly lower in patients with AVD (348.6 +/- 123.1 nM) compared to the control group (571.6 +/- 153.9 nM, p < 0.001). Testing the effect of coumarin in mice revealed that also the mRNA expression of MGP in the aorta was downregulated. Multifactorial analysis revealed a significant effect of glomerular filtration rate and long-term OAC therapy on circulating ucMGP levels in the patient group. Subsequently, patients on long-term OAC had significantly increased AVC scores. In conclusion, patients with calcific AVD had significantly lower levels of circulating ucMGP as compared to a reference population, free of coronary and valvular calcifications. In addition, our data suggest that OAC treatment may decrease local expression of MGP, resulting in decreased circulating MGP levels and subsequently increased aortic valve calcifications as an adverse side effect.

Longitudinal monocyte human leukocyte antigen-DR expression is a prognostic marker in critically ill patients with decompensated liver cirrhosis.

BACKGROUND: Critical illness in cirrhotic patients is associated with a poor prognosis and increased susceptibility to infections. Monocyte HLA-DR expression is decreased in cirrhotic patients, but its prognostic value has not been investigated prospectively. METHODS: Thirty-eight critically ill patients with decompensated liver cirrhosis were included in this prospective study. On admission to the intensive care unit (ICU), inflammatory parameters (C-reactive protein, procalcitonin and lipopolysaccharide-binding protein), interleukin (IL)-10, interferon (IFN)-gamma serum levels, tumour necrosis factor (TNF)-alpha ex vivo stimulation (whole blood assay) and HLA-DR expression on monocytes (FACS analysis) were determined. Immune parameters were furthermore measured every third day until discharge from the ICU or death of the patients. RESULTS: Intensive care unit mortality of the cirrhotic patients was 34.2%. During admission, TNF ex vivo, IFN-gamma and HLA-DR expression were lower in non-survivors (all P<0.05), while IL-10 levels were increased in non-survivors compared with survivors (P=0.001). However, individual values clearly overlapped between groups. Prospective analysis revealed that monocyte HLA-DR expression remained stable or increased in survivors, but decreased in non-survivors (P=0.002). A decrease in HLA-DR expression between admission and day 3 was strongly associated with decreased IFN-gamma levels and increased ICU mortality (hazard ratio 3.36, P=0.008), mostly owing to late sepsis. This association was independent of the sequential organ failure assessment and model for end-stage liver disease score. CONCLUSIONS: Here we establish the relative HLA-DR expression (admission/day 3) as a prognostic marker for ICU mortality in critically ill cirrhotic patients. These results may guide the evaluation of immune-modulating therapies in these patients.

Automated measurement of lymph nodes: a phantom study.

The purpose of this study was to assess the accuracy of automated nodal quantification in a phantom. MDCT of a phantom with 17 synthetic lymph nodes of different sizes (diameter 6.0-30.0 mm) was performed at varying tube currents, reconstruction kernels and slice thicknesses. RECIST diameter and volume were measured using an automated software tool. Results were compared with the reference diameter and volume by calculating the absolute percentage error (APE). Degree of agreement between software and reference measurements was evaluated by computing corresponding concordance correlation coefficients (CCC). Under varying tube currents the mean APE (CCC) varied between 5.18% and 10.12% (0.95-0.99) for RECIST diameter and between 7.22% and 16.21% (0.94-1.00) for the volume. At different reconstruction kernels the mean APE values ranged between 7.20% and 7.55% (0.99) (RECIST) and between 8.96% and 14.42% (1.00) (volume). With different slice thicknesses the mean APE values differed from 5.81% to 9.20% (0.97-0.99) (RECIST) and from 8.16% to 22.66% (0.99-1.00) (volume). Regarding RECIST criteria and volume, automated evaluation of lymph nodes in a phantom demonstrated a high accuracy under varying MDCT parameters.

The role of the composite interleukin-1 genotype in the association between periodontitis and acute myocardial infarction.

