Wolfgang M. Thaiss

Preclinical and Translational PET/MR Imaging

Combined PET and MR imaging (PET/MR imaging) has progressed tremendously in recent years. The focus of current research has shifted from technologic challenges to the application of this new multimodal imaging technology in the areas of oncology, cardiology, neurology, and infectious diseases. This article reviews studies in preclinical and clinical translation. The common theme of these initial results is the complementary nature of combined PET/MR imaging that often provides additional insights into biologic systems that were not clearly feasible with just one modality alone. However, in vivo findings require ex vivo validation. Combined PET/MR imaging also triggers a multitude of new developments in image analysis that are aimed at merging and using multimodal information that ranges from better tumor characterization to analysis of metabolic brain networks. The combination of connectomics information that maps brain networks derived from multiparametric MR data with metabolic information from PET can even lead to the formation of a new research field that we would call cometomics that would map functional and metabolic brain networks. These new methodologic developments also call for more multidisciplinarity in the field of molecular imaging, in which close interaction and training among clinicians and a variety of scientists is needed.

A Comparative pO2 Probe and [18F]-Fluoro-Azomycinarabino-Furanoside ([18F]FAZA) PET Study Reveals Anesthesia-Induced Impairment of Oxygenation and Perfusion in Tumor and Muscle.

Tumor hypoxia can be identified by [18F]FAZA positron emission tomography, or invasively using oxygen probes. The impact of anesthetics on tumor hypoxia remains controversial. The aim of this comprehensive study was to investigate the impact of isoflurane and ketamine/xylazine anesthesia on [18F]FAZA uptake and partial oxygen pressure (pO2) in carcinoma and muscle tissue of air- and oxygen-breathing mice. Methods CT26 colon carcinoma-bearing mice were anesthetized with isoflurane (IF) or ketamine/xylazine (KX) while breathing air or oxygen (O2). We performed 10 min static PET scans 1 h, 2 h and 3 h after [18F]FAZA injection and calculated the [18F]FAZA-uptake and tumor-to-muscle ratios (T/M). In another experimental group, we placed a pO2 probe in the tumor as well as in the gastrocnemius muscle to measure the pO2 and perfusion. Results Ketamine/xylazine-anesthetized mice yielded up to 3.5-fold higher T/M-ratios compared to their isoflurane-anesthetized littermates 1 h, 2 h and 3 h after [18F]FAZA injection regardless of whether the mice breathed air or oxygen (3 h, KX-air: 7.1 vs. IF-air: 1.8, p = 0.0001, KX-O2: 4.4 vs. IF-O2: 1.4, p < 0.0001). The enhanced T/M-ratios in ketamine/xylazine-anesthetized mice were mainly caused by an increased [18F]FAZA uptake in the carcinomas. Invasive pO2 probe measurements yielded enhanced intra-tumoral pO2 values in air- and oxygen-breathing ketamine/xylazine-anesthetized mice compared to isoflurane-anesthetized mice (KX-air: 1.01 mmHg, IF-air: 0.45 mmHg; KX-O2 9.73 mmHg, IF-O2: 6.25 mmHg). Muscle oxygenation was significantly higher in air-breathing isoflurane-anesthetized (56.9 mmHg) than in ketamine/xylazine-anesthetized mice (33.8 mmHg, p = 0.0003). Conclusion [18F]FAZA tumor uptake was highest in ketamine/xylazine-anesthetized mice regardless of whether the mice breathed air or oxygen. The generally lower [18F]FAZA whole-body uptake in isoflurane-anesthetized mice could be due to the higher muscle pO2-values in these mice compared to ketamine/xylazine-anesthetized mice. When performing preclinical in vivo hypoxia PET studies, oxygen should be avoided, and ketamine/xylazine-anesthesia might alleviate the identification of tumor hypoxia areals.

