Methodische und technische Weiterentwicklung der 3-He-MRT im Hinblick auf erweiterte lungendiagnostische Anwendungsmöglichkeiten

Die vorliegende Arbeit untersucht die Möglichkeiten und Limitierungen der MR-Lungenbildgebung mit hyperpolarisiertem 3-He bei gegenüber üblichen Magnetfeldstärken reduzierten magnetischen Führungsfeldern. Dabei werden insbesondere auch die funktionellen Bildgebungstechniken (dynamische Bildgebung, diffusionsgewichtete Bildgebung und Bestimmung des Sauerstoff-Partialdrucks) berücksichtigt. Experimentell geschieht dies durch in vivo Messungen an einem 0.1 T-Ganzkörpertomographen. Zur systematischen Untersuchung der MR-Bildgebung unter dem Einfluss diffundierender Kontrastmittel werden analytische Simulationen, Monte-Carlo-Studien und Referenzexperimente durchgeführt. Hier wird das Augenmerk besonders auf den Einfluss von Diffusions- und Suszeptibilitätsartefakten auf die morphologische und die diffusionsgewichtete Bildgebung gerichtet. Die Entwicklung und der Vergleich verschiedener Konzepte zur Erzeugung von MR-Führungsmagnetfeldern führt zur Erfindung eines neuartigen Prinzips zur weiträumigen Homogenisierung von Magnetfeldern. Die Umsetzung dieses Prinzips erfolgt in Form eines besonders kompakten Transportbehälters für kernspinpolarisierte Edelgase. Die Arbeit beinhaltet eine ausführliche Diskussion der MR-Bildgebungstechnik in Theorie und Praxis, um die Anknüpfungspunkte an die angestellten Untersuchungen herauszuarbeiten. Teile dieser Studien wurden von der Europäischen Raumfahrtorganisation ESA finanziert (Contract No.15308/01/NL/PA).

Konstruktion und Inbetriebnahme eines kompakten 3-He-Polarisators

Im Jahr 1996 wurde die erste Aufnahme der menschlichen Lunge in einem Kernspintomographen unter Benutzung des hyperpolarisierten Edelgases ³He als Kontrastgas veröffentlicht. Es folgten zahlreiche medizinische Studien mit diesem neuen Lungenbildgebungsverfahren. Als Konsequenz aus dem steigenden Bedarf an hyperpolarisiertem ³He wurde am Institut für Physik der Universität Mainz ein ³He-Polarisator entwickelt, der die Versorgung dieser Studien mit polarisiertem Gas gewährleistet. Für den Fall jedoch, dass die Lungenbildgebung mit hyperpolarisiertem ³He in die medizinische Praxis übernommen wird, wären die Produktionskapazitäten der bestehenden Anlage nicht mehr ausreichend. Daher wurde im Rahmen dieser Arbeit ein kompaktes System zum Polarisieren von ³He direkt am Einsatzort entwickelt, welches als eine Art Industrieprodukt in beliebiger Stückzahl nachgebaut werden kann. So steht nun ein kompakter, mobiler ³He Polarisator zur Verfügung, dessen Produktionsrate in der Größenordnung eines Standardliters (1 l, 1 bar, Raumtemperatur) pro Stunde bei einer Polarisation von > 60% liegt.

Design and Optimization of Four-dimensional Cone-beam Computed Tomography in Image-guided Radiation Therapy