BACKGROUND: Recent data indicate that interleukin (IL)-1 polymorphism may influence the susceptibility to periodontitis and coronary heart diseases. The aim of this study was to evaluate the impact of the composite IL-1 genotype (allele 2 at IL-1A -889 and IL-1B +3954) in the association between acute myocardial infarction (AMI) and periodontitis. METHODS: One hundred four white subjects (54 patients with AMI and 50 healthy controls) were studied; each received a comprehensive periodontal examination, including measurement of periodontal probing depth (PD) and clinical attachment level (CAL). The extent of periodontitis was assessed by the percentage of sites with clinical AL >3 mm. Polymorphisms in the IL-1 gene cluster were assessed using a reverse hybridization assay. RESULTS: Compared to controls, mean values for PD (4.6 mm versus 3.7 mm; P <0.0001) and CAL (5.4 mm versus 4.5 mm; P = 0.0001) were significantly increased among patients with AMI. Significantly more subjects with moderate or severe periodontitis (> or =33% of sites with clinical AL >3 mm) were found in the AMI group compared to controls (31.5% versus 8%; P = 0.0016). These differences remained statistically significant after adjustment for smoking, age, and gender. No significant differences were observed in the allele frequencies of the gene loci IL-1A -889 and IL-1B +C3954 between patients with AMI and controls. Also, there was no difference in the frequency of the composite IL-1 genotype. IL-1 genotype-positive patients with AMI had slightly increased PD and AL compared to IL-1 genotype-negative patients with AMI. CONCLUSIONS: The results confirmed an association between periodontitis and AMI but failed to detect a modifying impact of the composite IL-1 genotype. Although the IL-1 genotype was only weakly associated with compromised periodontal health, it was not associated with AMI.

Ablation of articular cartilage with an erbium:YAG laser: an ex vivo study using porcine models under real conditions-ablation measurement and histological examination.

BACKGROUND AND OBJECTIVES: The use of an erbium:YAG laser in arthroscopic surgery has the advantage of a precise treatment of soft tissue. Due to the high absorption in water, the laser energy is perfectly matched to smoothing the hydrous, fibrillated articular cartilage surface. In minimal invasive surgery, the workspace is filled with aqueous liquids for enlargement. This appears contrary to the absorption characteristics of erbium:YAG laser radiation in water. The purpose of this study was to evaluate the ablated volume per pulse of cartilage lesions and the potential side effects including thermal damage and tissue necrosis. STUDY DESIGN/MATERIALS AND METHODS: Twenty-four osteochondral specimens of porcine knee joints were irradiated with an Er:YAG laser completely submerged in water, with distances to the cartilage surface of 1, 3 and 5 mm and pulse durations of 75 and 100 microseconds. To keep a constant peak power of approximately 6 kW, pulse energies of 450 and 580 mJ were used at a pulse repetition rate of 15 Hz. After a histological preparation, ablated volumes, depths, and widths of the cuts were investigated. Additionally, laser protocols were correlated with different markers of cartilage tissue damage and apoptosis. RESULTS: Ablation could be observed for every measurement. The influence of the distance showed a statistical significance (P < 0.001) for the volume, depth, and width of the cuts. For the pulse duration, statistical significance (P < 0.001) was found only for the volume and the depth. We observed no loss of proteoglycan or collagen type II. The total cell number, cell morphology, and number of apoptotic cells in an area close to the cutting edge and in a corresponding unaffected area of the same specimens revealed no differences regardless of the applied protocol. CONCLUSION: The use of an Er:YAG laser demonstrates the successful application in liquid environments for cartilage removal without any damage of the surrounding tissue.

[Non-contact monitoring of heart and lung activity using magnetic induction measurement in a neonatal animal model]. / Kontaktlose Uberwachung von Atemtätigkeit und Herzaktion mittels magnetischer Bioimpedanzmessung in einem neonatalen Tiermodell.

BACKGROUND: Magnetic induction measurement (MIM) allows the identification of resistance in biologic tissues by alternating magnetic fields. These occur when well-conducting (blood) and poor-conducting matter (air) is moved through the thorax during heart and lung activity. As a result, allocation of the resistance changes and the total resistance of the thorax is shifted. By using coils, these changes can be registered in a non-contact manner and recorded. To date, this measuring principle was employed only in adult volunteers or in full-grown pigs. A neonatal animal model has not yet been described. The aim of this study was to test the hypothesis that non-contact monitoring of heart and lung activity using MIM in a porcine newborn piglet model can be applied in order to evaluate neonatal disorders of heart and lung activity in the future. MATERIALS AND METHODS: By using five coils (three measurement and two excitation coils), placed at the bottom of an experimental incubator, magnetic induction changes, depending on the heart and lung activity in 16 analgosedated piglets, were simultaneously measured and compared with pulse oximetry and airflow detection (flow resistance and pressure differential sensor) as reference signals. In addition, spontaneous breathing, including apnea, CPAP (continuous positive airway pressure to prevent end-expiratory alveolar collapse, flow 8 l/min; pressure 5 cm H(2)O), mechanical ventilation (inspiratory pressure 14 cm H(2)O; frequency 40/min) and high frequency oxygenation ventilation (HFOV, ventilation method in lung failure) (frequency 10 Hz, mean pressure 10 cm H(2)O, amplitude 1.5) were performed. Lung activity with MIM compared with the reference signal was estimated with a detection rate (%) of "correct registered lung activity". To quantify the analogy between MIM and reference signal for heart activity, the concordance correlation coefficient after Lin (95% confidence interval) and the Bland-Altman plot were calculated. RESULTS AND DISCUSSION: The detection rate for breathing [%] of MIM compared with the reference signal under CPAP was 88% [95% CI: (87.1%; 88.5%)], mechanical ventilation 91% [95% CI: (90.3%; 91.2%)] and under HFOV 95% [95% CI: (94.7%; 94.9%)]. For heart activity, during apnea the difference between MIM and reference signal was 1.1 bpm (+/-11.3 SD) in apnea and during HFOV 5.3 bpm (+/-26.4 SD). Under spontaneous breathing it was not possible to achieve a correlation. Owing to interference problems, registration of heart activity with MIM during simultaneous breathing activity (CPAP, conventional mechanical ventilation, HFOV) was insufficient. CONCLUSION: Non-contact monitoring of lung activity using MIM in a neonatal piglet model is possible under specific conditions. These results might be a basis for the development of non-invasive parameters in neonatology. It also provides the possibility of obtaining more information about the characteristics of lung activity of the newborn.

