Significance of a Single-Time-Point Somatostatin Receptor SPECT/Multiphase CT Protocol in the Diagnostic Work-up of Gastroenteropancreatic Neuroendocrine Neoplasms.

UNLABELLED: This prospective study compared a 1-d SPECT/CT protocol with the commonly used 3-d protocol for somatostatin receptor scintigraphy in patients with gastroenteropancreatic neuroendocrine neoplasms. Additionally, the influence of SPECT/CT on patient management was evaluated. METHODS: From October 2011 to October 2012, all gastroenteropancreatic neuroendocrine neoplasm patients undergoing restaging with somatostatin receptor scintigraphy on a modern SPECT/CT device were enrolled in this study. The protocol consisted of planar imaging at 4, 24, and 48 h; low-dose SPECT/CT at 24 and 48 h; diagnostic CT at 24 h using a triple-phase delay after administration of contrast; and diagnostic SPECT/CT at 24 h. All components of the imaging data were reassessed by 3 masked interpreters. The results were compared with a reference standard based on all clinical, imaging, and histopathology follow-up data available (follow-up range, 24-36 mo; mean, 29.9 mo). The reference standard was defined by a study-specific interdisciplinary tumor board that also reassessed treatment decisions. RESULTS: Thirty-one patients were eligible for analysis (18 men and 13 women; mean age, 60.4 y). Ten had no imaging signs of disease and remained disease-free during follow-up. Twenty-one had persistent or recurrent disease (82 lesions: 24 in the liver, 21 in the lymph nodes, 16 in bone, 12 in the pancreas, and 9 in other locations). The respective lesion detection rates for interpreters 1, 2, and 3 were 51.9%, 49.4%, and 71.6% for low-dose SPECT/CT at 24 h; 51.9%, 55.6%, and 67.9% for low-dose SPECT/CT at 48 h; 63.0%, 70.4%, and 85.2% for diagnostic CT; and 77.8%, 84.0%, and 88.9% for diagnostic SPECT/CT. Interobserver agreement was moderate for diagnostic SPECT/CT (κ = 0.44), diagnostic CT (κ = 0.43), low-dose SPECT/CT at 48 h (κ = 0.61), and low-dose SPECT/CT at 24 h (κ = 0.55). For planar imaging, interobserver agreement was fair after 48 h (κ = 0.36) and 24 h (κ = 0.38) and moderate after 4 h (κ = 0.42). Every lesion detectable on planar imaging or low-dose SPECT/CT was also detectable on diagnostic SPECT/CT. The CT and SPECT components of diagnostic SPECT/CT strongly complemented each other, as 34 of 82 lesions (41.4%) were detected on only the CT component or only the SPECT component. Therapeutic management was influenced by the diagnostic SPECT/CT interpretation in 8 of 31 patients (25.8%). CONCLUSION: The highest detection rates were achieved by diagnostic SPECT/CT. Thus, a more patient-friendly 1-d protocol is feasible. Furthermore, multiphase SPECT/CT affected management in about a quarter of patients.

CT-guided Interstitial Brachytherapy of Hepatocellular Carcinoma before Liver Transplantation: an Equivalent Alternative to Transarterial Chemoembolization?

OBJECTIVES: Transarterial chemoembolization (TACE) is established as bridging therapy of HCC listed for transplantation (LT). CT-guided brachytherapy (CTB) has not been evaluated as a bridging concept. We compared CTB and TACE for bridging before LT in HCC patients. METHODS: Twelve patients with HCC received LT after CTB (minimal tumour dose, 15-20 Gy). Patients were matched (CTB:TACE, 1:2) by sex, age, number and size of lesions, and underlying liver disease with patients who received TACE before transplantation. Study endpoints were extent of necrosis at histopathology and recurrence rate after OLT. RESULTS: There were no significant differences between the CTB and TACE groups regarding Child-Pugh category (p = 0.732), AFP (0.765), time on waiting list (p = 0.659), number (p = 0.698) and size (p = 0.853) of HCC lesions, fulfilment of Milan-criteria (p = 0.638), or previous liver-specific treatments. CTB achieved higher tumour necrosis rates than TACE (p = 0.018). The 1- and 3-year recurrence rate in the CTB group was 10 and 10 % vs. TACE, 14 and 30 % (p = 0.292). CONCLUSIONS: Our data show comparable or even better response and post-LT recurrence rates of CTB compared to TACE for treating HCC in patients prior to LT. CTB should be further evaluated as an alternative bridging modality, especially for patients not suited for TACE. KEY POINTS: • CT-guided interstitial brachytherapy (CTB) is a promising alternative to transarterial chemoembolization (TACE). • CTB instead of TACE is possible for bridging to liver transplantation in HCC patients. • HCC recurrence was not associated with CTB despite potential tumour seeding.

