Jan-Hinrich Rabe, Denis A. Sammour, Sandra Schulz, Bogdan Munteanu, Martina Ott, Katharina Ochs, Peter Hohenberger, Alexander Marx, Michael Platten, Christiane A. Opitz, Daniel S. Ory & Carsten Hopf
Scientific Reports 8, Article number: 313 (2018), doi:10.1038/s41598-017-18477-6
Multimodal imaging combines complementary platforms for spatially resolved tissue analysis that are poised for application in life science and personalized medicine. Unlike established clinical in vivo multimodality imaging, automated workflows for in-depth multimodal molecular ex vivo tissue analysis that combine the speed and ease of spectroscopic imaging with molecular details provided by mass spectrometry imaging (MSI) are lagging behind. Here, we present an integrated approach that utilizes non-destructive Fourier transform infrared (FTIR) microscopy and matrix assisted laser desorption/ionization (MALDI) MSI for analysing single-slide tissue specimen. We show that FTIR microscopy can automatically guide high-resolution MSI data acquisition and interpretation without requiring prior histopathological tissue annotation, thus circumventing potential human-annotation-bias while achieving >90% reductions of data load and acquisition time. We apply FTIR imaging as an upstream modality to improve accuracy of tissue-morphology detection and to retrieve diagnostic molecular signatures in an automated, unbiased and spatially aware manner. We show the general applicability of multimodal FTIR-guided MALDI-MSI by demonstrating precise tumor localization in mouse brain bearing glioma xenografts and in human primary gastrointestinal stromal tumors. Finally, the presented multimodal tissue analysis method allows for morphology-sensitive lipid signature retrieval from brains of mice suffering from lipidosis caused by Niemann-Pick type C disease.
Received: 12 September 2017
Accepted: 12 December 2017
Published online: 10 January 2018
Julia Klicks, Elena von Molitor, Torsten Ertongur-Fauth, Rüdiger Rudolf, Mathias Hafner
Journal of Cellular Biotechnology, vol. 3, no. 1, pp. 21-39, 2017
Abstract. Skin fulﬁls a plethora of eminent physiological functions ranging from physical barrier over immunity shield to
the interface mediating social interaction. Prone to several acquired and inherited diseases, skin is therefore a major target
of pharmaceutical and cosmetic research. The lack of similarity between human and animal skin and rising ethical concerns
in the use of animal models have driven the search for novel realistic three-dimensional skin models. This review provides a
survey of contemporary skin models and compares them in terms of applicability, reliability, cost and complexity.
Keywords: Skin, phenotypic screening, 3D models, pharmaceutical research
Tanja Gaa, Wiebke Neumann, Sonja Sudarski, Ulrike I. Attenberger, Stefan O. Schönberg, Lothar R. Schad & Frank G. Zöllner
In: Scientific Reports 7, Article number: 12036 (2017), doi:10.1038/s41598-017-12194-w
In this work, the two compartment exchange model and two compartment uptake model were applied to obtain quantitative perfusion parameters in rectum carcinoma and the results were compared to those obtained by the deconvolution algorithm. Eighteen patients with newly diagnosed rectal carcinoma underwent 3 T MRI of the pelvis including a T1 weighted dynamic contrastenhanced (DCE) protocol before treatment. Mean values for Plasma Flow (PF), Plasma Volume (PV) and Mean Transit Time (MTT) were obtained for all three approaches and visualized in parameter cards. For the two compartment models, Akaike Information Criterion (AIC) and χ2 were calculated. Perfusion parameters determined with the compartment models show results in accordance with previous studies focusing on rectal cancer DCE-CT (PF2CX = 68 ± 44 ml/100 ml/min, PF2CU = 55 ± 36 ml/100 ml/min) with similar fit quality (AIC:169 ± 81/179 ± 77, χ2:10 ± 12/9 ± 10). Values for PF are overestimated whereas PV and MTT are underestimated compared to results of the deconvolution algorithm. Significant differences were found among all models for perfusion parameters as well as between the AIC and χ2 values. Quantitative perfusion parameters are dependent on the chosen tracer kinetic model. According to the obtained parameters, all approaches seem capable of providing quantitative perfusion values in DCE-MRI of rectal cancer.
© The Author(s) 2017
Mathias Meyer, Nicole Geiger, Urs Benck, Daniela Rose, Sonja Sudarski, Melissa M. Ong, Stefan O. Schoenberg & Thomas Henzler
In: Scientific Reports 7, Article number: 12563 (2017), doi: 10.1038/s41598-017-12902-6
To evaluate the feasibility and potential on therapy management of time-resolved dynamic computed tomography angiography (dCTA) in patients with forearm arterio-venous fistula (AVF)/arterio-venous grafts (AVG). Thirty-five patients with complex failing forearm AVF/AVGs were examined with ultrasound and a dCTA protocol. Diagnosis and therapy management was evaluated versus duplex ultrasound (DUS) in three different readouts: 1. all dCTA datasets; 2. one arterial phase of the dCTA dataset; 3. one arterial and one venous dataset out of the dCTA dataset. All reads were performed >30 days apart from each other. Using all data of the dCTA examination, 20 patients were classified as having a stenosis >50%, 12 high-shunt flow, 11 partial thrombosis, 5 venous aneurysms and 5 complete thrombosis of their AVF/AVG grafts. This lead to 13 additional pathologic findings not visible on DUS and reclassification as normal in one patient with suspected AVF stenosis and complete thrombus on DUS. These additional findings lead to a direct change of therapeutic management in 8 patients. Compared to readout 1 (53 pathologies), readout number 2 and 3 revealed only 33 and 41 pathologies, respectively. dCTA provides additional information, improving diagnostic confidence and leading to changes in therapy management when compared to DUS alone.
© The Author(s) 2017
Attarwala AA, Karanja YW, Hardiansyah D, Romanó C, Roscher M, Wängler B, Glatting G.
