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Karin Klooster,1,* T David Koster,1,* Christoph Ruwwe-Glösenkamp,2 Dorothea Theilig,3 Felix Doellinger,3 Jacopo Saccomanno,2 Huib AM Kerstjens,1 Dirk-Jan Slebos,1 Ralf-Harto Hübner2 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands; 2Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Pneumology, Berlin, Germany; 3Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Radiology, Berlin, Germany*These authors contributed equally to this workCorrespondence: Karin Klooster Email k.klooster@umcg.nlPurpose: Lung volume reduction using one-way endobronchial valves is a bronchoscopic treatment for patients with severe emphysema without collateral ventilation between the treatment target lobe and the ipsilateral lobe(s). CT-scan fissure analysis is often used as a surrogate to predict the absence of collateral ventilation. We aimed to evaluate the predictive value of the fissure completeness score (FCS) compared to the functional Chartis measurement of collateral ventilation and to provide cut-off values of the FCS in patient selection.Patients and Methods: Multicenter study in patients eligible for treatment with one-way valves. The FCS was calculated by quantitative CT analysis (Thirona, the Netherlands) and compared to status of interlobar collateral ventilation measured with Chartis system (PulmonX, USA). Thresholds were calculated for the predictive values of the presence of collateral ventilation.Results: An FCS > 95% of the left major fissure had a positive predictive value (PPV) of 91%, with 1 in 11 fissures demonstrating collateral ventilation with Chartis measurement, whereas an FCS of ≤ 80% had a negative predictive value (NPV) of 100% for the presence of collateral ventilation. For the right major fissure, the NPV was 100% for an FCS ≤ 90%, but 69.7% for the right upper lobe fissure.Conclusion: Quantitative CT analysis is recommended in all patients evaluated for endobronchial valves. Patients with incomplete fissures (left major fissure: FCS < 80%; right major fissure: < 90%) can be excluded from Chartis measurement and endobronchial valve treatment. In patients with more complete fissures, the FCS is not specific enough for endobronchial valve treatment decisions. In this case, additional Chartis measurements are always recommended in the right lung. For the left lung, Chartis assessments may be omitted if the FCS is > 95%.Keywords: COPD, lung volume reduction, fissure, collateral ventilation, CT scan

Dorothea Theilig,1 Felix Doellinger,1 Alexander Poellinger,1 Vera Schreiter,1 Konrad Neumann,2 Ralf-Harto Hubner31Department of Radiology, Charité Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, Berlin, Germany; 2Institute of Biometrics and Clinical Epidemiology, Charité Campus Benjamin Franklin, Charité, Universitätsmedizin Berlin, Berlin, Germany; 3Department of Pneumology, Charité Campus Virchow Klinikum, Charité, Universitätsmedizin Berlin, Berlin, GermanyBackground: The degree of interlobar emphysema heterogeneity is thought to play an important role in the outcome of endoscopic lung volume reduction (ELVR) therapy of patients with advanced COPD. There are multiple ways one could possibly define interlobar emphysema heterogeneity, and there is no standardized definition.Purpose: The aim of this study was to derive a formula for calculating an interlobar emphysema heterogeneity index (HI) when evaluating a patient for ELVR. Furthermore, an attempt was made to identify a threshold for relevant interlobar emphysema heterogeneity with regard to ELVR.Patients and methods: We retrospectively analyzed 50 patients who had undergone technically successful ELVR with placement of one-way valves at our institution and had received lung function tests and computed tomography scans before and after treatment. Predictive accuracy of the different methods for HI calculation was assessed with receiver-operating characteristic curve analysis, assuming a minimum difference in forced expiratory volume in 1 second of 100 mL to indicate a clinically important change.Results: The HI defined as emphysema score of the targeted lobe (TL) minus emphysema score of the ipsilateral nontargeted lobe disregarding the middle lobe yielded the best predicative accuracy (AUC =0.73, P=0.008). The HI defined as emphysema score of the TL minus emphysema score of the lung without the TL showed a similarly good predictive accuracy (AUC =0.72, P=0.009). Subgroup analysis suggests that the impact of interlobar emphysema heterogeneity is of greater importance in patients with upper lobe predominant emphysema than in patients with lower lobe predominant emphysema.Conclusion: This study reveals the most appropriate ways of calculating an interlobar emphysema heterogeneity with regard to ELVR. Keywords: CT-quantitative, COPD, emphysema heterogeneity, endoscopic lung volume reduction