Sequencing chemotherapy and radiotherapy in locoregional advanced breast cancer patients after mastectomy - a retrospective analysis.

BACKGROUND: Combined chemo- and radiotherapy are established in breast cancer treatment. Chemotherapy is recommended prior to radiotherapy but decisive data on the optimal sequence are rare. This retrospective analysis aimed to assess the role of sequencing in patients after mastectomy because of advanced locoregional disease. METHODS: A total of 212 eligible patients had a stage III breast cancer and had adjuvant chemotherapy and radiotherapy after mastectomy and axillary dissection between 1996 and 2004. According to concerted multi-modality treatment strategies 86 patients were treated sequentially (chemotherapy followed by radiotherapy) (SEQgroup), 70 patients had a sandwich treatment (SW-group) and 56 patients had simultaneous chemoradiation (SIM-group) during that time period. Radiotherapy comprised the thoracic wall and/or regional lymph nodes. The total dose was 45-50.4 Gray. As simultaneous chemoradiation CMF was given in 95.4% of patients while in sequential or sandwich application in 86% and 87.1% of patients an anthracycline-based chemotherapy was given. RESULTS: Concerning the parameters nodal involvement, lymphovascular invasion, extracapsular spread and extension of the irradiated region the three treatment groups were significantly imbalanced. The other parameters, e.g. age, pathological tumor stage, grading and receptor status were homogeneously distributed. Looking on those two groups with an equally effective chemotherapy (EC, FEC), the SEQ- and SW-group, the sole imbalance was the extension of LVI (57.1 vs. 25.6%, p < 0.0001).5-year overall- and disease free survival were 53.2%/56%, 38.1%/32% and 64.2%/50%, for the sequential, sandwich and simultaneous regime, respectively, which differed significantly in the univariate analysis (p = 0.04 and p = 0.03, log-rank test). Also the 5-year locoregional or distant recurrence free survival showed no significant differences according to the sequence of chemo- and radiotherapy. In the multivariate analyses the sequence had no independent impact on overall survival (p = 0.2) or disease free survival (p = 0.4). The toxicity, whether acute nor late, showed no significant differences in the three groups. The grade III/IV acute side effects were 3.6%, 0% and 3.5% for the SIM-, SW- and SEQ-group. By tendency the SIM regime had more late side effects. CONCLUSION: No clear advantage can be stated for any radio- and chemotherapy sequence in breast cancer therapy so far. This could be confirmed in our retrospective analysis in high-risk patients after mastectomy. The sequential approach is recommended according to current guidelines considering a lower toxicity.

Which Iodine concentration in chest CT?--a prospective study in 300 patients.

In computed tomography (CT) several contrast media with different iodine concentrations are available. The aim of this study is to prospectively compare contrast media with iodine concentrations of 300, 370 and 400 mg iodine/ml for chest- CT. 300 consecutive patients were prospectively enrolled, under a waiver of the local ethics committee. The first (second, third) 100 patients, received contrast medium with 300 (370, 400) mg iodine/ml. Injection protocols were adapted for an identical iodine delivery rate (1.3 mg/s) and total iodine load (33 g) for all three groups. Standardized MDCT of the chest (16 x 0.75 mm, 120 kVp, 100 mAseff.) was performed. Intravascular attenuation values were measured in the pulmonary trunk and the ascending aorta; subjective image quality was rated on a 3-point-scale. Discomfort during and after injection was evaluated. There were no statistically significant differences in contrast enhancement comparing the three contrast media at the pulmonary trunk (p = 0.3198) and at the ascending aorta (p = 0.0840). Image quality (p = 0.0176) and discomfort during injection (p = 0.7034) were comparable for all groups. General discomfort after injection of contrast media with 300 mg iodine/ml was statistically significant higher compared to 370 mg iodine/ml (p = 0.00019). Given identical iodine delivery rates of 1.3 g/s and iodine loads of 33 g, contrast media with concentrations of 300, 370 and 400 mg iodine/ml do not result in different intravascular enhancement in chest-CT.