Gd-EOB enhanced MRI T1-weighted 3D-GRE with and without elevated flip angle modulation for threshold-based liver volume segmentation.

BACKGROUND: Despite novel software solutions, liver volume segmentation is still a time-consuming procedure and often requires further manual optimization. With the high signal intensity of the liver parenchyma in Gd-EOB enhanced magnetic resonance imaging (MRI), liver volume segmentation may be improved. PURPOSE: To evaluate the practicability of threshold-based segmentation of the liver volume using Gd-EOB-enhanced MRI including a customized three-dimensional (3D) sequence. MATERIAL AND METHODS: A total of 20 patients examined with Gd-EOB MRI (hepatobiliary phase T1-weighted (T1W) 3D sequence [VIBE]; flip angle [FA], 10° and 30°) were enrolled in this retrospective study. The datasets were independently processed by two blinded observers (O1 and O2) in two ways: manual (man) and threshold-based (thresh; study method) segmentation of the liver each followed by an optimization step (man+opt and thresh+opt; man+opt [FA10°] served as reference method). Resulting liver volumes and segmentation times were compared. A liver conversion factor was calculated in percent, describing the non-hepatocellular fraction of the total liver volume, i.e. bile ducts and vessels. RESULTS: Thresh+opt (FA10°) was significantly faster compared to the reference method leading to a median volume overestimation of 4%/8% (P < 0.001). Using thresh+opt (FA30°), segmentation was even faster (P < 0.001) and even reduced median volume deviation of 0%/2% (O1/O2; both P > 0.2). The liver conversion factor was found to be 10%. CONCLUSION: Threshold-based liver segmentation employing Gd-EOB-enhanced hepatobiliary phase standard T1W 3D sequence is accurate and time-saving. The performance of this approach can be further improved by increasing the FA.

Implications of imaging criteria for the management and treatment of intraductal papillary mucinous neoplasms - benign versus malignant findings.

OBJECTIVES: Evaluation of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiation of pancreatic intraductal papillary mucinous neoplasm (IPMN) subtypes based on objective imaging criteria. METHODS: Fifty-eight patients with 60 histologically confirmed IPMNs were included in this retrospective study. Eighty-three imaging studies (CT,n = 42; MRI,n = 41) were analysed by three independent blinded observers (O1-O3), using established imaging criteria to assess likelihood of malignancy (-5, very likely benign; 5, very likely malignant) and histological subtype (i.e., low-grade (LGD), moderate-grade (MGD), high-grade dysplasia (HGD), early invasive carcinoma (IPMC), solid carcinoma (CA) arising from IPMN). RESULTS: Forty-one benign (LGD IPMN,n = 20; MGD IPMN,n = 21) and 19 malignant (HGD IPMN,n = 3; IPMC,n = 6; solid CA,n = 10) IPMNs located in the main duct (n = 6), branch duct (n = 37), or both (n = 17) were evaluated. Overall accuracy of differentiation between benign and malignant IPMNs was 86/92 % (CT/MRI). Exclusion of overtly malignant cases (solid CA) resulted in overall accuracy of 83/90 % (CT/MRI). The presence of mural nodules and ductal lesion size ≥30 mm were significant indicators of malignancy (p = 0.02 and p < 0.001, respectively). CONCLUSIONS: Invasive IPMN can be identified with high confidence and sensitivity using CT and MRI. The diagnostic problem that remains is the accurate radiological differentiation of premalignant and non-invasive subtypes. KEY POINTS: • CT and MRI can differentiate benign from malignant forms of IPMN. • Identifying (pre)malignant histological IPMN subtypes by CT and MRI is difficult. • Overall, diagnostic performance with MRI was slightly (not significantly) superior to CT.