Christian Thomsen,1 Dorothea Theilig,2 Dominik Herzog,1 Alexander Poellinger,2 Felix Doellinger,2 Nils Schreiter,3 Vera Schreiter,2 Dirk Schürmann,1 Bettina Temmesfeld-Wollbrueck,1 Stefan Hippenstiel,1 Norbert Suttorp,1 Ralf-Harto Hubner1 1Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, 2Institute of Radiology, 3Institute of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany Abstract: The exclusion of collateral ventilation (CV) and other factors affect the clinical success of endoscopic lung volume reduction (ELVR). However, despite its benefits, the outcome of ELVR remains difficult to predict. We investigated whether clinical success could be predicted by emphysema distribution assessed by computed tomography scan and baseline perfusion assessed by perfusion scintigraphy. Data from 57 patients with no CV in the target lobe (TL) were retrospectively analyzed after ELVR with valves. Pulmonary function tests (PFT), St George’s Respiratory Questionnaire (SGRQ), and 6-minute walk tests (6MWT) were performed on patients at baseline. The sample was grouped into high and low levels at the median of TL perfusion, ipsilateral nontarget lobe (INL) perfusion, and heterogeneity index (HI). These groups were analyzed for association with changes in outcome parameters from baseline to 3 months follow-up. Compared to baseline, patients showed significant improvements in PFT, SGRQ, and 6MWT (all P≤0.001). TL perfusion was not associated with changes in the outcome. High INL perfusion was significantly associated with increases in 6MWT (P=0.014), and high HI was associated with increases in forced expiratory volume in 1 second (FEV1), (P=0.012). Likewise, there were significant correlations for INL perfusion and improvement of 6MWT (r=0.35, P=0.03) and for HI and improvement in FEV1 (r=0.45, P=0.001). This study reveals new attributes that associate with positive outcomes for patient selection prior to ELVR. Patients with high perfusions in INL demonstrated greater improvements in 6MWT, while patients with high HI were more likely to respond in FEV1. Keywords: endoscopic lung volume reduction, COPD, valves, lung perfusion, emphysema distribution

Felix W Feldhaus,1 Dorothea Cornelia Theilig,1 Ralf-Harto Hubner,2 Jan-Martin Kuhnigk,3 Konrad Neumann,4 Felix Doellinger11Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Department of Radiology, Berlin, Germany; 2Department of Internal Medicine/Infectious and Respiratory Disease, Charité Universitätsmedizin Berlin, Berlin, Germany; 3Institute for Medical Image Computing, Fraunhofer MEVIS, Bremen, Germany; 4Institute of Biometrics and Clinical Epidemiology, Charité Universitätsmedizin Berlin, Berlin, GemanyPurpose: Quantitative analysis of CT scans has proven to be a reproducible technique, which might help to understand the pathophysiology of chronic obstructive pulmonary disease (COPD) and combined pulmonary fibrosis and emphysema. The aim of this retrospective study was to find out if the lung function of patients with COPD with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III or IV and pulmonary emphysema is measurably influenced by high attenuation areas as a correlate of concomitant unspecific fibrotic changes of lung parenchyma.Patients and methods: Eighty-eight patients with COPD GOLD stage III or IV underwent CT and pulmonary function tests. Quantitative CT analysis was performed to determine low attenuation volume (LAV) and high attenuation volume (HAV), which are considered to be equivalents of fibrotic (HAV) and emphysematous (LAV) changes of lung parenchyma. Both parameters were determined for the whole lung, as well as peripheral and central lung areas only. Multivariate regression analysis was used to correlate HAV with different parameters of lung function.Results: Unlike LAV, HAV did not show significant correlation with parameters of lung function. Even in patients with a relatively high HAV of more than 10%, in contrast to HAV (p=0.786) only LAV showed a significantly negative correlation with forced expiratory volume in 1 second (r=−0.309, R2=0.096, p=0.003). A severe decrease of DLCO% was associated with both larger HAV (p=0.045) and larger LAV (p=0.001). Residual volume and FVC were not influenced by LAV or HAV.Conclusion: In patients with COPD GOLD stage III-IV, emphysematous changes of lung parenchyma seem to have such a strong influence on lung function, which is a possible effect of concomitant unspecific fibrosis is overwhelmed.Keywords: COPD, quantitative CT, pulmonary fibrosis, pulmonary emphysema, CPFE

