Publications by authors named "Max Masthoff"

29 Publications

  • Page 1 of 1

Multispectral optoacoustic tomography of peripheral arterial disease based on muscle hemoglobin gradients-a pilot clinical study.

Ann Transl Med 2021 Jan;9(1):36

Department for Clinical Radiology, University Hospital Münster, Münster, Germany.

Background: Current imaging assessment of peripheral artery disease (PAD) relies on anatomical cross-sectional visualizations of the affected arteries. Multispectral optoacoustic tomography (MSOT) is a novel molecular imaging technique that provides direct and label-free visualizations of soft tissue perfusion and oxygenation.

Methods: MSOT was prospectively assessed in a pilot trial in healthy volunteers (group n=4, mean age 31, 50% male and group n=4, mean age 37.3, 75% male) and patients with intermittent claudication (group n=4, mean age 72, 75% male, PAD stage IIb). We conducted cuff-induced ischemia (group n) and resting state measurements (groups n and n) over the calf region. Spatially resolved mapping of oxygenated (HbO), deoxygenated (Hb) and total (THb) hemoglobin, as well as oxygen saturation (SO), were measured via hand-held hybrid MSOT-Ultrasound based purely on hemoglobin contrast.

Results: Calf measurements in healthy volunteers revealed distinct dynamics for HbO, Hb, THb and SO under cuff-induced ischemia. HbO, THb and SO levels were significantly impaired in PAD patients compared to healthy volunteers (P<0.05 for all parameters). Revascularization led to significant improvements in HbO of the affected limb.

Conclusions: Clinical MSOT allows for non-invasive, label-free and real-time imaging of muscle oxygenation in health and disease with implications for diagnostics and therapy assessment in PAD.
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http://dx.doi.org/10.21037/atm-20-3321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859778PMC
January 2021

Invasive diagnostic and therapeutic measures are unnecessary in patients with symptomatic van Neck-Odelberg disease (ischiopubic synchondrosis): a retrospective single-center study of 21 patients with median follow-up of 5 years.

Acta Orthop 2021 Feb 4:1-5. Epub 2021 Feb 4.

Department of Orthopedics and Tumor Orthopedics; University Hospital of Münster, Münster.

Background and purpose - Van Neck-Odelberg disease (VND) is a self-limiting skeletal phenomenon characterized by a symptomatic or asymptomatic uni- or bilateral overgrowth of the pre-pubescent ischiopubic synchondrosis. It is frequently misinterpreted as a neoplastic, traumatic, or infectious process, often resulting in excessive diagnostic and therapeutic measures. This study assessed the demographic, clinical, and radiographic features of the condition and analyzed diagnostic and therapeutic pathways in a large single-center cohort. Patients and methods - We retrospectively analyzed 21 consecutive patients (13 male) with a median age of 10 years (IQR 8-13) and a median follow-up of 5 years (IQR 42-94 months), who were diagnosed at our department between 1995 and 2019. Results - VND was unilateral in 17 cases and bilateral in 4 cases. Initial referral diagnoses included suspected primary bone tumor (n = 9), fracture (n = 3), osteomyelitis (n = 2), and metastasis (n = 1). The referral diagnosis was more likely to be VND in asymptomatic than symptomatic patients (4/6 vs. 2/15). More MRI scans were performed in unilateral than bilateral VND (median 2 vs. 0). All 15 symptomatic patients underwent nonoperative treatment and reported a resolution of symptoms and return to physical activity after a median time of 5 months (IQR 0-6). Interpretation - By understanding the physiological course of VND during skeletal maturation, unnecessary diagnostic and therapeutic measures can be avoided and uncertainty and anxiety amongst affected patients, their families, and treating physicians can be minimized.
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http://dx.doi.org/10.1080/17453674.2021.1882237DOI Listing
February 2021

Intraosseous contrast administration for emergency stroke CT.

Neuroradiology 2021 Jan 18. Epub 2021 Jan 18.

Clinic for Radiology, University Hospital Muenster, Muenster, Germany.

Computed tomography (CT) imaging in acute stroke is an established and fairly widespread approach, but there is no data on applicability of intraosseous (IO) contrast administration in the case of failed intravenous (IV) cannula placement. Here, we present the first case of IO contrast administration for CT imaging in suspected acute stroke providing a dedicated CT examination protocol and analysis of achieved image quality as well as a review of available literature.
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http://dx.doi.org/10.1007/s00234-021-02642-wDOI Listing
January 2021

Portal and hepatic vein embolization prior to major hepatectomy.

