Clinical Hemorheology and Microcirculation - Volume 73, issue 1

Authors: Schaible, J. | Stroszczynski, C. | Beyer, L.P. | Jung, E.M.

Article Type: Research Article

Abstract: OBJECTIVE: The use of a standardized dynamic contrast enhanced ultrasound (CEUS) protocol to determine perfusion of hepatocellular carcinomas (HCC) using quantitative analysis. METHODS: Retrospective analysis of 27 patients with hepatocellular carcinoma examined by a standardized protocol (bolus injection of 2.4 ml sulphur hexafluoride microbubbles, arterial phase to portal venous phase using continuous CINE-loops over 1 minute, short CINE-loops after 2, 3, 4, 5 and 6 minutes and additional single images for B-mode, CCDS). The examination was performed by an experienced sonographer with a high resolution, multi-frequency transducer (1–6 MHz). The reading of the reference imaging (contrast enhanced CT and MRI) …and histopathology, if necessary, was performed independently. Retrospective analysis of the CEUS DICOM loops was done using time intensity curve analysis (TIC) with evaluation of the time to peak (TTP) and the area under the curve (AUC). RESULTS: All tumor lesions were characterized by CEUS, based on typical contrast patterns for HCC lesions with arterial enhancement and wash out in the late phase, corresponding to MRI with liver specific contrast agent or contrast enhanced CT. Mean TTP (SD) in the tumor centre (C) was 19.93 (11.31), in the periphery (P) 22.94 (9.44) and in the normal liver tissue (LT) 28.19 (11.34) with significant differences between all zones C/P (p  = 0.013), C/LT (p  = 0.005) and P/LT (p  = 0.022). AUC mean (SD) in the tumor centre (C) was 660.03 (292.64), in the periphery (P) 586.04 (237.01) and in the normal liver tissue (LT) 484.20 (236.99), also with significant differences between all zones C/P (p  = 0.001), C/LT (p  < 0.001) and P/LT (p  < 0.001). CONCLUSION: TIC-analysis is an easy-to-use tool for the dynamic evaluation of microvascularization in hepatocellular carcinoma and allows a fast and cost-efficient quantitative analysis. Show more

Keywords: CEUS, Contrast enhanced ultrasound, hepatocellular carcinoma, TIC-analysis, quantitative analysis

DOI: 10.3233/CH-199221

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 95-104, 2019

Authors: Chaloupka, M. | Bischoff, R. | Pfitzinger, P. | Lellig, E. | Ledderose, S. | Buchner, A. | Schlenker, B. | Stief, C. | Clevert, D.-A. | Apfelbeck, M.

Article Type: Research Article

Abstract: INTRODUCTION: Multiparametric-Magnetic Resonance Imaging (mpMRI)-Ultrasound fusion guided biopsy (Fbx) has emerged as the new standard of risk stratification for prostate cancer (PCa) with superior detection rates of clinically significant PCa than randomized biopsy. In the present study, we evaluated patients with suspicion of clinically significant PCa on mpMRI, but histopathologically proven Gleason 6 PCa in Fbx. MATERIAL AND METHODS: Between 2015 and 2019, 849 patients underwent Fbx and concurrent systematic 12-core biopsy at our department. 234 patients were diagnosed with Gleason 6 PCa in either mpMRI-targeted and/or concurrent systematic biopsy. Patients were analyzed regarding PSA, mpMRI findings according …to PI-RADS classification, histopathological results of Fbx and systematic 12-core biopsy. 99/234 patients were also analyzed in regards of histopathology of the whole-mount specimen of subsequent radical prostatectomy (RP). RESULTS: In 131/234 patients (56%), Gleason 6 PCa was detected in the mpMRI target. In 103/234 patients (44%), Gleason 6 PCa was detected in the concurrent systematic 12-core biopsy with negative mpMRI-targeted biopsy. Men with evidence of Gleason 6 in the mpMRI target had significantly higher amounts of overall positive biopsies (median 4 vs. 2, p  < 0.001) and higher maximum tumor infiltration per biopsy core (30% vs. 20%, p  < 0.001) compared to men with negative mpMRI-targeted biopsy. Detection of Gleason 6 in mpMRI Target lesions correlated significantly with the PI-RADS score (p  < 0.001). Patients with positive mpMRI-target had significantly higher tumor infiltration in whole-mount specimen after prostatectomy (20% vs. 15%, p  = 0.0026) compared to men without detection of Gleason 6 in mpMRI-targeted biopsy but in additional systematic biopsy. CONCLUSION: Detection of Gleason 6 PCa in mpMRI-targeted biopsy indicates higher tumor burden compared to detection of Gleason 6 PCa in concurrent systematic biopsy and negative mpMRI-targeted biopsy. Show more