Quantitative chest CT analysis in patients with systemic sclerosis before and after autologous stem cell transplantation: comparison of results with those of pulmonary function tests and clinical tests

OBJECTIVES The aim of this study was to evaluate the course of SSc-related pulmonary abnormalities following high-dose chemotherapy with autologous stem cell transplantation (SCT) by quantitative chest CT analysis and compare the results with those of pulmonary function tests and the response of cutaneous involvement. METHODS Chest CT quantification was performed before, directly after [0.49 years (sd 0.20)] and at a mean of 2.2 years (sd 2.1) following autologous SCT in 26 consecutive patients with SSc between March 2001 and March 2015. Quantitative CT used fully automated software to calculate inspiratory total lung volume, mean lung density, high attenuation value and their pulmonary distribution (core vs peel). All patients underwent pulmonary function tests. We additionally analysed parallels in the response of associated skin changes by using the modified Rodnan skin score (mRSS). RESULTS The forced vital capacity (FVC) course at 6 months was used to classify patients into responders [n = 20 (76.9%)] and non-responders [n = 6 (23.1%)]. FVC, forced expiratory volume in 1 s, vital capacity (VC) as well as single-breath diffusion capacity for carbon monoxide significantly improved (P = 0.03, 0.001, 0.001 and 0.013, respectively) in responders. At quantitative CT, total lung volume increased (P = 0.018), whereas mean lung density (P = 0.026) and high attenuation value decreased (P = 0.020) after autologous SCT in responders. Correspondingly, mRSS improved from 27.35 (sd 9.25) before to 10.81 (sd 8.64) after autologous SCT (P = 0.003) in responders. Changes in mRSS before autologous SCT and thereafter correlated significantly with those 24 months after autologous SCT (r = 0.575; P = 0.031). CONCLUSIONS CT quantification of lung volume and parenchymal attenuation in SSc patients presenting with alveolitis and fibrosis that undergo autologous SCT yields parameters that match well with those of pulmonary function and even clinical tests. It might therefore be used as a substitute marker in patients who are unable to adequately perform lung function tests.

Impact of transjugular intrahepatic portosystemic shunt implantation on liver perfusion measured by volume perfusion CT

Background Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) induces changes of liver perfusion. Purpose To determine the changes in arterial, portal venous, and total perfusion of the liver parenchyma induced by TIPS using the technique of volume perfusion computed tomography (VPCT) and compare results with invasively measured hepatic intravascular pressure values. Material and Methods VPCT quantification of liver perfusion was performed in 23 patients (mean age, 62.5 ± 8.8 years) with portal hypertension in the pre-TIPS and post-TIPS setting, respectively. A commercially available software package was used for post-processing, enabling separate calculation of the dual (arterial [ALP] and portal venous [PVP]) blood supply and additionally of the hepatic perfusion index (HPI) (HPI = ALP/(ALP + PVP)*100%). Invasive pressure measurements were performed during the intervention, before and after TIPS placement. Liver function tests performed before and after the procedure were compared. Results Mean decrease of pressure gradient through TIPS was 13.3 mmHg. Mean normal values for ALP, PVP, and total perfusion (ALP + PVP) before TIPS were 15.9, 37.7, and 53.5 mL/100 mL/min, respectively, mean HPI was 35.4%. After TIPS, ALP increased to a mean value of 37.7 mL/100 mL/min, PVP decreased (15.7 mL/100 mL/min, P < 0.05), whereas total perfusion remained unchanged (53.4 mL/100 mL/min, P = 0.97). HPI increased (71.9%; P < 0.05). No correlation between invasive pressure measurement and VPCT parameters was observed. After TIPS, liver function tests were found to worsen with a significant increase of bilirubin (P < 0.05). Conclusion Following TIPS placement, ALP and HPI increased in all patients, whereas PVP markedly decreased. Interestingly, the magnitude of decrease in portosystemic pressure gradients was not found to correlate with VPCT parameters.