Objectives: To investigate the impact of the interventionalist's experience and gender on radiation dose and procedural time in CT-guided interventions., Methods: We retrospectively analyzed 4380 CT-guided interventions performed at our institution with the same CT scanner from 2009 until 2018, 1287 (29%) by female and 3093 (71%) by male interventionalists. Radiation dose, number of CT fluoroscopy images taken per intervention, total procedural time, type of intervention, and degree of difficulty were derived from the saved dose reports and images. All 16 interventionalists included in this analysis performed their first CT-guided interventions during the study period, and interventions performed by each interventionalist were counted to assess the level of experience for each intervention in terms of the number of prior interventions performed by her or him. The Mann-Whitney U test (MWU test), multivariate regression, and linear mixed model analysis were performed., Results: Assessment of the impact of gender with the MWU test revealed that female interventionalists took a significantly smaller number of images (p < 0.0001) and achieved a lower dose-length product per intervention (p < 0.0001) while taking more time per intervention (p = 0.0001). This finding was confirmed for most types of interventions when additionally accounting for other possible impact factors in multivariate regression analysis. In linear mixed model analysis, we found that radiation dose, number of images taken per intervention, and procedural time decreased statistically significantly with interventionalist's experience., Conclusions: Radiation doses of CT-guided interventions are reduced by interventionalist's experience and, for most types of interventions, when performed by female interventionalists., Key Points: • Radiation doses in CT-guided interventions are lower when performed by female interventionalists. • Procedural times of CT-guided interventions are longer when performed by female interventionalists. • Radiation doses of CT-guided interventions decrease with the interventionalist's experience.

Purpose: We evaluated pharmacokinetic models which quantify liver function including biliary elimination based on a dynamic Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) technique with sparse data collection feasible in clinical routine., Methods: Twelve patients with embolized liver segments following interventional treatment of primary liver cancer or hepatic metastasis underwent MRI. During Gd-EOB-DTPA bolus administration, a 3D dynamic gradient-echo (GRE) MRI examination was performed over approx. 28 min. Interrupted data sampling was started approx. 5 min after contrast agent administration. Different implementations of dual-inlet models were tested, namely the Euler method (DE) and convolution with residue functions (C). A simple uptake model (U) and an uptake- elimination model (UE) extended by incorporating the biliary contrast agent elimination rate (K e ) were evaluated., Results: The uptake-elimination model, calculated via the simple Euler method (UE- DE) and by convolution (UE-C), yielded similar overall estimates in terms of fitting quality and agreement with published values. The Euler method was approx. 50 times faster and yielded a mean elimination rate of K e =1.8±1.2mL/(min·100 mL) in nonembolized liver tissue, which was significantly higher (p=8.8·10 -4 ) than in embolized tissue K e =0.4±0.4 mL/(min·100 mL). Fractional hepatocyte volume v h was not significantly higher in nonembolized tissue (52.4 ± 13.4 mL/100 mL) compared to embolized tissue (44.4 ± 26.1 mL/100 mL)., Conclusions: Interrupted late enhancement MRI data sampling in conjunction with the uptake-elimination model, deconvolved by integration of the differential rate equation and combined with the simple uptake model implemented with the Euler method (U-DE), turned out to be a stable and practical method for reliable noninvasive assessment of liver function., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to evaluate the risk of pneumothorax and need for chest tube insertion in CT-guided lung biopsies and identify predictors focusing on pulmonary emphysema determined with quantitative computed tomography. To that end, we retrospectively analysed the incidence of pneumothorax and chest tube insertion in 371 CT-guided lung biopsies with respect to the quantitative emphysema score determined with the density mask technique. Other possible impact factors considered were lesion diameter, length of biopsy pathway within the lung parenchyma, lung lobe, needle size, puncture technique, patient positioning and interventionalist's level of experience. Quantitative emphysema scores of the lung were significantly higher in patients who developed instant pneumothorax (27%, p < 0.0001), overall pneumothorax (38%, p = 0.001) and had chest tube insertion (9%, p = 0.006) compared to those who did not when analysed with the Mann-Whitney U-test. In logistic regression analysis with inclusion of the other possible impact factors, the quantitative emphysema score remained a statistically significant predictor for all three output parameters. This was confirmed with least absolute shrinkage and selection operator (Lasso) regression analysis. In conclusion, quantitatively determined pulmonary emphysema is a positive predictor of the pneumothorax rate in CT-guided lung biopsy and likelihood of chest tube insertion.