Evaluation of gadolinium-EOB-DTPA uptake after portal vein embolization: value of an increased flip angle.

BACKGROUND: The optimal sequence for Gd-EOB-DTPA uptake measurement in the liver with the purpose of liver function measurement is still not defined. PURPOSE: To prospectively evaluate the effect of an increased flip angle (FA) of a T1-weighted fat-saturated 3D sequence for the measurement of hepatocyte uptake of Gd-EOB-DTPA magnetic resonance imaging (MRI) after right portal vein embolization (PVE). MATERIAL AND METHODS: Ten patients who received a PVE prior to an extended hemihepatectomy were examined 14 days after PVE using Gd-EOB-DTPA enhanced MRI of the liver using the standard FA of 10° and the increased FA of 30°. RESULTS: Relative enhancement of the right liver lobe (RLL) was 0.52 ± 0.12 for 10° and 1.41 ± 0.39 for 30°. Relative enhancement of the left liver lobe (LLL) was 0.58 ± 0.11 for 10° and 2.05 ± 0.61 for 30°. Relative enhancement of the RLL was significantly higher for 30° than for 10° (P = 0.009) and significantly higher in the 30° than in the 10° sequences (P = 0.005) for the LLL. CONCLUSION: A flip angle of 30° increases the contrast between liver partitions with and without portal venous embolization. Thereby, the sensitivity for differences in uptake intensity is increased. This could be of value for a more exact determination of differences in regional liver function and, consequently, the estimation of the future remnant liver function.

Evaluation of arginine deiminase treatment in melanoma xenografts using (18)F-FLT PET.

PURPOSE: This study aims to develop a molecular imaging strategy for response assessment of arginine deiminase (ADI) treatment in melanoma xenografts using 3'-[(18)F]fluoro-3'-deoxythymidine ([(18)F]-FLT) positron emission tomography (PET). PROCEDURES: F-FLT response to ADI therapy was studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was investigated, with a particular emphasis on biological pathways known to regulate (18)F-FLT metabolism. RESULTS: Proliferation of SK-MEL-28 melanoma tumors was potently inhibited by ADI treatment. However, no metabolic response was observed in FLT PET, presumably based on the known ADI-induced degradation of PTEN, followed by instability of the tumor suppressor p53 and a relative overexpression of thymidine kinase 1, the enzyme mainly responsible for intracellular FLT processing. CONCLUSION: The specific pharmacological properties of ADI preclude using (18)F-FLT to evaluate clinical response in melanoma and argue for further studies to explore the use of other clinically applicable PET tracers in ADI treatment.

Functionalizable silica-based micron-sized iron oxide particles for cellular magnetic resonance imaging.

Cellular therapies require methods for noninvasive visualization of transplanted cells. Micron-sized iron oxide particles (MPIOs) generate a strong contrast in magnetic resonance imaging (MRI) and are therefore ideally suited as an intracellular contrast agent to image cells under clinical conditions. However, MPIOs were previously not applicable for clinical use. Here, we present the development and evaluation of silica-based micron-sized iron oxide particles (sMPIOs) with a functionalizable particle surface. Particles with magnetite content of >40% were composed using the sol-gel process. The particle surfaces were covered with COOH groups. Fluorescein, poly-L-lysine (PLL), and streptavidin (SA) were covalently attached. Monodisperse sMPIOs had an average size of 1.18 µm and an iron content of about 1.0 pg Fe/particle. Particle uptake, toxicity, and imaging studies were performed using HuH7 cells and human and rat hepatocytes. sMPIOs enabled rapid cellular labeling within 4 h of incubation; PLL-modified particles had the highest uptake. In T2*-weighted 3.0 T MRI, the detection threshold in agarose was 1,000 labeled cells, whereas in T1-weighted LAVA sequences, at least 10,000 cells were necessary to induce sufficient contrast. Labeling was stable and had no adverse effects on labeled cells. Silica is a biocompatible material that has been approved for clinical use. sMPIOs could therefore be suitable for future clinical applications in cellular MRI, especially in settings that require strong cellular contrast. Moreover, the particle surface provides the opportunity to create multifunctional particles for targeted delivery and diagnostics.