Semi-automated measurement of hyperdense, hypodense and heterogeneous hepatic metastasis on standard MDCT slices. Comparison of semi-automated and manual measurement of RECIST and WHO criteria.

As semi-automated measurement would be desirable for lesion quantification and therapy-response control, the purpose of this study was to compare semi-automated measurements with manual assessment of different types of hepatic metastases. Seventy-six patients with known liver metastases were analysed. All of them underwent contrast-enhanced 16-MDCT (16 x 0.75 mm collimation, 120 kV, 0.5 s rotation time, 160 mAs(eff)) for evaluation of follow-up status. On the basis of standard reconstructed 5-mm slices (in 4-mm increments), each lesion was quantified based on RECIST and WHO criteria using a semi-automated software tool (Syngo Oncology) and also manually by an experienced radiologist. Results from the software were compared to manual measurements. Statistical analysis was performed applying the concordance correlation coefficient, and results were represented graphically in Bland-Altman plots. A total of 52 hyperdense, 57 hypodense and 56 heterogeneous metastases were found and correctly measured by the software. All three lesion types revealed a strong correlation agreement between measurement techniques [RECIST diameter: 0.93 (hyperdense), 0.95(hypodense), 0.94 (heterogeneous); WHO area: 0.95, 0.98, 0.93]. Semi-automatic measurement of hyperdense, hypodense and heterogeneous liver metastases showed reliable results on standard axial reconstructions in comparison to manual quantification.

Feasibility and initial experience of assessment of mechanical dyssynchrony using cardiovascular magnetic resonance and semi-automatic border detection.

BACKGROUND: The systolic dyssynchrony index (SDI) has been introduced as a measure of mechanical dyssynchrony using three-dimensional echocardiography to select patients who may benefit from cardiac resynchronization therapy (CRT). However, three-dimensional echocardiography may be inadequate in a number of patients with suboptimal acoustic window and no single echocardiographic measure of dyssynchrony has proven to be of value in selecting patients for CRT. Thus, the aim of this study was to determine the value of cardiovascular magnetic resonance (CMR) for the assessment of the SDI in patients with reduced LV function as well as in healthy controls using semi-automatic border tracking. METHODS: We investigated a total of 45 patients including 35 patients (65 +/- 8 years) with reduced LV function (EF 30 +/- 11%) and a wide QRS complex as well as 10 control subjects (42 +/- 21 years, EF 70 +/- 11%). For cine imaging a standard SSFP imaging sequence was used with a temporal resolution of 40 frames per RR-interval. Quantitative analysis was performed off-line using a software prototype for semi-automatic border detection. Global volumes, ejection fraction and the SDI were calculated in each subject. SDI was compared with standard echocardiographic parameters of dyssynchrony. RESULTS: The mean SDI differed significantly between patients (14 +/- 5%) and controls (5 +/- 2%, p < 0.001). An exponential correlation between the EF and the SDI was observed (r = -0.84; p < 0.001). In addition, a significant association between the SDI and the standard deviation of time to peak systolic motion of 12 LV segments (Ts-SD) determined by echocardiography was observed (r = 0.66, p = 0.002). CONCLUSION: The results of this preliminary study suggest that CMR with semi-automatic border detection may be useful for the assessment of mechanical dyssynchrony in patients with reduced LV function.

Intraindividual comparison of contrast media concentrations for combined abdominal and thoracic MDCT.

OBJECTIVE: The purpose of this study was an intraindividual comparison of the degrees of MDCT contrast enhancement achieved with agents containing 300 and 370 mg I/mL. SUBJECTS AND METHODS: Seventy-five patients underwent baseline and follow-up MDCT of the chest and abdomen with contrast media containing a high concentration of iodine (iopromide 370 mg I/mL) and standard iodine concentration (iopromide 300 mg I/mL). The total iodine load (37 g) and the iodine delivery rate (1.29 g/s) were identical for the two protocols. Contrast enhancement in the chest (right and left ventricles, pulmonary trunk, descending aorta) and the abdomen (aorta, inferior vena cava, portal vein, and liver) was determined. Results were compared by use of paired Student's t tests, and p was adjusted with Bonferroni correction for multiple comparisons (p 0.0056). CONCLUSION: Given equivalent iodine load and delivery rate, the use of 300 mg I/mL contrast medium results in better contrast enhancement than use of 370 mg I/mL contrast medium in CT of the chest. For the portal venous phase of CT of the abdomen, there was no significant difference in contrast enhancement for the two concentrations of iodine.