Purpose: To evaluate the hepatotoxicity of different chemotherapeutic agents used to treat neuroendocrine tumours (NETs) with gadoxetic acid-enhanced magnetic resonance imaging (MRI)., Material and Methods: A total of 129 patients with NETs who underwent two or more serial gadoxetic-acid-enhanced MRI examinations between 2014 and 2018 and started chemotherapy in the beginning of that time period were retrospectively analysed. Linear mixed model analysis evaluating relative enhancement (RE) of the liver in the hepatobiliary phase with respect to time between MRI examinations, primary chemotherapy, hepatotoxicity score of preceding and subsequent chemotherapies as well as age and gender as fixed variables was performed. Binary logistic regression was used to verify whether the hepatotoxicity score predicts a significant impact of a chemotherapeutic regimen on RE and hence liver function., Results: Linear mixed model analysis of a total of 539 MRI examinations identified all chemotherapeutic agents with known hepatoxicity as a factor with a statistically significant negative impact on RE of the liver in gadoxetic-acid-enhanced MRI in addition to age. This result was confirmed by binary logistic regression analysis., Conclusion: Our results confirm that gadoxetic acid-enhanced MRI can be used as an imaging-based liver function test for assessing hepatotoxicity of chemotherapeutic agents used for NETs. The findings underscore the known degrees of hepatotoxicity of the chemotherapeutic agents currently used in the treatment of NETs., Competing Interests: Declaration of Competing Interest Drs. Geisel and Hamm have received travel support and honoraria from Bayer AG. Beyond that there is nothing to disclose., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Predicting post-hepatectomy liver failure (PHLF) after extended right hepatectomy following portal vein embolization (PVE) from serial gadoxetic acid-enhanced magnetic resonance imaging (MRI)., Methods: Thirty-six patients who underwent hepatectomy following PVE were evaluated prospectively with gadoxetic acid-enhanced MRI examinations at predefined intervals during the course of their treatment, i.e., before and 14 days and 28 days after PVE as well as 10 days after hepatectomy. Relative enhancement (RE) and volume of the left and right liver lobes were determined. The study population was divided into two groups with respect to signs of PHLF. Differences between the two groups were assessed using the Mann-Whitney U test, and predictive parameters for group membership were investigated using ROC and logistic regression analysis., Results: RE of the left lobe prior to PVE versus 14 days after PVE was significantly lower in patients with PHLF than in those without PHLF (Mann-Whitney U test p < 0.001) and proved to be the best predictor of PHLF in ROC analysis with an AUC of 0.854 (p < 0.001) and a cutoff value of - 0.044 with 75.0% sensitivity and 92.6% specificity. Consistent with this result, logistic linear regression analysis adjusted for age identified the same parameter to be a significant predictor of PHLF (p = 0.040)., Conclusions: Gadoxetic acid-enhanced MRI performed as an imaging-based liver function test before and after PVE can help to predict PHLF. The risk of PHLF can be predicted as early as 14 days after PVE., Key Points: • To predict the likelihood of post-hepatectomy liver failure, it is important to estimate not only future liver remnant volume prior to extended liver resection but also future liver remnant function. • Future liver remnant function can be predicted by performing gadoxetic acid-enhanced MRI as an imaging-based liver function test before and after portal vein embolization. • A reduction of relative enhancement of the liver in gadoxetic acid-enhanced MRI after portal vein embolization of 0.044 predicts post-hepatectomy liver failure with 75.0% sensitivity and 92.6% specificity.