The influence of respiratory motion on patient anatomy poses a challenge to accurate radiation therapy, especially in lung cancer treatment. Modern radiation therapy planning uses models of tumor respiratory motion to account for target motion in targeting. The tumor motion model can be verified on a per-treatment session basis with four-dimensional cone-beam computed tomography (4D-CBCT), which acquires an image set of the dynamic target throughout the respiratory cycle during the therapy session. 4D-CBCT is undersampled if the scan time is too short. However, short scan time is desirable in clinical practice to reduce patient setup time. This dissertation presents the design and optimization of 4D-CBCT to reduce the impact of undersampling artifacts with short scan times. This work measures the impact of undersampling artifacts on the accuracy of target motion measurement under different sampling conditions and for various object sizes and motions. The results provide a minimum scan time such that the target tracking error is less than a specified tolerance. This work also presents new image reconstruction algorithms for reducing undersampling artifacts in undersampled datasets by taking advantage of the assumption that the relevant motion of interest is contained within a volume-of-interest (VOI). It is shown that the VOI-based reconstruction provides more accurate image intensity than standard reconstruction. The VOI-based reconstruction produced 43% fewer least-squares error inside the VOI and 84% fewer error throughout the image in a study designed to simulate target motion. The VOI-based reconstruction approach can reduce acquisition time and improve image quality in 4D-CBCT.

Imaging and lung cancer

Lung cancer remains the most common cause of cancer-related mortality in Scotland, accounting for 28.9% of all cancer deaths in 2007. Current guidelines recommend assessment of patient fitness and operability by a multidisciplinary team when selecting management options. Two of the most important prognostic markers are the stage of disease and ECOG performance status. In 1996, the International Association for the Study of Lung Cancer (IASLC) launched a worldwide TNM staging project to create international databases that would be used to continue the excellent efforts of Dr. Cliff Mountain, who pioneered this approach to lung cancer staging in 1973. Successive iterations of tumor, nodule, metastasis (TNM) staging for lung cancer have addressed shortcomings identified by the oncology community. Similarly, the IASLC recognized that it is important that further revisions continue to be made to ensure that the international staging system for lung cancer remains fit for its purpose. The last work of the International Staging Committee (ISC) was the conduct of the study that informed the seventh edition of the international staging system for lung cancer, in 2010. This review of image and staging in non small cell lung cancer (NSCLC), includes a summary of the different noninvasive tests currently available for staging non small cell lung cancer.

Micropapillary pattern in lung adenocarcinoma: aspect on 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging.

We diagnosed a non-small cell lung carcinoma in a 49-year-old female patient with the histopathological diagnosis of stage IIIB mixed bronchioloalveolar and papillary adenocarcinoma with extensive micropapillary feature, which was not visualized on the preoperative multimodality imaging with positron emission tomography (PET) and computed tomography (CT). The micropapillary component characterized by a unique growth pattern with particular morphological features can be observed in all subtypes of lung adenocarcinoma. Micropapillary component is increasingly recognized as a distinct entity associated with higher aggressiveness. Even the most modern multimodality PET/CT imaging technology may fail to adequately visualize this important component with highly relevant prognostic implications. Thus, the pathologist needs to consciously look for a micropapillary component in the surgical specimen or in preoperative biopsies or cytology. This may have potential future treatment implications, as adjuvant or neoadjuvant chemotherapy may be of relevance, even in the early stages of the disease.

Comparison between magnetic resonance imaging and computed tomography of the lung in patients with cystic fibrosis with regard to clinical, laboratory, and pulmonary functional parameters