Imaging of tumor vascularization using fluorescence molecular tomography to monitor arginine deiminase treatment in melanoma.

Based on their inability to express argininosuccinate synthetase (ASS), some cancer entities feature the characteristic of L-arginine (Arg) auxotrophy. This inability to intrinsically generate Arg makes them applicable for arginine deiminase (ADI) treatment, an Arg-depleting drug. Arg is also used for the synthesis of endothelial nitric oxide (NO), which mainly confers vasodilatation but is also considered to have a major influence on tumor vascularization. The purpose of this study was to define changes in tumor vasculature in an ADI-treated melanoma xenograft mouse model using the blood pool agent AngioSense 750 and fluorescence molecular tomography (FMT). We used an ASS-negative melanoma xenograft mouse model and subjected it to weekly ADI treatment. Changes in tumor size were measured, and alterations in tumor vasculature were depicted by FMT and CD31 immunohistochemistry (IHC). On ADI treatment and effective antitumor therapy, we observed a drop in NO plasma levels and visualized changes in tumor vascularization with FMT and IHC. ADI treatment in melanoma xenografts has a tumor-reducing effect, which can be noninvasively imaged by quantifying tumor vascularization with FMT and IHC.

Tumor-specific targeting with modified Sindbis viral vectors: evaluation with optical imaging and positron emission tomography in vivo.

PURPOSE: Sindbis virus (SINV) infect tumor cells specifically and systemically throughout the body. Sindbis vectors are capable of expressing high levels of transduced suicide genes and thus efficiently produce enzymes for prodrug conversion in infected tumor cells. The ability to monitor suicide gene expression levels and viral load in patients, after administration of the vectors, would significantly enhance this tumor-specific therapeutic option. PROCEDURES: The tumor specificity of SINV is mediated by the 67-kDa laminin receptor (LR). We probed different cancer cell lines for their LR expression and, to determine the specific role of LR-expression in the infection cycle, used different molecular imaging strategies, such as bioluminescence, fluorescence molecular tomography, and positron emission tomography, to evaluate SINV-mediated infection in vitro and in vivo. RESULTS: All cancer cell lines showed a marked expression of LR. The infection rates of the SINV particles, however, differed significantly among the cell lines. CONCLUSION: We used novel molecular imaging techniques to visualize vector delivery to different neoplatic cells. SINV infection rates proofed to be not solely dependent on cellular LR expression. Further studies need to evaluate the herein discussed ways of cellular infection and viral replication.

Flip angle modulations in late phase Gd-EOB-DTPA MRI improve the identification of the biliary system.

OBJECTIVES: To assess the improvement of bile duct visualization in Gd-EOB-DTPA enhanced MR-cholangiography (EOB-MRC) by using an increased flip angle. METHODS: 35 patients underwent Gd-EOB-DTPA enhanced MRI of the liver including T2-weighted MRCP and hepatobiliary phase EOB-MRC using a flip angle of 10° (FA10) and of 35° (FA35), respectively. Images were evaluated regarding the delineation of biliary ducts, the order of branching and anatomic visualization of the biliary tree. ROI analysis was performed to estimate the signal-to-noise (SNR) and contrast-to-noise (CNR) ratios. RESULTS: Applying the FA35 resulted in a significantly better SNR and CNR as compared to FA10. The overall image quality was rated as good for both, FA10 and FA35. The overall rating for regional delineation of the biliary system was rated significantly better for FA35 than for FA10 (p=0.02). Classification of bile duct anatomy variations, however, was equivalent in both techniques. CONCLUSIONS: Increasing the flip angle of a T1-weighted 3D-sequence from 10° to 35° during the hepatobiliary phase of Gd-EOB enhanced MRI visually and quantitatively improved the visualization of the biliary ducts.

Novel mechanistic insights into arginine deiminase pharmacology suggest 18F-FDG is not suitable to evaluate clinical response in melanoma.