Z Gastroenterol 2021 Jan 11;59(1):35-42. Epub 2021 Jan 11.

Department for General, Visceral and Transplantation Surgery, University Hospital Muenster, Muenster, Germany.

Purpose:  To analyze safety and effectiveness of simultaneous portal and hepatic vein embolization (PHVE) or sequential hepatic vein embolization (HVE) compared to portal vein embolization (PVE) for future remnant liver (FRL) hypertrophy prior to major hepatic surgery.

Methods:  Patients undergoing PVE, PHVE or HVE at our tertiary care center between 2018 and 2020 were retrospectively included. FRLV, standardized FRLV (sFRLV) and sFRLV growth rate per day were assessed via volumetry, as well as laboratory parameters.

Results:  36 patients (f = 15, m = 21; median 64.5 y) were included, 16 patients received PHVE and 20 patients PVE, of which 4 received sequential HVE. Significant increase of FRLV was achieved with both PVE and PHVE compared to baseline (p < 0.0001). sFRLV growth rate did not significantly differ following PHVE (2.2 ± 1.2 %/d) or PVE (2.2 ± 1.7 %/d, p = 0.94). Left portal vein thrombosis (LPVT) was observed after PHVE in 6 patients and in 1 patient after PVE. Sequential HVE showed a considerably high growth rate of 1.42 ± 0.45 %/d after PVE.

Conclusion:  PHVE effectively induces FRL hypertrophy but yields comparable sFRLV to PVE. Sequential HVE further induces hypertrophy after insufficient growth due to PVE. Considering a potentially higher rate of LPVT after PHVE, PVE might be preferred in patients with moderate baseline sFRLV, with optional sequential HVE in non-sufficient responders.
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http://dx.doi.org/10.1055/a-1330-9450DOI Listing
January 2021

S100A9-Imaging Enables Estimation of Early Therapy-Mediated Changes in the Inflammatory Tumor Microenvironment.

Biomedicines 2021 Jan 3;9(1). Epub 2021 Jan 3.

University Clinic of Radiology, Medical Faculty, University of Muenster and University Hospital Muenster, D-48149 Muenster, Germany.

(1) Background: The prognosis of cancer is dependent on immune cells in the tumor microenvironment (TME). The protein S100A9 is an essential regulator of the TME, associated with poor prognosis. In this study, we evaluated early therapy effects on the TME in syngeneic murine breast cancer via S100A9-specific in vivo imaging. (2) Methods: Murine 4T1 cells were implanted orthotopically in female BALB/c mice ( = 59). Tumor size-adapted fluorescence imaging was performed before and 5 days after chemo- (Doxorubicin, = 20), anti-angiogenic therapy (Bevacizumab, = 20), or placebo (NaCl, = 19). Imaging results were validated ex vivo (immunohistochemistry, flow cytometry). (3) Results: While tumor growth revealed no differences ( = 0.48), fluorescence intensities (FI) for S100A9 in Bevacizumab-treated tumors were significantly lower as compared to Doxorubicin (2.60 vs. 15.65 AU, < 0.0001). FI for Doxorubicin were significantly higher compared to placebo (8.95 AU, = 0.01). Flow cytometry revealed shifts in monocytic and T-cell cell infiltrates under therapy, correlating with imaging. (4) Conclusions: S100A9-specific imaging enables early detection of therapy effects visualizing immune cell activity in the TME, even before clinically detectable changes in tumor size. Therefore, it may serve as a non-invasive imaging biomarker for early therapy effects.
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http://dx.doi.org/10.3390/biomedicines9010029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823872PMC
January 2021

Analysis of failed therapy evaluations in radioembolization of primary and secondary liver cancers.

J Cancer Res Clin Oncol 2021 May 6;147(5):1537-1545. Epub 2020 Nov 6.

Institute of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Munster, Germany.

Purpose: To analyze patients' characteristics and reasons for not performing planned transarterial radioembolization (TARE) in liver cancer after Tc-labeled macroaggregated albumin (Tc-MAA) evaluation.

Methods: In this retrospective single-center cohort, all patients undergoing Tc-MAA evaluation prior to planned TARE for primary or secondary liver cancer between 2009 and 2018 were analyzed. Patients were assigned to either "TARE" or "no TARE" group. Patients' characteristics, arising reasons for not performing the planned TARE treatment as well as predictive factors for occurrence of these causes were analyzed.