OBJECTIVE To evaluate whether magnetic resonance imaging (MRI) is effective as computed tomography (CT) in determining morphologic and functional pulmonary changes in patients with cystic fibrosis (CF) in association with multiple clinical parameters. MATERIALS AND METHODS Institutional review board approval and patient written informed consent were obtained. In this prospective study, 30 patients with CF (17 men and 13 women; mean (SD) age, 30.2 (9.2) years; range, 19-52 years) were included. Chest CT was acquired by unenhanced low-dose technique for clinical purposes. Lung MRI (1.5 T) comprised T2- and T1-weighted sequences before and after the application of 0.1-mmol·kg gadobutrol, also considering lung perfusion imaging. All CT and MR images were visually evaluated by using 2 different scoring systems: the modified Helbich and the Eichinger scores. Signal intensity of the peribronchial walls and detected mucus on T2-weighted images as well as signal enhancement of the peribronchial walls on contrast-enhanced T1-weighted sequences were additionally assessed on MRI. For the clinical evaluation, the pulmonary exacerbation rate, laboratory, and pulmonary functional parameters were determined. RESULTS The overall modified Helbich CT score had a mean (SD) of 15.3 (4.8) (range, 3-21) and median of 16.0 (interquartile range [IQR], 6.3). The overall modified Helbich MR score showed slightly, not significantly, lower values (Wilcoxon rank sum test and Student t test; P > 0.05): mean (SD) of 14.3 (4.7) (range, 3-20) and median of 15.0 (IQR, 7.3). Without assessment of perfusion, the overall Eichinger score resulted in the following values for CT vs MR examinations: mean (SD), 20.3 (7.2) (range, 4-31); and median, 21.0 (IQR, 9.5) vs mean (SD), 19.5 (7.1) (range, 4-33); and median, 20.0 (IQR, 9.0). All differences between CT and MR examinations were not significant (Wilcoxon rank sum tests and Student t tests; P > 0.05). In general, the correlations of the CT scores (overall and different imaging parameters) to the clinical parameters were slightly higher compared to the MRI scores. However, if all additional MRI parameters were integrated into the scoring systems, the correlations reached the values of the CT scores. The overall image quality was significantly higher for the CT examinations compared to the MRI sequences. CONCLUSIONS One major diagnostic benefit of lung MRI in CF is the possible acquisition of several different morphologic and functional imaging features without the use of any radiation exposure. Lung MRI shows reliable associations with CT and clinical parameters, which suggests its implementation in CF for routine diagnosis, which would be particularly important in follow-up imaging over the long term.

Ventilation/perfusion SPECT or SPECT/CT for lung function imaging in patients with pulmonary emphysema?

PURPOSE To evaluate the utility of attenuation correction (AC) of V/P SPECT images for patients with pulmonary emphysema. MATERIALS AND METHODS Twenty-one patients (mean age 67.6 years) with pulmonary emphysema who underwent V/P SPECT/CT were included. AC/non-AC V/P SPECT images were compared visually and semiquantitatively. Visual comparison of AC/non-AC images was based on a 5-point likert scale. Semiquantitative comparison assessed absolute counts per lung (aCpLu) and lung lobe (aCpLo) for AC/non-AC images using software-based analysis; percentage counts (PC = (aCpLo/aCpLu) × 100) were calculated. Correlation between AC/non-AC V/P SPECT images was analyzed using Spearman's rho correlation coefficient; differences were tested for significance with the Wilcoxon rank sum test. RESULTS Visual analysis revealed high conformity for AC and non-AC V/P SPECT images. Semiquantitative analysis of PC in AC/non-AC images had an excellent correlation and showed no significant differences in perfusion (ρ = 0.986) or ventilation (ρ = 0.979, p = 0.809) SPECT/CT images. CONCLUSION AC of V/P SPECT images for lung lobe-based function imaging in patients with pulmonary emphysema do not improve visual or semiquantitative image analysis.

Assessment of cone beam computed tomography techniques for imaging lung damage in mice in vivo

Lung damage is a common side effect of chemotherapeutic drugs such as bleomycin. This study used a bleomycin mouse model which simulates the lung damage observed in humans. Noninvasive, in vivo cone-beam computed tomography (CBCT) was used to visualize and quantify fibrotic and inflammatory damage over the entire lung volume of mice. Bleomycin was used to induce pulmonary damage in vivo and the results from two CBCT systems, a micro-CT and flat panel CT (fpCT), were compared to histologic measurements, the standard method of murine lung damage quantification. Twenty C57BL/6 mice were given either 3 U/kg of bleomycin or saline intratracheally. The mice were scanned at baseline, before the administration of bleomycin, and then 10, 14, and 21 days afterward. At each time point, a subset of mice was sacrificed for histologic analysis. The resulting CT images were used to assess lung volume. Percent lung damage (PLD) was calculated for each mouse on both the fpCT (PLDfpcT) and the micro-CT (PLDμCT). Histologic PLD (PLDH) was calculated for each histologic section at each time point (day 10, n = 4; day 14, n = 4; day 21, n = 5; control group, n = 5). A linear regression was applied to the PLDfpCT vs. PLDH, PLDμCT vs. PLDH and PLDfpCT vs. PLDμCT distributions. This study did not demonstrate strong correlations between PLDCT and PLDH. The coefficient of determination, R, was 0.68 for PLDμCT vs. PLDH and 0.75 for the PLD fpCT vs. PLDH. The experimental issues identified from this study were: (1) inconsistent inflation of the lungs from scan to scan, (2) variable distribution of damage (one histologic section not representative of overall lung damage), (3) control mice not scanned with each group of bleomycin mice, (4) two CT systems caused long anesthesia time for the mice, and (5) respiratory gating did not hold the volume of lung constant throughout the scan. Addressing these issues might allow for further improvement of the correlation between PLDCT and PLDH. ^

Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung

The binding of immune inhibitory receptor Programmed Death 1 (PD-1) on T cells to its ligand PD-L1 has been implicated as a major contributor to tumor induced immune suppression. Clinical trials of PD-L1 blockade have proven effective in unleashing therapeutic anti-tumor immune responses in a subset of patients with advanced melanoma, yet current response rates are low for reasons that remain unclear. Hypothesizing that the PD-1/PD-L1 pathway regulates T cell surveillance within the tumor microenvironment, we employed intravital microscopy to investigate the in vivo impact of PD-L1 blocking antibody upon tumor-associated immune cell migration. However, current analytical methods of intravital dynamic microscopy data lack the ability to identify cellular targets of T cell interactions in vivo, a crucial means for discovering which interactions are modulated by therapeutic intervention. By developing novel imaging techniques that allowed us to better analyze tumor progression and T cell dynamics in the microenvironment; we were able to explore the impact of PD-L1 blockade upon the migratory properties of tumor-associated immune cells, including T cells and antigen presenting cells, in lung tumor progression. Our results demonstrate that early changes in tumor morphology may be indicative of responsiveness to anti-PD-L1 therapy. We show that immune cells in the tumor microenvironment as well as tumors themselves express PD-L1, but immune phenotype alone is not a predictive marker of effective anti-tumor responses. Through a novel method in which we quantify T cell interactions, we show that T cells are largely engaged in interactions with dendritic cells in the tumor microenvironment. Additionally, we show that during PD-L1 blockade, non-activated T cells are recruited in greater numbers into the tumor microenvironment and engage more preferentially with dendritic cells. We further show that during PD-L1 blockade, activated T cells engage in more confined, immune synapse-like interactions with dendritic cells, as opposed to more dynamic, kinapse-like interactions with dendritic cells when PD-L1 is free to bind its receptor. By advancing the contextual analysis of anti-tumor immune surveillance in vivo, this study implicates the interaction between T cells and tumor-associated dendritic cells as a possible modulator in targeting PD-L1 for anti-tumor immunotherapy.

Animated solid model of the lung constructed from unsynchronized MR sequential images

This work discusses a 4D lung reconstruction method from unsynchronized MR sequential images. The lung, differently from the heart, does not have its own muscles, turning impossible to see its real movements. The visualization of the lung in motion is an actual topic of research in medicine. CT (Computerized Tomography) can obtain spatio-temporal images of the heart by synchronizing with electrocardiographic waves. The FOV of the heart is small when compared to the lung`s FOV. The lung`s movement is not periodic and is susceptible to variations in the degree of respiration. Compared to CT, MR (Magnetic Resonance) imaging involves longer acquisition times and it is not possible to obtain instantaneous 3D images of the lung. For each slice, only one temporal sequence of 2D images can be obtained. However, methods using MR are preferable because they do not involve radiation. In this paper, based on unsynchronized MR images of the lung an animated B-Repsolid model of the lung is created. The 3D animation represents the lung`s motion associated to one selected sequence of MR images. The proposed method can be divided in two parts. First, the lung`s silhouettes moving in time are extracted by detecting the presence of a respiratory pattern on 2D spatio-temporal MR images. This approach enables us to determine the lung`s silhouette for every frame, even on frames with obscure edges. The sequence of extracted lung`s silhouettes are unsynchronized sagittal and coronal silhouettes. Using our algorithm it is possible to reconstruct a 3D lung starting from a silhouette of any type (coronal or sagittal) selected from any instant in time. A wire-frame model of the lung is created by composing coronal and sagittal planar silhouettes representing cross-sections. The silhouette composition is severely underconstrained. Many wire-frame models can be created from the observed sequences of silhouettes in time. Finally, a B-Rep solid model is created using a meshing algorithm. Using the B-Rep solid model the volume in time for the right and left lungs were calculated. It was possible to recognize several characteristics of the 3D real right and left lungs in the shaded model. (C) 2007 Elsevier Ltd. All rights reserved.