Keywords: Low-risk prostate cancer, multiparametric MRI, fusion biopsy, active surveillance, PI-RADS classification

DOI: 10.3233/CH-199223

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 105-111, 2019

Authors: Schiltz, Daniel | Taeger, Christian D. | Biermann, Niklas | Ranieri, Marco | Klein, Silvan | Prantl, Lukas | Geis, Sebastian

Article Type: Research Article

Abstract: BACKGROUND: Reconstruction of soft tissue defects with free flaps is a common procedure in plastic and reconstructive surgery. Most postoperative complications occur within the first 48–72 hours after surgery. After postoperative complications, short perfusion restoration times may improve flap survival rates by up to 30–50%. Ratiometric fluorescence imaging is an additional or alternative method of postoperative flap monitoring. OBJECTIVE: To test the efficacy and utility of transepidermal oxygen flux imaging to evaluate postoperative skin oxygenation of free and local flaps in the first 48 hours after surgery. METHODS: The study included 32 patients (aged between 18 …and 80 years; mean age 52.9) with a tissue defect covered with a free flap transplant at the Department of Plastic and Reconstructive Surgery of the University Medical Center Regensburg. Postoperative oxygen flux was measured with the ‘VisiSens system’ placed on the vascular pedicle as well as on the peripheral and central part of the flap. RESULTS: Values of oxygen flux were higher in case of flap congestion (0.069±0.012) or flap necrosis (0.155±0.083) than in cases without any complications (0.061±0.006). Flux values of different areas of the same flap showed only minimal differences (central part: 0.065±0.008, peripheral part: 0.070±0.009, vascular pedicle: 0.056±0.004); the level of significance was p  = 0.904. CONCLUSION: Imaging transepidermal oxygen flux by ratiometric luminescence seems to be a reliable alternative, indirect method of postoperative flap monitoring with regard to microcirculatory function and flap viability. Show more

Keywords: Postoperative free flap monitoring, microcirculatory function, tissue oxygenation, tissue perfusion, flux imaging, flap monitoring, transcutaneous oxygen measurement

DOI: 10.3233/CH-199225

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 113-123, 2019

Authors: Brebant, V. | Heine, N. | Lamby, P. | Heidekrueger, PI | Forte, A.J. | Prantl, L. | Aung, T.

Article Type: Research Article

Abstract: BACKGROUND: A physiological and minimal invasive form of surgery with minimal risk to treat lymphedemas is the so-called supermicrosurgical lymphovenous anastomosis (LVA) where a lymph vessel is connected with a venule. METHODS: 30 patients (between 2018 and 2019) with secondary upper extremity lymphedema refractory to conservative therapy (manual lymph drainage and compression therapy were operated using the “simplified lymphovenous anastomosis” method). For the assessment of lymphatic supermicrosurgery, an operating microscope in which a near-infrared illumination system is integrated (Leica M530 OHX with glow technology ULT530, Leica Microsystems) and the IC-FlowTM Imaging System(Diagnostic Green)/Visionsense System (Medtronic) together with …a ZEISS S8 microscope was used. Augmented reality intraoperative indocyanin green (ICG) lymphography-navigated modified “simplified lymphovenous anastomosis” were performed on the Leica microscope. All patients were informed about Off-label-use of ICG lymphography. RESULTS: 57 LVAs were performed with modified “simplified lymphovenous anastomosis” lymphography-guidance on 30 upper extremities. All patients showed good patency after lymphovenous anastomosis. CONCLUSIONS: Supermicrosurgery in the case of LVA is minimally invasive, highly effective, and shows a very low complication rate. The surgeon/equipment-related factors restrict the pratice of LVA, and its effectiveness limited by technical constraints. Show more

Keywords: Lymphedema, lymph node transplantation, lymph vessel transplantation, LVA, augmented reality, indocyanine green (ICG)

DOI: 10.3233/CH-199220

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 125-133, 2019

Authors: Apfelbeck, M. | Chaloupka, M. | Schlenker, B. | Stief, C.G. | Clevert, D.-A.