Zeitschrift für Medizinische Physik, Volume 27, Issue 2, June 2017, Pages 132–144
In this study the performance characteristics of the Albira II PET sub-system and the response of the system for the following radionuclides 18F, 68Ga and 64Cu was analyzed.
MATERIALS AND METHODS:
The Albira II tri-modal system (Bruker BioSpin MRI GmbH, Ettlingen, Germany) is a pre-clinical device for PET, SPECT and CT. The PET sub-system uses single continuous crystal detectors of lutetium yttrium orthosilicate (LYSO). The detector assembly consists of three rings of 8 detector modules. The transaxial field of view (FOV) has a diameter of 80mm and the axial FOV is 148mm. A NEMA NU-4 image quality phantom (Data Spectrum Corporation, Durham, USA) having five rods with diameters of 1, 2, 3, 4 and 5mm and a uniform central region was used. Measurements with 18F, 68Ga and 64Cu were performed in list mode acquisition over 10h. Data were reconstructed using a maximum-likelihood expectation-maximization (MLEM) algorithm with iteration numbers between 5 and 50. System sensitivity, count rate linearity, convergence and recovery coefficients were analyzed.
The sensitivities for the entire FOV (non-NEMA method) for 18F, 68Ga and 64Cu were (3.78±0.05)%, (3.97±0.18)% and (3.79±0.37)%, respectively. The sensitivity based on the NEMA protocol using the 22Na point source yielded (5.53±0.06)%. Dead-time corrected true counts were linear for activities ≤7MBq (18F and 68Ga) and ≤17MBq (64Cu) in the phantom. The radial, tangential and axial full widths at half maximum (FWHMs) were 1.52, 1.47 and 1.48mm. Recovery coefficients for the uniform region with a total activity of 8MBq in the phantom were (0.97±0.05), (0.98±0.06), (0.98±0.06) for 18F, 68Ga and 64Cu, respectively.
The Albira II pre-clinical PET system has an adequate sensitivity range and the system linearity is suitable for the range of activities used for pre-clinical imaging. Overall, the system showed a favorable image quality for pre-clinical applications.
Copyright © 2017. Published by Elsevier GmbH.
PET isotopes; PET-Isotope; Positron emission tomography (PET); Positronen-Emissions-Tomographie (PET); Recovery-Koeffizienten; pre-clinical imaging; präklinische Bildgebung; recovery coefficients
Kostrzewa M, Kara K, Pilz L, Mueller-Muertz H, Rathmann N, Schoenberg SO, Diehl SJ.
Cardiovasc Intervent Radiol. 2017 May 9. doi: 10.1007/s00270-017-1670-9. [Epub ahead of print]
To evaluate the hemodynamic effect of percutaneous transluminal intervention (PTI) on stenosis of the superficial femoral (SFA) and popliteal arteries (PA) using time–density curves (TDCs) derived from digital subtraction angiography (DSA) series in correlation with ultrasound peak systolic velocity ratio (PSVR) and ankle brachial index (ABI).
MATERIALS AND METHODS:
DSA series of SFA or PA of patients with symptomatic peripheral arterial occlusive disease was obtained with a flat-panel angiography system with intention-to-treat. In DSA series acquired before and after PTI, TDCs were analyzed proximal and distal of each stenosis using parametric color coding (PCC). For correlation, ABI and PSVR measurements pre- and post-PTI were recorded for all patients.
In total, 25 stenoses of the SFA or PA were treated by PTI in 22 patients (17 male, 5 female, mean age 68 years). After treatment, peak-to-peak (PTP) times between TDCs proximal and distal to the treated vessel segment decreased statistically significantly (p = 0.01) on average from PTP = 1.9 ± 1.7 s to mean PTP = 1 ± 1 s. ABI and PSVR also changed statistically significantly after treatment (pretreatment ABI = 0.7 ± 0.2, PSVR = 4.2 ± 1.9; post-ABI = 0.9 ± 0.2, PSVR = 1.3 ± 0.4, both p\0.05). Correlation parameters did not show a strong correlation between change in TDC and clinical parameters ABI and PSVR.
Using PCC for analyzing contrast medium dynamics in DSA series is clinically useful for evaluating stenoses of the SFA and PA and for immediate treatment control after PTA.
LEVEL OF EVIDENCE:
Case series, IV
KEYWORDS: Parametric color coding; Digital subtraction angiography ; Peak systolic velocity ratio; Ankle brachial index; Peripheral arterial occlusive disease
PMID: 28488106 DOI:10.1007/s00270-017-1670-9
© Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2017
Trimborn B., Wolf I., Abu-Sammour D., Henzler T., Schad L.R., Zöllner F.G. (2017) 3D Histograms of Oriented Gradients zur Registrierung von regulären CT mit interventionellen CBCT Daten. In: Maier-Hein, geb. Fritzsche K., Deserno, geb. Lehmann T., Handels H., Tolxdorff T. (eds) Bildverarbeitung für die Medizin 2017. Informatik aktuell. Springer Vieweg, Berlin, Heidelberg
Zur Unterstützung onkologischer Interventionen können durch die Registrierung präoperativer Bildaten zu intraoperativen Cone-Beam-Computertomographieaufnahmen (CBCT) zusätzliche Informationen über die Anatomie und Morphologie des Patienten erhalten werden. In der vorliegenden Arbeit wird eine neuartige Metrik für die gradientenbasierte Bildregistrierung vorgestellt.
Conference paper First Online:
01 March 2017
Kostrzewa M, Kara K, Rathmann N, Tsagogiorgas C, Henzler T, Schoenberg SO, Hohenberger P, Diehl SJ, Roessner ED.