UNLABELLED: Because of deficiencies in l-arginine biosynthesis, some cancers are susceptible to therapeutic intervention with arginine deiminase (ADI), an enzyme responsible for consuming the dietary supply of l-arginine to deprive the disease of an essential nutrient. ADI is currently being evaluated in several clinical trials, and fully realizing the drug's potential will depend on invoking the appropriate metrics to judge clinical response. Without a clear biologic mandate, PET/CT with (18)F-FDG is currently used to monitor patients treated with ADI. However, it is unclear if it can be expected that (18)F-FDG responses will indicate (or predict) clinical benefit. METHODS: (18)F-FDG responses to ADI therapy were studied in preclinical models of melanoma in vitro and in vivo. The molecular mechanism of response to ADI therapy was also studied, with a particular emphasis on biologic pathways known to regulate (18)F-FDG avidity. RESULTS: Although proliferation of SK-MEL 28 was potently inhibited by ADI treatment in vitro and in vivo, no clear declines in (18)F-FDG uptake were observed. Further investigation showed that ADI treatment induces the posttranslational degradation of phosphatase and tensin homolog and the activation of the PI3K signaling pathway, an event known to enhance glycolysis and (18)F-FDG avidity. A more thorough mechanistic study showed that ADI triggered a complex mechanism of cell death, involving apoptosis via poly (ADP-ribose) polymerase cleavage-independent of caspase 3. CONCLUSION: These findings suggest that some unexpected pharmacologic properties of ADI preclude using (18)F-FDG to evaluate clinical response in melanoma and, more generally, argue for further studies to explore the use of PET tracers that target apoptotic pathway activation or cell death.

Arterial versus portal venous embolization for induction of hepatic hypertrophy before extended right hemihepatectomy in hilar cholangiocarcinomas: a prospective randomized study.

PURPOSE: To assess the efficacy and safety of portal vein (PV) embolization versus hepatic artery embolization (HAE) for induction of hepatic hypertrophy before extended right hemihepatectomy in patients with hilar cholangiocarcinoma. MATERIALS AND METHODS: Fifty patients (female, n = 15; male, n = 35; age range, 37-80 y) with hilar cholangiocarcinomas who were planned to undergo extended right hemihepatectomy were prospectively included in 2003-2006. In addition to biliary decompression of the left liver, patients were randomized to undergo embolization of the right hepatic artery (with transfemoral access and polyvinyl alcohol [PVA] particles plus coils) or right PV branches (with computed tomography [CT]-guided transhepatic access and PVA particles). CT was performed before and approximately 3 weeks after embolization for volumetric assessment of the liver. RESULTS: In the HAE group, median growth of the left lateral segments was 40 mL (P < .01), with a median reduction of the whole liver of 10 mL (P = .41); adverse events were observed in two of 25 patients (8%), who each developed an abscess in the right liver lobe. In the PV embolization group, median growth of the left lateral segments was 110 mL (P < .01), with a median growth of the whole liver of 10 mL (P = .92); a subcapsular seroma occurred in one of 25 patients (4%). The median growth of the left lateral segments after PV embolization was significantly greater than after HAE (P = .004). CONCLUSIONS: Compared with HAE, PV embolization was significantly superior regarding induction of hepatic hypertrophy of the left lateral segments.

Preoperative multidetector row computed tomography for evaluation and assessment of resection criteria in patients with pancreatic masses.

BACKGROUND: preoperative assessment of pancreatic masses is still challenging as regards the characterization and assessment of irresectability. The opportunities of modern multidetector computed tomography (MDCT) with image postprocessing can be expected to enhance the diagnostic performance if accurate criteria are elaborated. PURPOSE: to estimate the accuracy of MDCT and multiplanar image reconstructions with the use of standardized imaging criteria for preoperative evaluation of pancreatic masses with respect to irresectability. MATERIAL AND METHODS: a total of 105 consecutive patients who underwent exploratory laparoscopy or pancreatic resection and had preoperative 3-phase MDCT (4-64 rows) were enrolled retrospectively. First, transverse sections and secondly additional 3Ds were reviewed by two independent blinded observers (O1/O2). Preoperative imaging findings were correlated with intraoperative and histopathologic results. RESULTS: among all 105 patients, 70 malignant pancreatic tumors and 35 benign pancreatic diseases were found (accuracy of 93% for O1 and 91% for O2). For arterial tumor invasion, receiver operator characteristic (ROC) analysis (values averaged from the results of O1 and O2) revealed an area under the curve (AUC) of 0.931 for transverse sections and 0.986 for 3Ds. Regarding irresectability, positive predictive values were 97% (with 3Ds, 97%) for O1/O2; negative predictive values were 84% (with 3Ds, 89%) for O1 and 86% (with 3Ds, 91%) for O2. CONCLUSION: MDCT with 3Ds was highly accurate for evaluation and assessment of irresectability criteria in patients with pancreatic masses. However, due to the limited specificity regarding arterial tumor infiltration, the indication for surgical exploration should be made generously in case of inconclusive findings.