Article Type: Research Article

Abstract: INTRODUCTION: Focal therapy (FT) of the prostate for low risk prostate cancer (PCa) is an alternative to traditional definite treatment options like external beam radiotherapy or radical prostatectomy. However, follow up after FT is still challenging and is subject to current studies. Significance of imaging after FT such as multiparametric MRI (mpMRI) is currently not well established. In this study, we aimed to evaluate the efficacy of alternative imaging during the follow up of low risk PCa treated with focal HIFU therapy using CEUS and image fusion. MATERIALS AND METHODS: Retrospective single arm study in patients with uni- …or bilateral, low or intermediate risk prostate cancer treated with HIFU at our institution between October 2016 and January 2018. CEUS in combination with image fusion using an axial T2-weighted MRI sequence was performed during follow up 3, 6, 9 and 12 months after the therapy. RESULTS: 4 consecutive patients with Gleason score (GS) 6 and 4 patients with GS 7a prostate cancer were included in the study. Hemiablation was performed in 7 patients with unilateral tumor. One patient underwent whole gland treatment due to histological proven bilateral PCa. Mean patient age at time of therapy was 70.3 (54–83) years and mean Prostate-specific antigen (PSA) level prior treatment was 7.8 ng/ml (2.1–14.4), after 3 months mean PSA level was 3.9 ng/ml (0.1–7.2), after 6 months 3.5 ng/ml (0.2–6.0), after 9 months 3.1 ng/ml (0.2–6.8) and 3.3 ng/ml (0.2–6.1) after 12 months. CEUS showed no signs of microvascularisation after 3, 6, 9 and 12 months in the ablated zone. 3 months posttreatment the necrotic tissue was still visible in the B-mode scan, although with no signs of vascularization performing CEUS. After 6 months the ablated side of the prostate was almost completely atrophic. And after 9 months the necrotic tissue was completely resolved. Between 9 and 12 months no changes in microvascularisation and perfusion could be shown. CONCLUSIONS: MpMRI/CEUS image fusion is a cost-effective and feasible technique to monitor the perfusion of the ablation zone after focal therapy of the prostate. Show more

Keywords: Prostate cancer, high intensity focused ultrasound therapy, contrast enhanced ultrasound, image fusion, follow up

DOI: 10.3233/CH-199222

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 135-143, 2019

Authors: Goetz, J. | Kaisermayer, E. | Haase, H. | Jünger, M. | Riebe, H.

Article Type: Research Article

Abstract: BACKGROUND: Although the efficacy of compression therapy through knee-length compression stockings with an interface pressure of 18–21 mmHg for leg oedemas has been confirmed by many studies, 91% of patients are still treated with a higher interface pressure. METHOD: In this prospective open randomised monocentric study 19 patients (age ≥65, movement restrictions and symptomatic leg oedema) received knee-length compression stockings with an interface pressure of 18–21 mmHg (stocking type 1 ) and 23–32 mmHg (stocking type 2 ). On two consecutive days each of the two compression stocking types were worn for at least 8 hours. After this test period, both …stocking types were assessed subjectively and skin changes were recorded. RESULT: A significantly (p -value <0.001) subjective improvement of the symptoms and complaints based on leg oedema was reported with the knee-length compression stockings. The Stocking type 1 recorded a significantly (p  = 0,045) better wearing comfort. In addition, the Stocking type 2 was significantly too large amongst women in the front foot area (p  = 0.044). The most common side effects were constrictions on the proximal lower leg (stocking type 1 = 73,7% (14/19); stocking type 2 = 78,9% (15/19)). Subjects with arthritis (p  = 0.006), hallux valgus (p  = 0.034) and/or digitus flexus (p  = 0.021) found the socking type 1 significantly more comfortable. CONCLUSION: In order to achieve optimal patient compliance it is recommended to prescribe knee-length compression stockings with an interface pressure of 18–21 mmHg if the following criteria are met: age ≥65 years, female sex, arthritis, digitus flexus (claw toe) or hallux valgus. Show more