Invest Radiol. 2017 Jan 30. doi: 10.1097/RLI.0000000000000353. [Epub ahead of print]
Minimally invasive resection of small, deep intrapulmonary lesions can be challenging due to the difficulty of localizing them during video-assisted thoracoscopic surgery (VATS). We report our preliminary results evaluating the feasibility of an image-guided, minimally invasive, 1-stop-shop approach for the resection of small, deep intrapulmonary lesions in a hybrid operating room (OR).
MATERIALS AND METHODS:
Fifteen patients (5 men, 10 women; mean age, 63 years) with a total of 16 solitary, deep intrapulmonary nodules of unknown malignant status were identified for intraoperative wire marking. Patients were placed on the operating table for resection by VATS. A marking wire was placed within the lesion under 3D laser and fluoroscopic guidance using a cone beam computed tomography system. Then, wedge resection by VATS was performed in the same setting without repositioning the patient.
Complete resection with adequate safety margins was confirmed for all lesions. Marking wire placement facilitated resection in 15 of 16 lesions. Eleven lesions proved to be malignant, either primary or secondary; 5 were benign. Mean lesion size was 7.7 mm; mean distance to the pleural surface was 15.1 mm (mean lesion depth-diameter ratio, 2.2). Mean procedural time for marking wire placement was 35 minutes; mean VATS duration was 36 minutes.
Computed tomography-assisted thoracoscopic surgery is a new, safe, and effective procedure for minimally invasive resection of small, deeply localized intrapulmonary lesions. The benefits of computed tomography-assisted thoracoscopic surgery are 1. One-stop-shop procedure, 2. Lower risk for the patient (no patient relocation, no marking wire loss), and 3. No need to coordinate scheduling between the CT room and OR.
PMID: 28141614 DOI: 10.1097/RLI.0000000000000353
Hardiansyah D, Guo W, Attarwala AA, Kletting P, Mottaghy FM, Glatting G.
To investigate the accuracy of treatment planning in peptide-receptor radionuclide therapy (PRRT) based on simulated PET data (using a PET noise model) and a physiologically based pharmacokinetic (PBPK) model.
The parameters of a PBPK model were fitted to the biokinetic data of 15 patients. True mathematical phantoms of patients (MPPs) were the PBPK model with the fitted parameters. PET measurements after bolus injection of 150 MBq 68Ga-DOTATATE were simulated for the true MPPs. PET noise with typical noise levels was added to the data (i.e. c = 0.3 [low], 3, 30 and 300 [high]). Organ activity data in the kidneys, tumour, liver and spleen were simulated at 0.5, 1 and 4 h p.i. PBPK model parameters were fitted to the simulated noisy PET data to derive the PET-predicted MPPs. Therapy was simulated assuming an infusion of 3.3 GBq of 90Y-DOTATATE over 30 min. Time-integrated activity coefficients (TIACs) of simulated therapy in tumour, kidneys, liver, spleen and remainder were calculated from both, true MPPs (true TIACs) and predicted MPPs (predicted TIACs). Variability v between true TIACs and predicted TIACs were calculated and analysed. Variability ≤ 10 % was considered to be an accurate prediction.
For all noise level, variabilities for the kidneys, liver, and spleen showed an accurate prediction for TIACs, e.g. c = 300: vkidney = (5 ± 2)%, vliver = (5 ± 2)%, vspleen = (4 ± 2)%. However, tumour TIAC predictions were not accurate for all noise levels, e.g. c = 0.3: vtumour = (8 ± 5)%.
PET-based treatment planning with kidneys as the dose limiting organ seems possible for all reported noise levels using an adequate PBPK model and previous knowledge about the individual patient.
[PubMed - as supplied by publisher]
Hardiansyah D, Maass C, Attarwala AA, Müller B, Kletting P, Mottaghy FM, Glatting G
Eur J Nucl Med Mol Imaging. 2016 May;43(5):871-80. doi: 10.1007/s00259-015-3248-6. Epub 2015 Nov 18.
Accurate treatment planning is recommended in peptide-receptor radionuclide therapy (PRRT) to minimize the toxicity to organs at risk while maximizing tumor cell sterilization. The aim of this study was to quantify the effect of different degrees of individualization on the prediction accuracy of individual therapeutic biodistributions in patients with neuroendocrine tumors (NETs).
A recently developed physiologically based pharmacokinetic (PBPK) model was fitted to the biokinetic data of 15 patients with NETs after pre-therapeutic injection of (111)In-DTPAOC. Mathematical phantom patients (MPP) were defined using the assumed true (true MPP), mean (MPP 1A) and median (MPP 1B) parameter values of the patient group. Alterations of the degree of individualization were introduced to both mean and median patients by including patient-specific information as a priori knowledge: physical parameters and hematocrit (MPP 2A/2B). Successively, measurable individual biokinetic parameters were added: tumor volume V tu (MPP 3A/3B), glomerular filtration rate GFR (MPP 4A/4B), and tumor perfusion f tu (MPP 5A/5B). Furthermore, parameters of MPP 5A/5B and a simulated (68)Ga-DOTATATE PET measurement 60 min p.i. were used together with the population values used as Bayesian parameters (MPP 6A/6B). Therapeutic biodistributions were simulated assuming an infusion of (90)Y-DOTATATE (3.3 GBq) over 30 min to all MPPs. Time-integrated activity coefficients were predicted for all MPPs and compared to the true MPPs for each patient in tumor, kidneys, spleen, liver, remainder, and whole body to obtain the relative differences RD.
The large RD values of MPP 1A [RDtumor = (625 ± 1266)%, RDkidneys = (11 ± 38)%], and MPP 1B [RDtumor = (197 ± 505)%, RDkidneys = (11 ± 39)%] demonstrate that individual treatment planning is needed due to large physiological differences between patients. Although addition of individual patient parameters reduced the deviations considerably [MPP 5A: RDtumor = (-2 ± 27)% and RDkidneys = (16 ± 43)%; MPP 5B: RDtumor = (2 ± 28)% and RDkidneys = (7 ± 40)%] errors were still large. For the kidneys, prediction accuracy was considerably improved by including the PET measurement [MPP 6A/MPP 6B: RDtumor = (-2 ± 22)% and RDkidneys = (-0.1 ± 0.5)%].