Modification of aminosilanized superparamagnetic nanoparticles: feasibility of multimodal detection using 3T MRI, small animal PET, and fluorescence imaging.

PURPOSE: The aim of our study was to modify an aminosilane-coated superparamagnetic nanoparticle for cell labeling and subsequent multimodal imaging using magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescent imaging in vivo. PROCEDURES: We covalently bound the transfection agent HIV-1 tat, the fluorescent dye fluorescein isothiocyanate, and the positron-emitting radionuclide gallium-68 to the particle and injected them intravenously into Wistar rats, followed by animal PET and MRI at 3.0 T. As a proof of principle hepatogenic HuH7 cells were labeled with the particles and observed for cell toxicity as well as detectability by MRI and biodistribution in vivo. RESULTS: PET imaging and MRI revealed increasing hepatic and splenic accumulation of the particles over 24 h. Adjacent in vitro studies in hepatogenic HuH7 cells showed a rapid intracellular accumulation of the particles with high labeling efficiency and without any signs of toxicity. In vivo dissemination of the labeled cells could be followed by dynamic biodistribution studies. CONCLUSIONS: We conclude that our modified superparamagnetic nanoparticles are stable under in vitro and in vivo conditions and are therefore applicable for efficient cell labeling and subsequent multimodal molecular imaging. Moreover, their multiple free amino groups suggest the possibility for further modifications and might provide interesting opportunities for various research fields.

Impact of Multiphase 68Ga-DOTATOC-PET/CT on therapy management in patients with neuroendocrine tumors.

AIM: Retrospective evaluation of the impact of integrated positron emission tomography/computed tomography (PET/CT) using (68)Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide ((68)Ga-DOTATOC) on the therapeutic management of patients with neuroendocrine tumors (NET). METHODS: The (68)Ga-DOTATOC-PET/CT data of 66 patients (31 male, 35 female; age: 29-79, mean age: 56 years) with known or suspected NET were included. Imaging data (PET and triple-phase contrast-enhanced CT) were evaluated in consensus by two readers for the visualization of NET manifestations. Combined PET/CT, clinical and imaging follow-up as well as histopathology (if available) served as the reference standard. In order to assess the impact of the respective submodalities on the therapeutic strategy chosen, the results were compared to the treatment decision made by the interdisciplinary NET tumor board of our institution. RESULTS: Two of the initial 66 patients included did not suffer from NET according to further immunohistopathological examination. In 50 of the remaining 64 (78%) NET patients, a total of 181 NET manifestations were detected by PET/CT. 59/181 (32.6%) were detected by one submodality only (CT 17.1%, PET 15.5%, p for comparison of both = 0.459). Combined PET/CT reading had an impact on the therapeutic management in 24 of 64 (38%) NET patients: primary resection (n = 5), curative lymph node resection (n = 1), initiation/switch of chemotherapy (CTx) due to progressive disease (n = 10), no surgery due to systemic disease (n = 2), radiopeptide receptor therapy instead of CTx (n = 1), additional bisphosphonate therapy (n = 4), and hepatic brachytherapy (n = 1). In 12 of 24 (50%) of these patients, relevant findings were detected by a single submodality only: CT (n = 5), PET (n = 7); p for comparison = 0.774). CONCLUSION: (68)Ga-DOTATOC-PET/CT influences therapeutic management in about one third of patients examined. CT and PET are comparably sensitive, deliver complementary information and equally contribute to therapeutic decision-making. Thus, despite the merits of the PET modality, the CT component must not be neglected and an optimized multiphase CT protocol is recommended.