Purpose: To assess the consistency of liver enhancement in gadoxetic acid-enhanced magnetic resonance imaging (MRI) over serial examinations., Methods: This retrospective study included 554 patients who underwent at least 2 serial gadoxetic acid-enhanced MRI scans at either 1.5 or 3.0 Tesla at our institution between 2014 and 2018. Signal intensities (SI) were measured on T1-weighted images before and approx. 20 min after intravenous injection of gadoxetic acid. Relative enhancement (RE) of the liver, liver-to-spleen SI ratio (LSR), and liver-to-muscle SI ratio (LMR) were calculated. Means were compared with the paired t test, Greenhouse-Geisser test, and linear mixed model analysis, accordingly. Multiple linear regression analysis was used to elucidate possible predictors of RE and bivariate correlation analysis of patient age with RE was performed., Results: No statistically significant difference in RE, LSR, and LMR between two consecutive MRI scans was found when tested with paired t test or Greenhouse-Geisser test (n = 554, 519, and 554, respectively), while the latter revealed a statistically significant difference between the first and fourth MRI scan which was not confirmed in the linear mixed model. Patient age correlated negatively with RE of the liver (p = 0.002), LSR (p < 0.001), and LMR (p = 0.006)., Conclusions: Relative enhancement of the liver in the hepatobiliary phase of gadoxetic acid-enhanced MRI is consistent over successive examinations, different scanner types, and field strengths while correlating negatively with age, which further underscores the validity of gadoxetic acid-enhanced MRI as an imaging-based liver function test.

Noninvasive early detection of liver cirrhosis and fibrosis is essential for management and therapy. The aim was to investigated whether a combination of the functional parameter relative enhancement (RE) on Gadoxetic Acid magnetic resonance imaging (Gd-EOB-DTPA-enhanced MRI) and the fibrosis parameter T1ρ distinguishes cirrhosis and healthy liver. We analyzed patients with Gd-EOB-DTPA-enhanced MRI and T1ρ mapping. Signal intensity was measured before and after contrast; RE was calculated. T1ρ was measured with circular regions of interest (T1ρ-cROI). A quotient of RE and T1ρ-cROI was calculated: the fibrosis function quotient (FFQ). Cirrhosis was evaluated based on morphology and secondary changes. 213 datasets were included. The difference between cirrhotic and noncirrhotic liver was 51.11 ms vs. 47.56 ms for T1ρ-cROI (p < 0.001), 0.59 vs. 0.70 for RE (p < 0.001), and 89.53 vs. 70.83 for FFQ (p < 0.001). T1ρ-cROI correlated with RE, r = -0.14 (p < 0.05). RE had an AUC of 0.73. The largest AUC had the FFQ with 0.79. The best cutoff value was 48.34 ms for T1ρ-cROI, 0.70 for RE and 78.59 ms for FFQ. In conclusion T1ρ and RE can distinguish between cirrhotic and noncirrhotic liver. The FFQ, which is the combination of the two, improves diagnostic performance.

Background: High fat diet-induced hyperglycemia and palmitate-stimulated apoptosis was prevented by specific inhibition of protein kinase C delta (PKCδ) in β-cells. To understand the role of PKCδ in more detail the impact of changes in PKCδ activity on proliferation and survival of insulin-secreting cells was analyzed under stress-free conditions., Methodology and Principal Findings: Using genetic and pharmacological approaches, the effect of reduced and increased PKCδ activity on proliferation, apoptosis and cell cycle regulation of insulin secreting cells was examined. Proteins were analyzed by Western blotting and by confocal laser scanning microscopy. Increased expression of wild type PKCδ (PKCδWT) significantly stimulated proliferation of INS-1E cells with concomitant reduced expression and cytosolic retraction of the cell cycle inhibitor p21(Cip1/WAF1). This nuclear extrusion was mediated by PKCδ-dependent phosphorylation of p21(Cip1/WAF1) at Ser146. In kinase dead PKCδ (PKCδKN) overexpressing cells and after inhibition of endogenous PKCδ activity by rottlerin or RNA interference phosphorylation of p21(Cip1/WAF1) was reduced, which favored its nuclear accumulation and apoptotic cell death of INS-1E cells. Human and mouse islet cells express p21(Cip1/WAF1) with strong nuclear accumulation, while in islet cells of PKCδWT transgenic mice the inhibitor resides cytosolic., Conclusions and Significance: These observations disclose PKCδ as negative regulator of p21(Cip1/WAF1), which facilitates proliferation of insulin secreting cells under stress-free conditions and suggest that additional stress-induced changes push PKCδ into its known pro-apoptotic role., (© 2011 Ranta et al.)