Extrapolation from ten sections can make CT-based quantification of lung aeration more practicable

Clinical applications of quantitative computed tomography (qCT) in patients with pulmonary opacifications are hindered by the radiation exposure and by the arduous manual image processing. We hypothesized that extrapolation from only ten thoracic CT sections will provide reliable information on the aeration of the entire lung. CTs of 72 patients with normal and 85 patients with opacified lungs were studied retrospectively. Volumes and masses of the lung and its differently aerated compartments were obtained from all CT sections. Then only the most cranial and caudal sections and a further eight evenly spaced sections between them were selected. The results from these ten sections were extrapolated to the entire lung. The agreement between both methods was assessed with Bland-Altman plots. Median (range) total lung volume and mass were 3,738 (1,311-6,768) ml and 957 (545-3,019) g, the corresponding bias (limits of agreement) were 26 (-42 to 95) ml and 8 (-21 to 38) g, respectively. The median volumes (range) of differently aerated compartments (percentage of total lung volume) were 1 (0-54)% for the nonaerated, 5 (1-44)% for the poorly aerated, 85 (28-98)% for the normally aerated, and 4 (0-48)% for the hyperaerated subvolume. The agreement between the extrapolated results and those from all CT sections was excellent. All bias values were below 1% of the total lung volume or mass, the limits of agreement never exceeded +/- 2%. The extrapolation method can reduce radiation exposure and shorten the time required for qCT analysis of lung aeration.

Three-dimensional sonographic measurement of contralateral lung volume in fetuses with isolated congenital diaphragmatic hernia

Purpose. To use 3-dimensional sonography (3DUS) to measure contralateral lung volume and evaluate the potential of this measurement to predict neonatal outcome in isolated congenital diaphragmatic hernia (CDH). Methods. Between January 2002 and December 2004, the contralateral lung volumes of 39 fetuses with isolated CDH were measured via 3DUS using rotational multiplanar imaging. The observed/expected contralateral fetal lung volume ratios (o/eContFLVR) were compared with the lung/head ratio (LHR), observed/expected total fetal lung volume ratio (o/e-TotFLVR), and postnatal outcome. Results. Contralateral lung volumes are less reduced than total lung volumes in CDH. The bias and precision of 3DUS in estimating contralateral lung volumes were 0.99 cm(3) and 1.11 cm(3), respectively, with absolute limits of agreement ranging from -1.19 cm(3) to + 3.17 cm(3). The o/e-ContFLVR was significantly lower in neonatal death cases (median, 0.49 cm(3); range, 0.22-0.99 cm(3)) than in survival cases (median, 0.58 cm(3); range, 0.42-0.92 cm(3) [p < 0.011). Overall accuracy of the o/e-ContFLVR, o/e-TotFLVR, and LHR in predicting neonatal death were 67.7% (21/31), 80.7% (25/31), and 77.4% (24/31), respectively. Conclusion. Although o/e-ContFLVR can be precisely measured with 3DUS and can be used to predict neonatal death in CDH, it is less accurate than LHR and o/e-TotFLVR for that purpose. (C) 2007 Wiley Periodicals, Inc.