Correlation between positron emission tomography and Cerenkov luminescence imaging in vivo and ex vivo using 64 Cu-labeled antibodies in a neuroblastoma mouse model

Antibody-based therapies gain momentum in clinical therapy, thus the need for accurate imaging modalities with respect to target identification and therapy monitoring are of increasing relevance. Cerenkov luminescence imaging (CLI) are a novel method detecting charged particles emitted during radioactive decay with optical imaging. Here, we compare Position Emission Tomography (PET) with CLI in a multimodal imaging study aiming at the fast and efficient screening of monoclonal antibodies (mAb) designated for targeting of the neuroblastoma-characteristic epitope disialoganglioside GD2. Neuroblastoma-bearing SHO mice were injected with a 64Cu-labeled GD2-specific mAb. The tumor uptake was imaged 3 h, 24 h and 48 h after tracer injection with both, PET and CLI, and was compared to the accumulation in GD2-negative control tumors (human embryonic kidney, HEK-293). In addition to an in vivo PET/CLI-correlation over time, we also demonstrate linear correlations of CLI- and γ-counter-based biodistribution analysis. CLI with its comparably short acquisition time can thus be used as an attractive one-stop-shop modality for the longitudinal monitoring of antibody-based tumor targeting and ex vivo biodistribution. These findings suggest CLI as a reliable alternative for PET and biodistribution studies with respect to fast and high-throughput screenings in subcutaneous tumors traced with radiolabeled antibodies. However, in contrast to PET, CLI is not limited to positron-emitting isotopes and can therefore also be used for the visualization of mAb labeled with therapeutic isotopes like electron emitters.

Evaluation of Texture Analysis Parameter for Response Prediction in Patients with Hepatocellular Carcinoma Undergoing Drug-eluting Bead Transarterial Chemoembolization (DEB-TACE) Using Biphasic Contrast-enhanced CT Image Data: Correlation with Liver Perfusion CT

RATIONALE AND OBJECTIVES This study aimed to evaluate the potential role of computed tomography texture analysis (CTTA) of arterial and portal-venous enhancement phase image data for prediction and accurate assessment of response of hepatocellular carcinoma undergoing drug-eluting bead transarterial chemoembolization (TACE) by comparison to liver perfusion CT (PCT). MATERIALS AND METHODS Twenty-eight patients (27 male; mean age 67.2 ± 10.4) with 56 hepatocellular carcinoma-typical liver lesions were included. Arterial and portal-venous phase CT data obtained before and after TACE with a mean time of 39.93 ± 62.21 days between examinations were analyzed. TACE was performed within 48 hours after first contrast-enhanced CT. CTTA software was a prototype. CTTA analysis was performed blinded (for results) by two observers separately. Combined results of modified Response Evaluation Criteria In Solid Tumors (mRECIST) and PCT of the liver were used as the standard of reference. Time to progression was additionally assessed for all patients. CTTA parameters included heterogeneity, intensity, average, deviation, skewness, and entropy of co-occurrence. Each parameter was compared to those of PCT (blood flow [BF], blood volume, arterial liver perfusion [ALP], portal-venous perfusion, and hepatic perfusion index) measured before and after TACE. RESULTS mRECIST + PCT yielded 28.6% complete response (CR), 42.8% partial response, and 28.6% stable disease. Significant correlations were registered in the arterial phase in CR between changes in mean heterogeneity and BF (P = .004, r = -0.815), blood volume (P = .002, r = -0.851), and ALP (P = .002, r = -0.851), respectively. In the partial response group, changes in mean heterogeneity correlated with changes in ALP (P = .003) and to a lesser degree with hepatic perfusion index (P = .027) in the arterial phase. In the stable disease group, BF correlated with entropy of nonuniformity (P = .010). In the portal-venous phase, no statistically significant correlations were registered in all groups. Receiver operating characteristic analysis of CTTA parameters yielded predictive cutoff values for CR in the arterial contrast-enhanced CT phase for uniformity of skewness (sensitivity: 90.0%; specificity: 45.8%), and in the portal-venous phase for uniformity of heterogeneity (sensitivity: 92.3%; specificity: 81.8%). CONCLUSIONS Significant correlations exist between CTTA parameters and those derived from PCT both in the pre- and the post-TACE settings, and some of them have predictive value for TACE midterm outcome.