Multislice computed tomography using a triple-phase contrast protocol for preoperative assessment of hepatic tumor load in patients with hepatocellular carcinoma before liver transplantation.

For evaluation of triple-phase multislice computed tomography (CT) for assessment of hepatocellular carcinoma (HCC) before liver transplantation. All HCC patients who underwent liver transplantation at our institution between 2001 and 2006 and had contrast-enhanced abdominal 4-/16-slice CT [unenhanced, arterial (20 s delay), portal venous (40 s), and venous (80 s) scan] within 100 days before transplantation were enrolled retrospectively. CT data were reviewed by two observers. Results were correlated to histopathologic findings by means of a lesion-by-lesion evaluation. Thirty-two patients with 76 HCC-lesions were included. The lesion-based sensitivity of observer 1 and 2 was 78% (59/76) and 83% (63/76) (false positives, n = 6 and n = 10). The sensitivity of observer 1/2 was 89%/95% for lesions >20 mm (n = 37), 94% for lesions 11-20 mm (n = 18), and 43%/53% for lesions <10 mm (n = 21). The mean detection rates of unenhanced, arterial, portal venous, and venous phase scans were 30%, 74%, 59%, and 40%. All detected lesions were visible on arterial and/or portal venous scans (arterial only, 24%; portal venous only, 9%). Arterial and portal venous phase scans are the strongest contributors to the high detection rate of triple-phase multislice-CT in HCC. However, the detection of small HCC measuring <10 mm and false positive findings remains a challenge.

Imaging of primary human hepatocytes performed with micron-sized iron oxide particles and clinical magnetic resonance tomography.

Transplantation of primary human hepatocytes is a promising approach in certain liver diseases. For the visualization of the hepatocytes during and following cell application and the ability of a timely response to potential complications, a non-invasive modality for imaging the transplanted cells has to be established. The aim of this study was to label primary human hepatocytes with micron-sized iron oxide particles (MPIOs), enabling the detection of cells by clinical magnetic resonance imaging (MRI). Primary human hepatocytes isolated from 13 different donors were used for the labelling experiments. Following the dose-finding studies, hepatocytes were incubated with 30 particles/cell for 4 hrs in an adhesion culture. Particle incorporation was investigated via light, fluorescence and electron microscopy, and labelled cells were fixed and analysed in an agarose suspension by a 3.0 Tesla MR scanner. The hepatocytes were enzymatically resuspended and analysed during a 5-day reculture period for viability, total protein, enzyme leakage (aspartate aminotransferase [AST], lactate dehydrogenase [LDH]) and metabolic activity (urea, albumin). A mean uptake of 18 particles/cell could be observed, and the primary human hepatocytes were clearly detectable by MR instrumentation. The particle load was not affected by resuspension and showed no alternations during the culture period. Compared to control groups, labelling and resuspension had no adverse effects on the viability, enzyme leakage and metabolic activity of the human hepatocytes. The feasibility of preparing MPIO-labelled primary human hepatocytes detectable by clinical MR equipment was shown in vitro. MPIO-labelled cells could serve for basic research and quality control in the clinical setting of human hepatocyte transplantation.

Planning transarterial radioembolization of colorectal liver metastases with Yttrium 90 microspheres: evaluation of a sequential diagnostic approach using radiologic and nuclear medicine imaging techniques.

The purpose of the study was to establish a diagnostic approach to the preparation of patients with colorectal liver metastases considered for transarterial radioembolization (RE). Twenty-two patients sequentially underwent computed tomography (CT; thorax/abdomen), magnetic resonance imaging (MRI; liver; hepatocyte-specific contrast), positron emission tomography (PET/PET-CT; F18-fluoro-desoxy-glucose), and angiography with perfusion scintigraphy [planar imaging; tomography with integrated CT (SPECT-CT)]. The algorithm was continued when no contraindication or alternative treatment option was found. The impact of each test on the therapy decision and RE management was recorded. Patient evaluation using CT revealed contraindications for RE in 4/22 patients (18%). Of the remaining 18 patients, 2 were excluded and 3 were assigned to locally ablative treatment based on MRI and PET results (28%). The remaining 13 patients entered the planning algorithm: SPECT-CT revealed gastrointestinal tracer accumulations in 4 (31%) patients [SPECT, 2 (15%)], making a modified application necessary. In five patients (38%), planar scintigraphy revealed relevant hepatopulmonary shunting. Therapy was finally administered to all 13 patients without therapy-related pulmonary or gastrointestinal morbidity. Each part of the diagnostic algorithm showed a relevant impact on patient management. The sequential approach appears to be suitable and keeps the number of unnecessary treatments and therapy risks to a minimum.

