Ralf Puls

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

A Genome-Wide Association Study Identifies Five Loci Influencing Facial Morphology in Europeans

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

Whole-body magnetic resonance imaging of healthy volunteers: pilot study results from the population-based SHIP study.

PURPOSE Approximately 4000 volunteers will undergo whole-body magnetic resonance imaging (WB-MRI) within the next 3 years in the population-based Study of Health in Pomerania (SHIP). Here we present a pilot study conducted (a) to determine the feasibility of adding a WB-MRI protocol to a large-scale population-based study, (b) to evaluate the reliability of standardized MRI interpretation, and (c) to establish an approach for handling pathological findings. MATERIALS AND METHODS The institutional review board approved the study, and oral and written informed consent was obtained from each participant. Two hundred healthy volunteers (99 women, 101 men; mean age 48.3 years) underwent a standardized WB-MRI protocol. The protocol was supplemented by contrast-enhanced cardiac MRI and magnetic resonance (MR) angiography in 61 men (60.4%) and cardiac MRI and MR mammography in 44 women (44.4%). MR scans were evaluated independently by two readers. Abnormalities were discussed by an advisory board and classified according to the need for further clinical work-up. RESULTS One hundred ninety-four (97.0%) WB-MRI examinations were successfully completed in a mean scan time per subject of 90 minutes. There were 431 pathological findings in 176 (88%) of the participants. Of those 45 (10.4%) required further clinical work-up and 386 (89.6%) characterized as benign lesions did not. The interobserver agreement for the detection of pathological findings was excellent (kappa = 0.799). CONCLUSION The preliminary results presented here indicate that a large prospective, population-based study using WB-MRI is feasible and that the results of image analysis are reproducible. A variety of positive findings provide valuable information regarding disease prevalence in a general adult population.

Laser Ablation of Metastatic Lesions of the Lung: Long-Term Outcome

OBJECTIVE Pulmonary metastatic lesions are present in 20-54% of all patients who die of cancer. Surgical studies have shown that local management of distant tumor metastasis as part of multimodal cancer therapy improves survival. Minimally invasive procedures such as thermal ablation are still to prove their clinical relevance. The aim of this study was to monitor therapeutic outcome and long-term results after percutaneous laser-induced thermal ablation. SUBJECTS AND METHODS Sixty-four patients with metastasis to the lung underwent laser-induced thermal ablation in an ongoing prospective study. A total of 129 percutaneous procedures were performed to manage a total of 108 lung lesions. The median tumor size was 2.0 cm (range, 0.4-8.5 cm). Adequate management of all known individual tumor correlates was critical for definitive patient therapy. The Kaplan-Meier method was used to calculate survival and recurrence rates. RESULTS Definitive management of initial pulmonary disease was achieved in 31 of 64 patients. The 1-, 2-, 3-, 4-, and 5-year survival rates after ablative therapy were 81%, 59%, 44%, 44%, and 27%. The median progression-free interval was 7.4 months. There were no therapy-related deaths. Pneumothorax occurred in 38% of the patients, necessitating periprocedural drainage in 5% of all cases. Parenchymal bleeding (13% of cases) always was self-limited. CONCLUSION Laser ablative therapy for pulmonary metastasis is a promising option in multimodal cancer therapy. The procedure is safe and effective. The initial clinical outcome data strongly suggest that this technique has the potential to improve survival among selected patients.

Laser Ablation of Liver Metastases from Colorectal Cancer with MR Thermometry: 5-Year Survival

PURPOSE To determine technical success, technique effectiveness, complications, and survival after laser ablation of liver metastases from colorectal cancer. MATERIALS AND METHODS Eighty-seven consecutive patients (65 men and 22 women; mean age, 62.8 years) with 180 liver metastases from colorectal carcinoma were included between 1998 and 2005. They underwent laser ablation with magnetic resonance (MR) thermometry in 170 sessions. Indications for laser ablation were locally unresectable tumors (16.1%), metastases in both liver lobes (34.5%), and refusal of surgery and/or general contraindications to surgery (49.4%). Technical success, technique effectiveness, and complication and survival rates were evaluated retrospectively. RESULTS Technical success was achieved in 178 of 180 sessions (99%). Follow-up after 24-48 hours demonstrated an effectiveness rate of 85.6%. Local tumor progression rate was 10% after 6 months. Major complications included large pleural effusion, large subcapsular hematoma, abscess, large pneumothorax, pleuritis with fever, intrahepatic hemorrhage, and biloma. Mean survival from the time of diagnosis of the primary tumor was 50.6 months for all patients treated (95% CI, 44.9-56.3 months). Median survival time was 54 months and survival rates were 95.7% at 1 year, 86.2% at 2 years, 72.4% at 3 years, 50.1% at 4 years, and 33.4% at 5 years. The mean survival time after the first treatment was 31.1 months (95% CI, 26.9-35.3 months). CONCLUSIONS Laser ablation of liver metastases of colorectal cancer with MR thermometry appears safe and efficacious. Although the results are encouraging, direct comparison with other ablative modalities in a prospective clinical trial would be necessary to definitely show one modality is superior.