Prognostic value of perfusion CT in hepatocellular carcinoma treatment with sorafenib: comparison with mRECIST in longitudinal follow-up:

Background Targeted therapies are of increasing clinical importance and classic radiologic therapy response-criteria often fail to detect early therapeutic response or failure. For hepatocellular carcinoma (HCC), this is of major importance as therapeutic options are limited. Purpose To investigate the impact of sorafenib-treatment on intralesional perfusion using perfusion computed tomography (PCT) in HCC and to correlate the observed changes with mRECIST and the course of serum alpha-fetoprotein (AFP) for identification of their prognostic value. Material and Methods PCT was performed before and after two months of sorafenib treatment in 28 consecutive HCC patients and AFP levels were registered. Changes in tumor perfusion parameters blood flow (BF), blood volume (BV), mean transit time (MTT), volume transfer constant (Ktrans), arterial liver perfusion (ALP), and hepatic perfusion index (HPI) were registered in one target lesion. mRECIST measurements were performed at baseline and after two and four months during sorafenib treatment. Results According to mRECIST, after two months of treatment, all patients showed stable disease (SD), whereas after four months, 13 patients (46%) showed SD and 15 patients (54%) showed progressive disease (PD). A significant decrease was found in perfusion parameters BF, BV, Ktrans, ALP, and HPI in patients with SD as well as a significant increase in MTT (P < 0.05) after two months compared to baseline, while patients with PD showed a significant increase in HPI, BF, and BV. There were no correlations between AFP and mRECIST or perfusion parameters. Conclusion Decreased intralesional BF and HPI after two months of sorafenib treatment predicts disease stabilization after four months, whereas AFP dynamics were of limited value.

Results of quantitative chest-CT in chronic pulmonary graftvs.- host disease (cGvHD) 3 years after allogeneic stem cell transplantation

BACKGROUND To quantify lung parenchymal changes in symptomatic patients with chronic pulmonary graft-versus-host disease 3 years after allogeneic stem cell transplantation (allo-SCT) by means of CT-densitometry (CTD) and to compare results with those of established pulmonary function tests (PFT). METHODS The study group consisted of 26 patients with pulmonary cGvHD (19 males, 7 females; mean age, 49.29±15.89; range, 19-72 years). The diagnosis was based on clinical symptoms, PFT and chest-CT findings. CTD and PFT were performed both in the pre- and post-transplantation setting and results compared with each other. CT scans were obtained during suspended deep inspiration including the whole lungs. The mean lung attenuation (MLD), low attenuation values (LAV) and distribution of focal parenchymal abnormalities compatible with emphysema (HU <-950) were quantitatively calculated with histograms and graphics. On PFT, total lung capacity (TLC), residual volume (RV), vital capacity (VC), forced expiratory volume in 1 s (FEV1s) and diffusion capacity for carbon monoxide (DLCOSB) were registered. RESULTS Changes in end-inspiratory lung volume and density (MLD and LAV) in symptomatic cGvHD patients in mean three years after allo-SCT proved all not significant, but there was a clear trend towards an increase in lung volume and a decrease in lung attenuation. These results were similar throughout all classes of bronchiolitis obliterans (BO) by cGvHD. PFT showed a significant decrease in VC, FEV1s but only a minimal decrease in DLCOSB. Changes in FVC after stem cell transplantation correlated with changes in LAV (r=0.649, P=0.031). Predicted VC correlated with changes in LAV (r=0.771, P=0.005). There was a correlation between the absolute difference of FEV1 and DLCOSB (r=0.64, P=0.14) before and after stem cell transplantation. CONCLUSIONS End-inspiratory phase CT lung parenchyma quantification in symptomatic patients with pulmonary cGvHD 3 years after allo-SCT shows discrete changes over the pre-transplantation setting representing airway obstruction, mirroring airflow limitation on PFT. Its use enables exclusion of relevant parenchymal destruction (emphysema-equivalent lung density) at this time.

