Jens Pinkernelle

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 hepa‐tocytes 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.

Imaging of single human carcinoma cells in vitro using a clinical whole-body magnetic resonance scanner at 3.0 T

The purpose of the present study was to examine whether single human carcinoma cells labeled with iron oxide nanoparticles could be detected by magnetic resonance (MR) imaging on a clinical 3‐T scanner using a surface coil only. WiDr human colon carcinoma cells were loaded with two kinds of iron oxide nanoparticles differing by coating and size: aminosilan‐coated (MagForce) and carboxy‐dextran‐coated particles (Resovist). The latter were preferred by the colon carcinoma cell line used here and taken up much faster (12 h) than the smaller carboxydextran‐coated Resovist (48 h). Labeled single carcinoma cells, distributed in an agarose gel in a monodisperse layer as controlled by light microscopy, became detectable as punctuate signal extinctions when using a small circularly polarized surface coil in conjunction with a T2*‐weighted GE sequence at 3 T. The threshold for the detectability of labeled colon carcinoma cells ranged at a load of 4–5 μg iron/106 cells. Obviating the need for special hardware additions, this study opens a new lane for single‐cell tracking on clinical 3‐T MR scanners amenable to patient studies. Magn Reson Med 53:1187–1192, 2005.

Local arterial infusion of superparamagnetic iron oxide particles in hepatocellular carcinoma: A feasibility and 3.0 T MRI study.

Objectives:We sought to prove feasibility of selective arterial infusion of superparamagnetic iron oxide (SPIO) particles in patients with hepatocellular carcinoma (HCC). Materials and Methods:We studied 13 patients with HCC who underwent modified transarterial chemoembolization (TACE). Six patients received concurrent infusion of Ferucarbotran (Resovist, Schering, Berlin, Germany) in tumor-feeding arteries, and another 6 received MFL AS (MagForce, Nanotechnologies, Berlin, Germany). The iron content of both dispersions was 3.92 mg. One patient served as a control. All patients underwent magnetic resonance imaging (MRI) as baseline and immediate follow-up investigation. Results:Selective arterial infusion of both SPIO particles resulted in significant intratumoral signal intensity decrease on T1-weighted sequences (P < 0.0001), which was greater after MagForce infusion compared with Resovist (P = 0.002). Only minimal amounts of dispersed particles were found in adjacent normal liver parenchyma. No change in intratumoral signal intensity was noted when ferromagnetic particles were omitted. Conclusions:Modified TACE with selective arterial infusion of SPIO particles can be used for precise tumor targeting in patients with HCC, for which MagForce appeared superior to Resovist.

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 68Ga-DOTATOC or 68Ga-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. 68Ga-DOTANOC strongly accumulated in the tumor tissue (mean 6.6-fold vs. control tissues) when compared to 68Ga-DOTATOC, which showed a higher renal clearance. In good agreement with the biodistribution data, the kidney-to-tumor ratio was higher for 68Ga-DOTATOC (2.43-fold vs. 1.75-fold). Consequently, 68Ga-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 68Ga-DOTANOC and 68Ga-DOTATOC, with 68Ga-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.

Development of a signal-inducing bone cement for magnetic resonance imaging

To develop a signal‐inducing bone cement for musculoskeletal procedures in magnetic resonance imaging (MRI).

Feasibility of Fast Dynamic MRI for Noninvasive Monitoring During Ectopic Liver Cell Transplantation to the Spleen in a Porcine Model