Individualized treatment planning is needed in the investigated patient group. The use of a PBPK model and the inclusion of patient specific data, e.g., weight, tumor volume, and glomerular filtration rate, do not suffice to predict the therapeutic biodistribution. Integrating all available a priori information in the PBPK model and using additionally PET data measured at one time point for tumor, kidneys, spleen, and liver could possibly be sufficient to perform an individualized treatment planning.
PMID: 26577941 [PubMed - in process]
Hardiansyah D, Guo W, Kletting P, Mottaghy FM, Glatting G
Med Phys. 2016 Sep;43(9):5145. doi: 10.1118/1.4961012.
The aim of this study was to investigate the accuracy of PET-based treatment planning for predicting the time-integrated activity coefficients (TIACs).
The parameters of a physiologically based pharmacokinetic (PBPK) model were fitted to the biokinetic data of 15 patients to derive assumed true parameters and were used to construct true mathematical patient phantoms (MPPs). Biokinetics of 150 MBq (68)Ga-DOTATATE-PET was simulated with different noise levels [fractional standard deviation (FSD) 10%, 1%, 0.1%, and 0.01%], and seven combinations of measurements at 30 min, 1 h, and 4 h p.i. PBPK model parameters were fitted to the simulated noisy PET data using population-based Bayesian parameters to construct predicted MPPs. Therapy simulations were performed as 30 min infusion of (90)Y-DOTATATE of 3.3 GBq in both true and predicted MPPs. Prediction accuracy was then calculated as relative variability vorgan between TIACs from both MPPs.
Large variability values of one time-point protocols [e.g., FSD = 1%, 240 min p.i., vkidneys = (9 ± 6)%, and vtumor = (27 ± 26)%] show inaccurate prediction. Accurate TIAC prediction of the kidneys was obtained for the case of two measurements (1 and 4 h p.i.), e.g., FSD = 1%, vkidneys = (7 ± 3)%, and vtumor = (22 ± 10)%, or three measurements, e.g., FSD = 1%, vkidneys = (7 ± 3)%, and vtumor = (22 ± 9)%.
(68)Ga-DOTATATE-PET measurements could possibly be used to predict the TIACs of (90)Y-DOTATATE when using a PBPK model and population-based Bayesian parameters. The two time-point measurement at 1 and 4 h p.i. with a noise up to FSD = 1% allows an accurate prediction of the TIACs in kidneys.
PMID: 27587044 [PubMed - in process]
Erich K, Sammour DA, Marx A, Hopf C.
Biochim Biophys Acta. 2016 Sep 6. pii: S1570-9639(16)30182-0. doi: 10.1016/j.bbapap.2016.08.020.
On-slide digestion of formalin-fixed and paraffin-embedded human biopsy tissue followed by mass spectrometry imaging of resulting peptides may have the potential to become an additional analytical modality in future ePathology. Multiple workflows have been described for dewaxing, antigen retrieval, digestion and imaging in the past decade. However, little is known about suitable statistical scores for method comparison and systematic workflow standardization required for development of processes that would be robust enough to be compatible with clinical routine. To define scores for homogeneity of tissue processing and imaging as well as inter-day repeatability for five different processing methods, we used human liver and gastrointestinal stromal tumor tissue, both judged by an expert pathologist to be >98% histologically homogeneous. For mean spectra-based as well as pixel-wise data analysis, we propose the coefficient of determination R2, the natural fold-change (natFC) value and the digest efficiency DE% as readily accessible scores. Moreover, we introduce two scores derived from principal component analysis, the variance of the mean absolute deviation, MAD, and the interclass overlap, Joverlap, as computational scores that may help to avoid user bias during future workflow development. This article is part of a Special Issue entitled: MALDI Imaging.
Copyright © 2016 Elsevier B.V. All rights reserved.
FFPE tissue; Gastrointestinal stromal tumor; MALDI imaging; Multivariate statistics; On-tissue digestion; Repeatability; Standardization; ePathology
Schwerter M, Lietzmann F, Schad LR.
Z Med Phys 2016 Sep 2;26(3):259-69. Epub 2016 May 2.
Minimally invasive interventions are frequently aided by 2D projective image guidance. To facilitate the navigation of medical tools within the patient, information from preoperative 3D images can supplement interventional data. This work describes a novel approach to perform a 3D CT data registration to a single interventional native fluoroscopic frame. The goal of this procedure is to recover and visualize a current 2D interventional tool position in its corresponding 3D dataset.
A dedicated routine was developed and tested on a phantom. The 3D position of a guidewire inserted into the phantom could successfully be reconstructed for varying 2D image acquisition geometries. The scope of the routine includes projecting the CT data into the plane of the fluoroscopy. A subsequent registration of the real and virtual projections is performed with an accuracy within the range of 1.16 ± 0.17 mm for fixed landmarks. The interventional tool is extracted from the fluoroscopy and matched to the corresponding part of the projected and transformed arterial vasculature. A root mean square error of up to 0.56 mm for matched point pairs is reached. The desired 3D view is provided by backprojecting the matched guidewire through the CT array.
Due to its potential to reduce patient dose and treatment times, the proposed routine has the capability of reducing patient stress at lower overall treatment costs.
© 2016 The Author(s). Published by Elsevier Ltd.
Neumann W, Lietzmann F, Schad LR, Zoellner FG
Zeitschrift für Medizinische Physik, Available online 2 September 2016, ISSN 0939-3889, http://dx.doi.org/10.1016/j.zemedi.2016.07.004.