Improved CT-detection of acute bowel ischemia using frequency selective non-linear image blending

Background Computed tomography (CT) as a fast and reliable diagnostic technique is the imaging modality of choice for acute bowel ischemia. However, diagnostic is often difficult mainly due to low attenuation differences between ischemic and perfused segments. Purpose To compare the diagnostic efficacy of a new post-processing tool based on frequency selective non-linear blending with that of conventional linear contrast-enhanced CT (CECT) image blending for the detection of bowel ischemia. Material and Methods Twenty-seven consecutive patients (19 women; mean age = 73.7 years, age range = 50–94 years) with acute bowel ischemia were scanned using multidetector CT (120 kV; 100–200 mAs). Pre-contrast and portal venous scans (65–70 s delay) were acquired. All patients underwent surgery for acute bowel ischemia and intraoperative diagnosis as well as histologic evaluation of explanted bowel segments was considered “gold standard.” First, two radiologists read the conventional CECT images in which linear blending was adapted for optimal contrast, and second (three weeks later) the frequency selective non-linear blending (F-NLB) image. Attenuation values were compared, both in the involved and non-involved bowel segments creating ratios between unenhanced and CECT. Results The mean attenuation difference between ischemic and non-ischemic wall in the portal venous scan was 69.54 HU (reader 2 = 69.01 HU) higher for F-NLB compared with conventional CECT. Also, the attenuation ratio between contrast-enhanced and pre-contrast CT data for the non-ischemic walls showed significantly higher values for the F-NLB image (CECT: reader 1 = 2.11 (reader 2 = 3.36), F-NLB: reader 1 = 4.46 (reader 2 = 4.98)]. Sensitivity in detecting ischemic areas increased significantly for both readers using F-NLB (CECT: reader 1/2 = 53%/65% versus F-NLB: reader 1/2 = 62%/75%). Conclusion Frequency selective non-linear blending improves detection of bowel ischemia compared with conventional CECT by increasing attenuation differences between ischemic and perfused segments.

CT-response patterns and the role of CT-textural features in inoperable abdominal/retroperitoneal soft tissue sarcomas treated with trabectedin

PURPOSE To evaluate CT patterns and textural features of soft tissue sarcomas following trabectedin therapy as well as their suitability for predicting therapeutic response. MATERIAL AND METHODS A total of 31 patients (18 female, 13 male; mean age, 58.0years; range, 38-79years) with sarcoma under trabectedin as a third-line therapy between October 2008 and July 2017 underwent baseline and follow-up contrast-enhanced CT. Response evaluation was based on modifiedCHOI-criteria and RECIST1.1, classified as partial response(PR), stable disease(SD), progressive disease(PD). For CT-texture analysis (CTTA), mean, entropy and uniformity of intensity/skewness/entropy of co-occurrence matrix (COM) and contrast of neighboring-grey-level-dependence-matrix (NGLDM) were calculated. RESULTS Following CHOI-criteria, 9 patients achieved PR, 10 SD and 12 PD. RECIST1.1. classified patients into 5 PR, 15 SD and 11 PD. A frequent (n = 6/31; 19.3%) pattern of response was tumor liquefaction. In responders differences in entropy of entropy-NGLDM(p = 0.028) and uniformity-NGLDM(p = 0.021), in non-responders entropy of average(p = 0.039), deviation(p = 0.04) and uniformity of deviation(p = 0.013) occured between baseline and follow-up. Mean intensity and average were higher when liquefication occured(p = 0.03; p = 0.02), whereas mean deviation was lower(p = 0.02) at baseline compared to other response patterns. Differences in mean(p = 0.023), entropy(p = 0.049) and uniformity(p = 0.023) of entropy-NGLDM were found between responders and non-responders at follow-up. For the mean of heterogeneity a cut-off value was calculated for prediction of response in baseline CTTA (0.12; sensitivity 89%; specificity 77%). CONCLUSION A frequent pattern of response to trabectedin was tumor liquefication being responsible for pseudoprogression, therefore modifiedCHOI should be preferred. Single CT-textural features can be used complementarily for prediction and monitoring response to trabectedin.