OBJECTIVE Liver cell transplantation is a promising approach for the treatment of metabolic liver disorders. However, a method for noninvasive monitoring during liver cell transplantation is not available clinically. The aim of this study was to investigate the feasibility of fast dynamic MRI monitoring during liver cell infusion to the spleen, which is considered an ectopic implantation site for liver cell transplantation. MATERIALS AND METHODS Porcine liver cells were labeled with micron-sized iron oxide particles and infused to the spleens of pigs (n = 5) via the lineal artery. MRI was performed using a 3-T MR scanner. Initially, T1- and T2-weighted pulse sequences were tested. Thereafter, fast dynamic MRI was performed during cell infusion. MR findings were verified by immunohistological examinations. RESULTS Images from static MRI (TR/TE, 2500/105.2) showed significantly lower signal intensity and signal-to-noise ratio after cell infusion compared with pretransplant images. T2-weighted fast dynamic MRI enabled visualization of signal decrease of the spleen during cell infusion. When cells were infused systemically, no signal changes in the spleen were observed. CONCLUSION This study shows that fast dynamic MRI can enable noninvasive monitoring during liver cell transplantation to the spleen. This approach could be useful for preclinical studies and for quality control of clinical liver cell transplantation.

Computed tomography findings in septic patients with acute respiratory distress syndrome: correlation with survival and pulmonary versus extrapulmonary septic focus.

Objective The objective of this study was to evaluate computed tomography (CT) findings in patients with sepsis with unknown inflammatory focus and acute respiratory distress syndrome. Methods Acute respiratory distress syndrome findings on CT of 36 patients with sepsis were graded on a 6-point scale, and the percentage of affected lung was estimated. Resulting CT scores were correlated to intensive care scores and survival. Results Forty-four percent of the patients died, revealing a significantly higher CT score than survivors (P = 0.01). Survivors showed larger areas of unaffected lung (P < 0.001), whereas patients with fatal outcome had more ground-glass opacities (P = 0.002; sensitivity, 73%; specificity, 57%) and traction bronchiectasis (P = 0.009; sensitivity, 54%; specificity, 68%). Pulmonary findings on CT did not allow discriminating between a pulmonary and extrapulmonary focus. No significant coherence between CT score and intensive care scores could be revealed. Conclusions A CT scoring system based on pulmonary findings in patients with sepsis with acute respiratory distress syndrome comprises prognostic implications in terms of the patients’ survival.

Sonographically guided placement of intravenous catheters in minipigs

Many procedures in minipigs require establishment of reliable deep venous access with a large-bore catheter. In animal experiments, such catheters are typically implanted surgically. In clinical settings, however, ultrasound imaging is routinely used to facilitate safe, minimally invasive puncture of deep vessels. The authors describe a technique for using ultrasound guidance to puncture and cannulate the minipig femoral vein. They carried out the procedure in six minipigs for the purpose of injecting contrast agents for subsequent imaging scans. The procedure was ultimately successful in all pigs, took 10 min on average and resulted in no physiological complications. In one minipig, however, a 10-cm-long catheter became dislodged from the femoral vein; use of a longer (25-cm-long) catheter was optimal for establishing reliable intravenous access.

Colorectal Cancer: Magnetic Resonance Imaging-Cellular and Molecular Imaging

Publisher Summary Colonography by computed tomography (CT) or magnetic resonance imaging (MRI) can be performed at a degree of sensitivity comparable to invasive endoscopy in some clinical settings. MRI of the rectum has already become a routine procedure for preoperative staging, providing excellent highly resolved images of cancer localized in the rectum or sigmoid. Molecular and cellular imaging is a considerably growing field of investigation. Because of its high spatial and temporal resolution in addition to its good sensitivity, MRI seems to be a favorable tool for the imaging of iron-oxide labeled cells in vivo. This imaging strategy is being used experimentally for monitoring labeled stem cells in vivo that were labeled in vitro before. Mammalian cells can be labeled efficiently without significant cytotoxic effects. Enhanced intracellular uptake of iron-oxide particles can be achieved by modifications of particle coatings in vitro. MRI can detect molecular markers of neo-angiogenesis. The combination of MRI with PET could offer new possibilities, combining outstanding sensitivity with excellent spatial and temporal resolution. MRI colonoscopy is being introduced for gastrointestinal cancer screening of high-risk patients. In addition, abdominal soft tissues can be evaluated for metastases or other primary lesions. MRI colonoscopy may develop into a reliable tool for the detection of small intraluminal lesions. Multimodal imaging combining PET sensitivity and MRI spatial resolution seems to be the most promising screening tool for cancer lesions.