Keywords: Chronic leg oedema, compression stocking therapy, chronic venous insufficiency, quality of life, wearing comfort

DOI: 10.3233/CH-199207

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 145-156, 2019

Authors: Asam, Claudia | Buerger, Korbinian | Felthaus, Oliver | Brébant, Vanessa | Rachel, Reinhard | Prantl, Lukas | Witzgall, Ralph | Haerteis, Silke | Aung, Thiha

Article Type: Research Article

Abstract: BACKGROUND: Doxorubicin is a cytostatic drug from the group of anthracycline antibiotics that is widely used as a chemotherapeutic agent. Side effects of the active substance include cardiotoxicity and nephrotoxicity. Doxorubicin-treated renal epithelial cells and (sarcoma) tumors are examined by correlative light and electron microscopy (CLEM) to investigate the subcellular localization of doxorubicin. METHODS: The kidney epithelial cell line MDCK II (Madin-Darby Canine Kidney) grown on culture dishes were treated with doxorubicin. Subsequently, the cells are analyzed by means of fluorescence and transmission electron microscopy (TEM). In vivo , alveolar rhabdomyosarcoma (RH 30) tumor cells are transferred to …the chorioallantoic membrane (CAM) of the chicken embryo. Doxorubicin is injected into a vein of the chicken embryo. After 24 hours, the tumor is removed and examined using CLEM. RESULTS: The kidney epithelial cells and the doxorubicin-injected tumors show a clear staining of the cell nucleus, which correlates with electron-dense regions (heterochromatin). High-resolution TEM shows that doxorubicin treatment leads to an enormous stress situation with an increased formation of membrane blebbings. CONCLUSIONS: CLEM is a promising new method to visualize the pattern of fluorescing drugs (e.g. doxorubicin) in renal epithelial cells and tumors, and to localize the drug in its subcellular context combined with high resolution. Show more

Keywords: Correlative light and electron microscopy (CLEM), chorioallantoic membrane (CAM), doxorubicin, chemotherapy, tumor, sarcoma, Epon

DOI: 10.3233/CH-199212

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 157-167, 2019

Authors: Haileka, V. | George, S. | Steinbrecht, S. | Jung, F. | Reinehr, R. | Küpper, J.-H.

Article Type: Research Article

Abstract: BACKGROUND: In most clinical studies older people are underrepresented compared to the demographic reality. However, risk for some severe diseases like cancer typically increase with age. Most insight into cancer treatment comes from mixed-age patient cohorts, leading to a lack of detailed understanding of cancer drug effects in the elderly population. There is growing evidence that cancer drug effects can be influenced by dehydration conditions often found in older people. Colon cancer remains the second leading cause of death by cancer in Europe. Inter- and intra-heterogeneity of tumors contribute to why some individuals do not respond to specific cancer therapies …or may often suffer a relapse. OBJECTIVE: Our study applies an in vitro drug test system for simulating treatment with cytostatics of colorectal cancer in elderly patients with dehydration condition. METHODS: Two well-known colon cancer cell lines, Caco-2 and RKO, harboring defined cancer-related mutations, were step-wisely adapted from routine culture medium to a severe hyperosmotic condition (397 mOmol/kg) by adding sodium chloride to the medium. We investigated the effects of these cell culture conditions, which should mimic cellular dehydration in elderly people, on the growth characteristics of the cells. Therefore, cell proliferation was investigated by measuring population doubling times. Furthermore, we investigated how the metabolic activity of the cells was influenced by treatment with different concentrations of cyclophosphamide (CPA) under normal and hyperosmotic conditions. RESULTS: We found that Caco-2 and RKO cell lines have an identical cell doubling time of 23 hours in normosmotic medium. However, hyperosmotic medium lifted the doubling time of Caco-2 cells to 31 hours while that of RKO cells did not change. Despite reduced cell proliferation rates, hyperosmotic medium sensitized Caco-2 cells to treatment with 10 mM CPA for 48 hours as measured by metabolic activity assays on ATP levels. CONCLUSIONS: The two investigated colon cancer cells lines reacted differently to hyperosmotic conditions. Only the growth of Caco-2 cells was reduced by increased osmolality. Despite this reduced growth their sensitivity to an alkylating cytostatic agent was even slightly increased. We are now in line to examine these effects in more detail and with more tumor cell lines. Show more