Noninvasive quantification of hepatic fat content using three-echo dixon magnetic resonance imaging with correction for T2* relaxation effects.

Objective:To investigate three-echo T2*-corrected Dixon magnetic resonance imaging (MRI) for noninvasively estimating hepatic fat content (HFC) compared with biopsy. Materials and Methods:One hundred patients (50 men, 50 women; mean age, 57.7 ± 14.2 years) underwent clinically indicated liver core biopsy (102 valid tissue samples) and liver MRI 24 to 72 hours later. MRI was performed at 1.5T (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany) using Dixon imaging with T2* correction (work in progress, WIP-432.rev.1, Siemens Healthcare). An ultrafast breath-hold three-echo 3D-gradient echo sequence with TR/TE1/TE2/TE3 of 11/2.4/4.8/9.6 milliseconds, and online calculation of T2*-corrected water images (signal intensities of water [SIW]), fat images (SIF), and fat content map (SIFAT = 10 × SIF/(SIW + SIF)) was used. SIs of the calculated fat content map (SIFAT) were verified using the histologically quantified HFC (HFC(path)). Spearman correlation for HFC(path) and SIFAT was calculated. Stage of fibrosis, hepatic iron content, and patterns of liver fat (macrovesicular, microvesicular, mixed) and their influence on predicting HFC by MRI were determined. Results:Correlation between SIFAT and HFC(path) was rspearman = 0.89. Agreement between HFC predicted by MRI and HFC(path) calculated by nonlinear saturation-growth regression was rspearman = 0.89. Kruskal-Wallis analysis revealed no significant difference for SIFAT across fibrosis grades (P = 0.90) and liver iron content (P = 0.76). Regarding the cellular architecture of liver fat, the microvesicular pattern showed lower mean ranks in SI than macrovesicular and mixed patterns (P = 0.01). Conclusion:T2*-corrected Dixon MRI is a noninvasive tool for estimating HFC, showing excellent correlation with liver biopsy without being limited by liver iron content and fibrosis/cirrhosis.

A fully automatic three-step liver segmentation method on LDA-based probability maps for multiple contrast MR images

Automatic 3D liver segmentation in magnetic resonance (MR) data sets has proven to be a very challenging task in the domain of medical image analysis. There exist numerous approaches for automatic 3D liver segmentation on computer tomography data sets that have influenced the segmentation of MR images. In contrast to previous approaches to liver segmentation in MR data sets, we use all available MR channel information of different weightings and formulate liver tissue and position probabilities in a probabilistic framework. We apply multiclass linear discriminant analysis as a fast and efficient dimensionality reduction technique and generate probability maps then used for segmentation. We develop a fully automatic three-step 3D segmentation approach based upon a modified region growing approach and a further threshold technique. Finally, we incorporate characteristic prior knowledge to improve the segmentation results. This novel 3D segmentation approach is modularized and can be applied for normal and fat accumulated liver tissue properties.

Percutaneous biliary drainage in patients with nondilated intrahepatic bile ducts compared with patients with dilated intrahepatic bile ducts.