This work proposes a modular, anthropomorphic MR and CT thorax phantom that enables the comparison of experimental studies for quantitative evaluation of deformable, multimodal image registration algorithms and realistic multi-nuclear MR imaging techniques.
A human thorax phantom was developed with insertable modules representing lung, liver, ribs and additional tracking spheres. The quality of human tissue mimicking characteristics was evaluated for 1H and 23Na MR as well as CT imaging. The position of landmarks in the lung lobes was tracked during CT image acquisition at several positions during breathing cycles. 1H MR measurements of the liver were repeated after seven months to determine long term stability.
The modules possess HU, T1 and T2 values comparable to human tissues (lung module: −756 ± 148 HU, artificial ribs: 218 ± 56 HU (low CaCO3 concentration) and 339 ± 121 (high CaCO3 concentration), liver module: T1 = 790 ± 28 ms, T2 = 65 ± 1 ms). Motion analysis showed that the landmarks in the lung lobes follow a 3D trajectory similar to human breathing motion. The tracking spheres are well detectable in both CT and MRI. The parameters of the tracking spheres can be adjusted in the following ranges to result in a distinct signal: HU values from 150 to 900 HU, T1 relaxation time from 550 ms to 2000 ms, T2 relaxation time from 40 ms to 200 ms.
The presented anthropomorphic multimodal thorax phantom fulfills the demands of a simple, inexpensive system with interchangeable components. In future, the modular design allows for complementing the present set up with additional modules focusing on specific research targets such as perfusion studies, 23Na MR quantification experiments and an increasing level of complexity for motion studies.
© 2016 The Author(s). Published by Elsevier Ltd.
Aydingül O, Spohrer K, Heinzl A, Kostrzewa M.
Patient consultation and briefing are essential for patients to make informed, self-determined decisions in their medical treatment. However, cost and time pressures lead to medical specialists spending less time with patient consultation, which may result in decreasing consultation quality. Electronic consultations are a potential solution to this problem. We propose patients’ trust and information satisfaction as key indicators of high consultation quality. We argue that the degree of social presence and personalization of information systems for informed consent and consultation positively influence these measures. Electronic consultation systems may therefore need to be designed to promote social presence and personalization. We develop five hypotheses on this relationship based on social presence theory. These hypotheses will be tested in a university hospital’s radiology department in the scope of an interdisciplinary research project on cancer therapy.
Hinsenkamp I, Schulz S, Roscher M, Suhr AM, Meyer B, Munteanu B, Fuchser J, Schoenberg SO, Ebert MP, Wängler B, Hopf C, Burgermeister E
Neoplasia. 2016 Aug;18(8):500-11. doi: 10.1016/j.neo.2016.07.002
Gastric cancer (GC) remains a malignant disease with high mortality. Patients are frequently diagnosed in advanced stages where survival prognosis is poor. Thus, there is high medical need to find novel drug targets and treatment strategies. Recently, the comprehensive molecular characterization of GC subtypes revealed mutations in the small GTPase RHOA as a hallmark of diffuse-type GC. RHOA activates RHO-associated protein kinases (ROCK1/2) which regulate cell contractility, migration and growth and thus may play a role in cancer. However, therapeutic benefit of RHO-pathway inhibition in GC has not been shown so far. The ROCK1/2 inhibitor 1-(5-isoquinoline sulfonyl)-homopiperazine (HA-1077, fasudil) is approved for cerebrovascular bleeding in patients. We therefore investigated whether fasudil (i.p., 10 mg/kg per day, 4 times per week, 4 weeks) inhibits tumor growth in a preclinical model of GC. Fasudil evoked cell death in human GC cells and reduced the tumor size in the stomach of CEA424-SV40 TAg transgenic mice. Small animal PET/CT confirmed preclinical efficacy. Mass spectrometry imaging identified a translatable biomarker for mouse GC and suggested rapid but incomplete in situ distribution of the drug to gastric tumor tissue. RHOA expression was increased in the neoplastic murine stomach compared with normal non-malignant gastric tissue, and fasudil reduced (auto) phosphorylation of ROCK2 at THR249 in vivo and in human GC cells in vitro. In sum, our data suggest that RHO-pathway inhibition may constitute a novel strategy for treatment of GC and that enhanced distribution of future ROCK inhibitors into tumor tissue may further improve efficacy.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Wenz H, Maros ME, Meyer M, Gawlitza J, Förster A, Haubenreisser H, Kurth S, Schoenberg SO, Groden C, Henzler T
Journal of Radiology Open, Volume 3, 2016, Pages 182-190, http://dx.doi.org/10.1016/j.ejro.2016.05.006
To prospectively evaluate image quality and organ-specific-radiation dose of spiral cranial CT (cCT) combined with automated tube current modulation (ATCM) and iterative image reconstruction (IR) in comparison to sequential tilted cCT reconstructed with filtered back projection (FBP) without ATCM.
31 patients with a previous performed tilted non-contrast enhanced sequential cCT aquisition on a 4-slice CT system with only FBP reconstruction and no ATCM were prospectively enrolled in this study for a clinical indicated cCT scan. All spiral cCT examinations were performed on a 3rd generation dual-source CT system using ATCM in z-axis direction. Images were reconstructed using both, FBP and IR (level 1–5). A Monte-Carlo-simulation-based analysis was used to compare organ-specific-radiation dose. Subjective image quality for various anatomic structures was evaluated using a 4-point Likert-scale and objective image quality was evaluated by comparing signal-to-noise ratios (SNR).
Spiral cCT led to a significantly lower (p < 0.05) organ-specific-radiation dose in all targets including eye lense. Subjective image quality of spiral cCT datasets with an IR reconstruction level 5 was rated significantly higher compared to the sequential cCT acquisitions (p < 0.0001). Consecutive mean SNR was significantly higher in all spiral datasets (FBP, IR 1–5) when compared to sequential cCT with a mean SNR improvement of 44.77% (p < 0.0001).