Keywords: Colon cancer, cyclophosphamide, dehydration, hyperosmotic, osmolality

DOI: 10.3233/CH-199210

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 169-176, 2019

Authors: Neuber, Christin | Schulze, Sabine | Förster, Yvonne | Hofheinz, Frank | Wodke, Johanna | Möller, Stephanie | Schnabelrauch, Matthias | Hintze, Vera | Scharnweber, Dieter | Rammelt, Stefan | Pietzsch, Jens

Article Type: Research Article

Abstract: Biomaterials coated with artificial extracellular matrices (aECM) are intended to support the healing of critical size bone defects. This pilot study investigated (i) the feasibility of dual-tracer PET/CT imaging for functional characterization of biomaterial-assisted bone healing in a rat femoral defect model and (ii) the bone healing ability of polycaprolactone-co -lactide (PCL) scaffolds, coated with various aECM consisting of collagen type I (Col) and glycosaminoglycans (GAGs) such as chondroitin sulfate (CS) or polysulfated hyaluronan (sHA3). [18 F]FDG and [18 F]fluoride PET 4 and 8 weeks after implantation of aECM-coated PCL scaffolds, which provide an in vivo measure of cellular …activation and bone mineralization, respectively, combined with CT imaging (in vivo/ex vivo ) and histological/immunohistochemical investigations (ex vivo ) showed that coating with CS in particular is beneficial for bone healing. The possible involvement of COX-2 and TGase 2, key enzymes of inflammation and ECM remodeling, in these processes offers starting points for targeted adjuvant therapy in the course of various bone healing phases. Our investigations show the feasibility of the selected dual-tracer approach for PET/CT imaging. In principle, this approach can be extended by further PET tracers for the functional characterization of physiological processes such as hypoxia/reperfusion or selected molecular players. Show more

Keywords: Artificial extracellular matrices, bone healing, [18F]fluorodeoxyglucose, [18F]fluoride, glycosaminoglycans, inflammation, metabolism, molecular imaging, revascularization

DOI: 10.3233/CH-199208

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 177-194, 2019

Authors: Nies, A. | Proft, L. | Nehring, M.E. | Gruber, C. | Sievers, H. | Hünigen, H. | Rodrigues, A.G. | Gemeinhardt, O. | Mrowietz, C. | Jung, F. | Hiebl, B.

Article Type: Research Article

Abstract: BACKGROUND: In cardiovascular research small pigs breeds like Göttingen® minipigs (GM) are established animal models, but systematic data about the micromorphology of the GM vasculature at different ages are scarce. OBJECTIVE: The study was aimed at gaining knowledge about the micromorphology of the femoral artery (FA) from German Landrace pigs (DL) and GM during the period of growth over a body weight range of 10–40 kg. METHODS: FA samples from DL aged two or three months were compared to GM ones, aged 18 or 40 months using transmitted light microscopy. RESULTS: All FA samples …showed typical characteristics of muscular arteries. Growth was associated with increased vessel wall thickness. In the GM this resulted in a slight decrease of the luminal diameter (LD), while in the DL pigs, an increase of the LD and smooth muscle cell content (10%) with decreased elastic fiber content (10%) has been detected. In contrast, within the 22 months lasting growth period of the GM, the tunica media content of smooth muscle cells and elastic fibers remained stable. CONCLUSIONS: FA maturation strongly depends on the pig breed and age. It can be different from what is described in humans. Show more

Keywords: Maturation, micromorphology, muscular artery type, porcine femoral artery, tunica media

DOI: 10.3233/CH-199219

Citation: Clinical Hemorheology and Microcirculation, vol. 73, no. 1, pp. 195-201, 2019