OBJECTIVE The purpose of this article is to compare the technical success and guidance of percutaneous transhepatic biliary drainage (PTBD) in patients with nondilated and dilated bile duct systems using different techniques to supplement the conventional approach. MATERIALS AND METHODS Between 2006 and 2008, 71 patients (mean age, 66.6 years) underwent PTBD with 97 interventions. According to sonographic evaluation of bile duct morphology, patients were divided into two groups: 50 patients with dilated and 21 patients with nondilated bile ducts. In a retrospective analysis, both groups were compared for technical success, fluoroscopy time, complications, and medical indications. The use of interventional guidance (deviations from the standard protocol) in patients with nondilated bile ducts was recorded. RESULTS The technical success rate was 90% in patients with dilated bile ducts versus 81% in patients with nondilated ducts, with no significant difference (p = 0.36). The greater complexity of the intervention in patients with nondilated bile ducts resulted in longer fluoroscopy times (p = 0.04). Complication rates were not different between the two groups. The main indication for PTBD was relief of a compressed biliary system in patients with dilated ducts and postoperative management of complications or prevention of tumor-associated bile duct obstruction in patients with nondilated ducts. T-drainage, additional CT-guided puncture, and temporary gallbladder drainage were performed in 16 of 21 interventions for patients with nondilated bile ducts, resulting in a 100% success rate, versus a success rate of 60% in the five PTBDs of nondilated ducts performed in the conventional manner. CONCLUSION T-drainage, additional CT-guided puncture, and temporary gallbladder drainage improve the technical success of PTBD when used in patients with nondilated bile ducts. With these measures, technical success and complication rates in patients with nondilated ducts are comparable to those for PTBD of dilated bile ducts.

Artifacts In Magnetic Resonance Imaging and Computed Tomography Caused By Dental Materials

Background Artifacts caused by dental restorations, such as dental crowns, dental fillings and orthodontic appliances, are a common problem in MRI and CT scans of the head and neck. The aim of this in-vitro study was to identify and evaluate the artifacts produced by different dental restoration materials in CT and MRI images. Methods Test samples of 44 materials (Metal and Non-Metal) commonly used in dental restorations were fabricated and embedded with reference specimens in gelatin moulds. MRI imaging of 1.5T and CT scan were performed on the samples and evaluated in two dimensions. Artifact size and distortions were measured using a digital image analysis software. Results In MRI, 13 out of 44 materials produced artifacts, while in CT 41 out of 44 materials showed artifacts. Artifacts produced in both MRI and CT images were categorized according to the size of the artifact. Significance Metal based restoration materials had strong influence on CT and less artifacts in MRI images. Rare earth elements such as Ytterbium trifluoride found in composites caused artifacts in both MRI and CT. Recognizing these findings would help dental materials manufacturers and developers to produce materials which can cause less artifacts in MRI and CT images.

In vivo imaging of pancreatic tumours and liver metastases using 7 Tesla MRI in a murine orthotopic pancreatic cancer model and a liver metastases model

BackgroundPancreatic cancer is the fourth leading cause of tumour death in the western world. However, appropriate tumour models are scarce. Here we present a syngeneic murine pancreatic cancer model using 7 Tesla MRI and evaluate its clinical relevance and applicability.Methods6606PDA murine pancreatic cancer cells were orthotopically injected into the pancreatic head. Liver metastases were induced through splenic injection. Animals were analyzed by MRI three and five weeks following injection. Tumours were detected using T2-weighted high resolution sequences. Tumour volumes were determined by callipers and MRI. Liver metastases were analyzed using gadolinium-EOB-DTPA and T1-weighted 3D-Flash sequences. Tumour blood flow was measured using low molecular gadobutrol and high molecular gadolinium-DTPA.ResultsMRI handling and applicability was similar to human systems, resolution as low as 0.1 mm. After 5 weeks tumour volumes differed significantly (p < 0.01) when comparing calliper measurments (n = 5, mean 1065 mm3+/-243 mm3) with MRI (mean 918 mm3+/-193 mm3) with MRI being more precise. Histology (n = 5) confirmed MRI tumour measurements (mean size MRI 38.5 mm2+/-22.8 mm2 versus 32.6 mm2+/-22.6 mm2 (histology), p < 0,0004) with differences due to fixation and processing of specimens. After splenic injection all mice developed liver metastases with a mean of 8 metastases and a mean volume of 173.8 mm3+/-56.7 mm3 after 5 weeks. Lymphnodes were also easily identified. Tumour accumulation of gadobutrol was significantly (p < 0.05) higher than gadolinium-DTPA. All imaging experiments could be done repeatedly to comply with the 3R-principle thus reducing the number of experimental animals.ConclusionsThis model permits monitoring of tumour growth and metastasis formation in longitudinal non-invasive high-resolution MR studies including using contrast agents comparable to human pancreatic cancer. This multidisciplinary environment enables radiologists, surgeons and physicians to further improve translational research and therapies of pancreatic cancer.