Spiral cCT combined with ATCM and IR allows for significant-radiation dose reduction including a reduce eye lens organ-dose when compared to a tilted sequential cCT while improving subjective and objective image quality.
© 2016 The Author(s). Published by Elsevier Ltd.
Zöllner FG, Gaa T, Zimmer F, Ong MM, Hausmann D, Schönberg SO, Weis M
Die Magnetresonanztomographie (MRT) zeichnet sich durch einen überlegenen Gewebekontrast aus, während sie nichtinvasiv und frei von ionisierender Strahlung ist. Sie bietet Zugang zu Gewebe- und Organfunktion. Eine dieser funktionellen bildgebenden Verfahren ist die Perfusionsbildgebung. Mit dieser Technik können u. a. Gewebeperfusion und Kapillarpermeabilität aus dynamischen Bilddaten bestimmt werden.
Perfusionsbildgebung mithilfe der MRT kann durch 2 Ansätze, nämlich „arterial spin labeling“ (ASL) und dynamische kontrastverstärkte (DCE-)MRT durchgeführt werden. Während die erste Methode magnetisch markierte Wasserprotonen im arteriellen Blut als endogenen Tracer verwendet, erfolgt bei der DCE-MRT eine Injektion eines Kontrastmittels, üblicherweise Gadolinium (Gd) als Tracer für die Berechnung hämodynamischer Parameter.
Aus Studien werden das Potenzial und die Möglichkeiten der MRT-Perfusionsbildgebung deutlich, sei es in Bezug auf die Diagnostik oder aber auch zunehmend im Bereich des Therapiemonitorings.
Nutzung und Anwendung der MRT-Perfusionsbildgebung beschränken sich jedoch auf spezialisierte Zentren wie Universitätskliniken. Eine breite Anwendung der Technik ist bisher leider nicht erfolgt.
Empfehlung für die Praxis
Die MRT-Perfusionsbildgebung ist ein wertvolles Tool, das im Rahmen europäischer und internationaler Standardisierungsbemühungen für die Praxis zukünftig einsetzbar werden sollte.
Magnetic resonance imaging (MRI) is recognized for its superior tissue contrast while being non-invasive and free of ionizing radiation. Due to the development of new scanner hardware and fast imaging techniques during the last decades, access to tissue and organ functions became possible. One of these functional imaging techniques is perfusion imaging with which tissue perfusion and capillary permeability can be determined from dynamic imaging data.
Standard radiological methods
Perfusion imaging by MRI can be performed by two approaches, arterial spin labeling (ASL) and dynamic contrast-enhanced (DCE) MRI. While the first method uses magnetically labelled water protons in arterial blood as an endogenous tracer, the latter involves the injection of a contrast agent, usually gadolinium (Gd), as a tracer for calculating hemodynamic parameters.
Studies have demonstrated the potential of perfusion MRI for diagnostics and also for therapy monitoring.
The utilization and application of perfusion MRI are still restricted to specialized centers, such as university hospitals. A broad application of the technique has not yet been implemented.
The MRI perfusion technique is a valuable tool that might come broadly available after implementation of standards on European and international levels. Such efforts are being promoted by the respective professional bodies.
Hagelstein C, Henzler T, Haubenreisser H, Meyer M, Sudarski S, Schoenberg SO, Neff KW, Weis M.
Zeitschrift für Medizinische Physik, Volume 26, Issue 4, December 2016, Pages 349-361, ISSN 0939-3889
Minimizing radiation dose while at the same time preserving image quality is of particular importance in pediatric chest CT. Very recently, CT imaging with a tube voltage of 70 kVp has become clinically available. However, image noise is inversely proportional to the tube voltage. We aimed to investigate radiation dose and image quality of pediatric chest CT performed at 70 kVp in an anthropomorphic pediatric phantom as well as in clinical patients.
METHODS AND MATERIALS:
An anthropomorphic pediatric phantom, which resembles a one-year-old child in physiognomy, was scanned on the 3rd generation dual-source CT (DSCT) system at 70 kVp and 80 kVp and a fixed ultra low tube-current of 8 mAs to solely evaluate the impact of lowering tube voltage. After the phantom measurements, 18 pediatric patients (mean 29.5 months; range 1-91 months; 21 examinations) underwent 3.2 high-pitch chest CT on the same DSCT system at 70 kVp tube voltage without any sedation. Radiation dose and presence of motion artifacts was compared to a retrospectively identified patient cohort examined at 80 kVp on a 16-slice single-source-CT (SSCT; n=15; 14/15 with sedation; mean 30.7 months; range 0-96 months; pitch=1.5) or on a 2nd generation DSCT without any sedation (n=6; mean 32.8 months; range 4-61 months; pitch=3.2).
Radiation dose in the phantom scans was reduced by approximately 40% when using a tube voltage of 70 kVp instead of 80 kVp. In the pediatric patient group examined at 70 kVp age-specific effective dose (ED; mean 0.5±0.2 mSv) was significantly lower when compared to the retrospective cohort scanned at 80 kVp on the 16-slice-SSCT (mean ED: 1.0±0.3 mSv; p<0.0001) and also considerably lower when compared to the cohort scanned at 80 kVp on the 2nd generation DSCT (mean ED: 0.9±0.5 mSv). None of the prospective, sedation-free CT examinations showed any motion artifacts whereas 13/15 examinations of the retrospective patient cohort scanned at 80 kVp with a pitch of 1.5 showed motion artifacts.
3.2 high-pitch chest CT performed with 70 kVp significantly reduces radiation dose when compared to 80 kVp while at the same time provides good image quality without any motion artifacts even without sedation.
Copyright © 2015. Published by Elsevier GmbH.