Origin of and therapeutic approach to cardiac syndrome X: results of the proton pump inhibitor therapy for angina-like lingering pain trial (PITFALL trial).

AIM: To investigate the frequency of gastroenterological diseases in the etiology and the efficacy of proton pump inhibitors (PPIs) in the treatment of cardiac syndrome X (CSX) as a subform of non-cardiac chest pain (NCCP). METHODS: We investigated 114 patients with CSX using symptom questionnaires. A subgroup of these patients were investigated regarding upper gastrointestinal disorders (GIs) and treated with PPI. Patients not willing to participate in investigation and treatment served as control group. RESULTS: Thirty-six patients denied any residual symptoms and were not further evaluated. After informed consent in 27 of the remaining 78 patients, we determined the prevalence of disorders of the upper GI tract and quantified the effect of treatment with pantoprazole. We found a high prevalence of gastroenterological pathologies (26/27 patients, 97%) with gastritis, gastroesophageal reflux disease (GERD) and acid reflux as the most common associated disorders. If treated according to the study protocol, these patients showed a significant improvement in the symptom score. Patients treated by primary care physicians, not according to the study protocol had a minor response to treatment (n = 19, -43%), while patients not treated at all (n = 26) had no improvement of symptoms (-0%). CONCLUSION: Disorders of the upper GI tract are a frequent origin of CSX in a German population and can be treated with pantoprazole if given for a longer period.

Computer-aided measurements of pulmonary emphysema in chest multidetector-row spiral computed tomography: effect of image reconstruction parameters.

OBJECTIVE: To evaluate the effect of different image reconstruction parameters on quantitative automated measurements of pulmonary emphysema in chest multidetector-row spiral computed tomography. MATERIALS AND METHODS: Thirty patients with known emphysema underwent multidetector-row spiral computed tomography. Retrospective reconstruction with a soft tissue kernel (Siemens B20 at 1-mm, 2-mm, and 3-mm slices) and 4 alternative kernel grades (from smooth to sharp: Siemens B30, B40, B50, B60 at 1-mm slices) was performed. Total lung volume, emphysema volume (EV), 15th percentile density, and 4 EV clusters were quantified. Results were compared with those of standard algorithm B20/1-mm slices. RESULTS: Differences in total lung volume were less than 0.2%. Alternative kernel grades resulted in a significantly increased average EV. The 15th percentile density showed a significant average difference for all alternative algorithms. The large emphysema cluster showed a significant change for reconstruction algorithms B50, B60, B20/2 mm and B20/3 mm. CONCLUSIONS: Pulmonary EV is significantly affected by different reconstruction algorithms.

Assessment of leech therapy for knee osteoarthritis: a randomized study.

BACKGROUND AND PURPOSE: Symptomatic treatment of osteoarthritis of the knee with leeches is presently undergoing a renaissance. Previous studies have shown methodical weaknesses. In the present study patients were blinded regarding the treatment, and a control group was included to explore possible differences in various subjective clinical scores and intake of pain medication over time between leech therapy and placebo control. PATIENTS AND METHODS: 113 patients with advanced osteoarthritis of the knee were included. The patients were randomized to a single treatment group, group I (single leech application, n = 38), a double treatment group, group II (double application, n = 35), and a control group (n = 40). The second treatment in group II took place after an interval of 4 weeks. The treatment in the control group was simulated with the help of an "artificial leech". Results were documented with the KOOS and WOMAC scores and also a visual analog scale (VAS) for pain. Changes in the use of pain medication were monitored over 26 weeks. RESULTS: An improvement in KOOS and WOMAC scores, and also in VAS, was found in all 3 groups following treatment. These improvements were statistically significant for treatment groups I and II during the complete follow-up period. The reduction in individual requirements for pain medication was also statistically significant. The greatest improvement was seen in the group treated twice with the leeches, with a long-term reduction of joint stiffness and improved function in the activities of daily living. INTERPRETATION: Leech therapy can reduce symptoms caused by osteoarthritis. Repeated use of the leeches appears to improve the long-term results. We have not determined whether the positive outcome of the leech therapy is caused by active substances released during the leeching, the placebo effect, or the high expectations placed on this unusual treatment form.