An orthotopic model of pancreatic somatostatin receptor (SSTR)-positive tumors allows bimodal imaging studies using 3T MRI and animal PET-based molecular imaging of SSTR expression.

Somatostatin receptor (SSTR) scintigraphy is currently used as one standard imaging modality in neuroendocrine tumors (NETs). However, future optimization of NET imaging may be achieved with positron emission tomography based methods utilizing more sensitive and specific tracers in combination with computed tomography or magnetic resonance imaging. Here we established an orthotopic mouse model that reflects relevant aspects of human pancreatic NETs such as SSTR expression, dense vascularization and metastatic disease. This model was then utilized to test the feasibility of combined magnetic resonance imaging and animal positron emission tomography. Orthotopic implantation of amphicrine, SSTR-positive pancreatic AR42J cells resulted in rapidly growing tumors, with concomitant metastatic spread into abdominal lymph nodes and peritoneal cavity. Primary tumors as well as their metastases expressed the neuroendocrine markers chromogranin A and synaptophysin. For imaging experiments, the SSTR ligands (68)Ga-DOTATOC or (68)Ga-DOTANOC were injected intravenously, and animals were subsequently examined in an animal positron emission tomography scanner and a clinical 3T (tesla) magnetic resonance imager. All animals showed radionuclide accumulation in the primary tumor. Definite anatomical correlation was achieved using digital image fusion of the positron emission tomography and magnetic resonance imaging data. (68)Ga-DOTANOC strongly accumulated in the tumor tissue (mean 6.6-fold vs. control tissues) when compared to (68)Ga-DOTATOC, which showed a higher renal clearance. In good agreement with the biodistribution data, the kidney-to-tumor ratio was higher for (68)Ga-DOTATOC (2.43-fold vs. 1.75-fold). Consequently, (68)Ga-DOTANOC achieved better signal enhancement in the primary tumor and allowed for detection of metastatic lesions. In summary, we established a novel orthotopic pancreatic SSTR-positive tumor model and used this model to provide proof of principle for the diagnostic combination of SSTR-based molecular imaging and magnetic resonance imaging. Specifically, the animal model allowed the comparative evaluation of (68)Ga-DOTANOC and (68)Ga-DOTATOC, with (68)Ga-DOTANOC providing better tumor-specific accumulation and renal activity. We conclude that this animal model will be of innovative value for further investigation in the imaging of NETs.

DeltaF508 mutation results in impaired gastric acid secretion.

The cystic fibrosis transmembrane conductance regulator (CFTR) is recognized as a multifunctional protein that is involved in Cl(-) secretion, as well as acting as a regulatory protein. In order for acid secretion to take place a complex interaction of transport proteins and channels must occur at the apical pole of the parietal cell. Included in this process is at least one K(+) and Cl(-) channel, allowing for both recycling of K(+) for the H,K-ATPase, and Cl(-) secretion, necessary for the generation of concentrated HCl in the gastric gland lumen. We have previously shown that an ATP-sensitive potassium channel (K(ATP)) is expressed in parietal cells. In the present study we measured secretagogue-induced acid secretion from wild-type and DeltaF508-deficient mice in isolated gastric glands and whole stomach preparations. Secretagogue-induced acid secretion in wild-type mouse gastric glands could be significantly reduced with either glibenclamide or the specific inhibitor CFTR-inh172. In DeltaF508-deficient mice, however, histamine-induced acid secretion was significantly less than in wild-type mice. Furthermore, immunofluorescent localization of sulfonylurea 1 and 2 failed to show expression of a sulfonylurea receptor in the parietal cell, thus further implicating CFTR as the ATP-binding cassette transporter associated with the K(ATP) channels. These results demonstrate a regulatory role for the CFTR protein in normal gastric acid secretion.