Litau S, Niedermoser S, Vogler N, Roscher M, Schirrmacher R, Fricker G, Wängler B, Wängler C.
Bioconjug Chem. 2015 Oct 14. [Epub ahead of print]
The Silicon-Fluoride-Acceptor (SiFA)-18F-labeling strategy has been shown before to enable the straightforward and efficient 18F-labeling of complex biologically active substances such as proteins and peptides. Especially in the case of peptides, the radiolabeling proceeds kit-like in short reaction times and without the need of complex product workup. SiFA-derivatized, 18F-labeled Tyr3-octreotate (TATE) derivatives demonstrated, besides strong somatostatin receptor (SSTR) binding, favorable in vivo pharmacokinetics as well as excellent tumor visualization by PET imaging. In this study, we intended to determine the influence of the underlying molecular design and used molecular scaffolds of SiFAlin-TATE derivatives on SSTR binding as well as on the in vivo pharmacokinetics of the resulting 18F-labeled peptides. For this purpose, new SiFAlin-(Asp)n-PEG1-TATE analogs (where n = 1-4) were synthesized, efficiently radiolabeled with 18F in a kit-like manner and obtained in radiochemical yields of 70-80%, radiochemical purities of ≥97%, and nonoptimized specific activities of 20.1-45.2 GBq/μmol within 20-25 min starting from 0.7-1.5 GBq of 18F. In the following, the radiotracer's lipophilicities and stabilities in human serum were determined. Furthermore, the SSTR-specific binding affinities were evaluated by a competitive displacement assay on SSTR-positive AR42J cells. The obtained in vitro results support the assumption that aspartic acids are able to considerably increase the radiotracer's hydrophilicity and that their number does not affect the SSTR binding potential of the TATE derivatives. The most promising tracer 18F-SiFAlin-Asp3-PEG1-TATE [18F]6 (LogD = -1.23 ± 0.03, IC50 = 20.7 ± 2.5 nM) was further evaluated in vivo in AR42J tumor-bearing nude mice via PET/CT imaging against the clinical gold standard 68Ga-DOTATATE as well as the previously developed SiFAlin-TATE derivative [18F]3. The results of these evaluations showed that [18F]6-although showing very similar chemical and in vitro properties to [18F]3-exhibits not only a slowed renal clearance compared to [18F]3, but also a higher absolute tumor uptake compared to 68Ga-DOTATATE, and furthermore enables excellent tumor visualization with high image resolution. These results emphasize the importance of systematic study of the influence of molecular design and applied structure elements of peptidic radiotracers, as these may considerably influence in vivo pharmacokinetics while not affecting other parameters such as radiochemistry, lipophilicity, serum stability, or receptor binding potential.
PMID: 26420336 [PubMed - as supplied by publisher]
Gaa T, Sudarski S, Lietzmann F, Schad LR, Zoellner FG
Magnetic Resonance Materials in Physics, Biology and Medicine, October 2015, Volume 28, Supplement 1, pp 277-418
Book of Abstracts ESMRMB 2015 (e-only) p.370 (No. 481)
Gaa T, Sudarski S, Lietzmann F, Schad LR, Zoellner FG
Magnetic Resonance Materials in Physics, Biology and Medicine, October 2015, Volume 28, Supplement 1, pp 419-519
Book of Abstracts ESMRMB 2015 (e-only) p.464 (No. 597)
Rathmann N, Kostrzewa M, Kara K, Bartling S, Haubenreisser H, Schoenberg SO, Diehl SJ.
Evaluation of absolute radiation exposure values for interventional radiologists (IRs) using a multiaxis interventional flat-panel C-arm cone beam CT (CBCT) system with three-dimensional laser guidance for biopsy in a triple-modality, abdominal phantom.
In the phantom, eight lesions were punctured in two different angles (in- and out-of-plane) using CBCT. One C-arm CT scan was performed to plan the intervention and one for post-procedural evaluation. Thermoluminescent dosemeters (TLDs) were used for dose measurement at the level of the eye lens, umbilicus and ankles on a pole representing the IRs. All measurements were performed without any lead protection. In addition, the dose-area product (DAP) and air kerma at the skin entrance point was documented.
Mean radiation values of all TLDs were 190 µSv for CBCT (eye lens: 180 µS, umbilicus: 230 µSv, ankle: 150 µSv) without a significant difference (p > 0.005) between in- and out-of-plane biopsies. In terms of radiation exposure of the phantom, the mean DAP was not statistically significantly different (p > 0.05) for in- and out-of-plane biopsies. Fluoroscopy showed a mean DAP of 7 or 6 μGym(2), respectively. C-arm CT showed a mean DAP of 5150 or 5130 μGym(2), respectively.
In our setting, the radiation dose to the IR was distinctly high using CBCT. For dose reduction, it is advisable to pay attention to lead shielding, to increase the distance to the X-ray source and to leave the intervention suite for C-arm CT scans.
ADVANCES IN KNOWLEDGE:
The results indicate that using modern navigation tools and CBCT can be accompanied with a relative high radiation dose for the IRs since detector angulation can make the use of proper lead shielding difficult.
PMID: 26370153 [PubMed - in process]
Bacher L, Fischer G, Litau S, Schirrmacher R, Wängler B, Baller M, Wängler C.
J Labelled Comp Radiopharm. 2015 Aug;58(10):395-402. doi: 10.1002/jlcr.3315. Epub 2015 Jul 27.
Peptidic radiotracers are highly potent substances for the specific in vivo imaging of various biological targets with Single Photon Emission Computed Tomography and Positron Emission Tomography. However, some radiolabeled peptides such as bombesin analogs were shown to exhibit only a limited stability, hampering a successful target visualization. One option to positively influence the stability of radiolabeled peptides is the introduction of certain artificial molecular scaffolds. In order to comparatively assess the influence of different structure elements on the stability of radiolabeled peptides and to identify those structure elements being most useful for peptide radiotracer stabilization, several monomeric and dimeric bombesin derivatives were synthesized, exhibiting differing molecular designs and the chelator NODAGA for (68) Ga-labeling. The radiolabeled peptides were evaluated regarding their in vitro stability in human serum to determine the influence of the introduced molecular scaffolds on the peptides' serum stabilities. The results of the evaluations showed that the introduction of scaffold structures and the overall molecular design have a substantial impact on the stabilities of the resulting peptidic radiotracers. But besides some general trends found using certain scaffold structures, the obtained results point to the necessity to empirically assess their influence on stability for each susceptible peptidic radiotracer individually.
Copyright © 2015 John Wiley & Sons, Ltd.
KEYWORDS: 68Ga; molecular design; peptide; radiotracer; serum stability
PMID: 26219022 [PubMed - in process]
Fischer G, Lindner S, Litau S, Schirrmacher R, Wängler B, Wängler C.
Bioconjug Chem. 2015 Aug 19;26(8):1479-83. doi: 10.1021/acs.bioconjchem.5b00362. Epub 2015 Jul 24.
As the gastrin releasing peptide receptor (GRPR) is overexpressed on several tumor types, it represents a promising target for the specific in vivo imaging of these tumors using positron emission tomography (PET). We were able to show that PESIN-based peptide multimers can result in substantially higher GRPR avidities, highly advantageous in vivo pharmacokinetics and tumor imaging properties compared to the respective monomers. However, the minimal distance between the peptidic binders, resulting in the lowest possible system entropy while enabling a concomitant GRPR binding and thus optimized receptor avidities, has not been determined so far. Thus, we aimed here to identify the minimal distance between two GRPR-binding peptides in order to provide the basis for the development of highly avid GRPR-specific PET imaging agents. We therefore synthesized dimers of the GRPR-binding bombesin analogue BBN(7-14) on a dendritic scaffold, exhibiting different distances between both peptide binders. The homodimers were further modified with the chelator NODAGA, radiolabeled with (68)Ga, and evaluated in vitro regarding their GRPR avidity. We found that the most potent of the newly developed radioligands exhibits GRPR avidity twice as high as the most potent reference compound known so far, and that a minimal distance of 62 bond lengths between both peptidic binders within the homodimer can result in concomitant peptide binding and optimal GRPR avidities. These findings answer the question as to what molecular design should be chosen when aiming at the development of highly avid homobivalent peptidic ligands addressing the GRPR.
PMID: 26200324 [PubMed - in process]
Kostrzewa M, Rathmann N, Kara K, Schoenberg SO, Diehl SJ.
Purpose of this phantom study was to compare the accuracy of needle placement using a multi-axis, C-arm-based, flat-panel, cone-beam computed tomography system (CBCT guidance) with that under multi-detector computed tomography guidance (MDCT guidance).
MATERIALS AND METHODS:
In an abdominal phantom, eight lesions (six lesions in the liver and two in the renal pelvises, respectively) were each punctured in-plane and off-plane with a 20G needle under CBCT and MDCT guidance. Access paths were initially defined and reproduced identically on the two systems. In total, 32 interventions were conducted. CBCT and MDCT guidance was compared prospectively with respect to technical success, accuracy, and overall procedural time.
All 32 interventions were technically successful in that it was possible to hit the respective lesion in each procedure. When comparing the accuracy of MDCT to CBCT guidance there was no significant difference in absolute, angular, and longitudinal deviation for either in- or off-plane interventions. Overall procedural duration was significantly longer under CBCT guidance for in-plane interventions (888 vs 527s, p=0.00005), whereas, for off-plane procedures there was no significant difference between CBCT and MDCT guidance (920 vs 701s, p=0.08). Off-plane interventions took significantly longer than in-plane interventions under MDCT guidance (701 vs 527s, p=0.03), whereas under CBCT guidance no significant difference could be found between off- and in-plane procedures (920 vs. 888s, p=0.2).
In this phantom study, we could show that percutaneous soft-tissue interventions under CBCT guidance can be conducted with an accuracy comparable to that under MDCT guidance. Although overall procedural duration is in general shorter using MDCT guidance, CBCT-guided interventions offer the advantage of more degrees of freedom, which is of particular importance for off-plane procedures.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
PMID: 26184039 [PubMed - as supplied by publisher]
Niedermoser S, Chin J, Wängler C, Kostikov A, Bernard-Gauthier V, Vogler N, Soucy JP, McEwan AJ, Schirrmacher R, and Wängler B
Radiolabeled peptides for tumor imaging with PET that can be produced with kits are currently in the spotlight of radiopharmacy and nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, (68)Ga and (18)F stand out because of the ease of radionuclide introduction (e.g., (68)Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring the (18)F isotope). The in vivo properties of good manufacturing practice-compliant, newly developed kitlike-producible (18)F-SiFA- and (18)F-SiFAlin- (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared with the current clinical gold standard (68)Ga-DOTATATE for high-quality imaging of somatostatin receptor-bearing tumors.
SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried (18)F and purified via a C18 cartridge (radiochemical yield 49.8% ± 5.9% within 20-25 min) without high-performance liquid chromatography purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution and in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles, and the results were compared with those of the current clinical gold standard (68)Ga-DOTATATE.
Synthetically easily accessible (18)F-labeled silicon-fluoride acceptor-modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor standardized uptake values in PET/CT imaging than (68)Ga-DOTATATE in vivo. The radioactivity uptake in nontumor tissue was higher than for (68)Ga-DOTATATE.
The introduction of the novel SiFA building block SiFAlin and of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios although lower than those observed with (68)Ga-DOTATATE. As further advantage, the SiFA methodology enables a kitlike labeling procedure for (18)F-labeled peptides advantageous for routine clinical application.