Results: 436 patients [male = 248, female = 188, median age 62 (23-88) years] with Tc-MAA evaluation prior to planned TARE of primary or secondary liver cancer were included in this study. 148 patients (33.9%) did not receive planned TARE. Patients with a hepatic tumor burden > 50%, no liver cirrhosis, no previous therapies and a higher bilirubin were significantly more frequent in "no TARE" compared to "TARE" group. Main reasons for not performing TARE were extrahepatic tracer accumulation (n = 70, 40.5%), non-target accumulation of Tc-MAA (n = 27, 15.6%) or a hepatopulmonary shunt fraction of more than 20% (n = 23, 13.3%). Independent preprocedural parameters for not performing planned TARE were elevated bilirubin (p = 0.021) and creatinine (p = 0.018) and lower MELD score (p = 0.031).

Conclusion: A substantial number of patients are precluded from TARE following Tc-MAA evaluation, which is, therefore, implicitly needed to determine contraindications to TARE and should not be refrained from in pretreatment process. However, a preceding careful patient selection is needed especially in patients with high hepatic tumor burden and alteration in lab parameters.
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http://dx.doi.org/10.1007/s00432-020-03443-zDOI Listing
May 2021

Repeated radioembolization in advanced liver cancer.

Ann Transl Med 2020 Sep;8(17):1055

Institute of Clinical Radiology, University Hospital Muenster, Muenster, Germany.

Background: To evaluate safety and clinical outcome of repeated transarterial Y (yttrium) radioembolization (TARE) in primary and metastatic liver cancer.

Methods: Between 2009 and 2018, n=288 patients underwent TARE for treatment of malignant liver disease in a tertiary care hospital. This retrospective single center study analyzed the safety and outcome of patients (n=11/288) undergoing repeated resin microsphere TARE. Included patients suffered from hepatocellular carcinoma (n=3), colorectal cancer (n=2), breast cancer (n=2), intrahepatic cholangiocarcinoma (n=3), and neuroendocrine carcinoma (n=1). All patients had shown either partial response (n=9) or stable disease (n=2) after first TARE. Lab parameters, response assessed by the Response Evaluation Criteria in Solid Tumors (mRECIST/RECIST) at 3 months and overall survival was analyzed. Additionally, patients with repeated TARE were compared to a matched control group (n=56) with single TARE therapy. Kaplan Meier analysis was performed to analyze survival.

Results: Patients after repeated TARE showed similar increase in lab parameters as compared to their first TARE. No case of radioembolization induced liver disease was observed. While n=5/11 patients showed a partial response and n=4/11 patients a stable disease after repeated TARE, only n=2/11 patients suffered from progressive disease. Median overall survival was 20.9±11.9 months for the repeated TARE group while it was 5.9±16.2 months for the control group.

Conclusions: Repeated Y TARE is safe and can be of benefit for patients yielding a comparable degree of local disease control compared to patients with singular TARE.
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http://dx.doi.org/10.21037/atm-20-2658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575953PMC
September 2020

EFFICACY OF 90Y-RADIOEMBOLIZATION IN METASTATIC COLORECTAL CANCER DEPENDING ON THE PRIMARY TUMOR SIDE.

Dig Dis 2020 Nov 3. Epub 2020 Nov 3.

Metastatic colorectal cancer (mCRC) is associated with different molecular biology, clinical characteristics and outcome depending on the primary tumor localization. We aimed to evaluate the effectiveness of 90Y-radioembolization (RE) for therapy of colorectal liver metastases depending on the primary tumor side. We performed a retrospective analysis of n=73 patients with mCRC and RE in our university liver center between 2009 and 2018. Patients were stratified according to the primary tumor side (left vs. right hemicolon), treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) at follow-up after 3 months. Kaplan-Meier analysis was performed to analyze survival followed by Cox regression to determine independent prognostic factors for survival. Prior to RE all patients had received systemic therapy, with either stable or progressive disease, but no partial or complete response. In n=22/73 (30.1%) patients the primary tumor side was in the right colon, in n=51/73 (69.9%) patients in the left colon. Hepatic tumor burden was ≤25% in n=36/73 (49.3%) patients and >25% in n=37/73 (50.7%) patients. At 3 months, n=21 (33.8%) patients showed treatment response [n=2 (3.2%) complete response, n=19 (30.6%) partial response], n=13 (21.0%) stable disease, and n=28 (45.2%) progressive disease after RE. The median survival in case of primary tumor side in the left colon was significantly higher than for primary tumors in the right colon (8.7 vs. 6.0 months, p=0.033). The median survival for a hepatic tumor burden ≤25% was significantly higher compared with >25% (13.9 vs. 4.3 months, p<0.001). The median overall survival was 6.1 months. The median survival after RE in hepatic-metastatic CRC depends on the primary tumor side and the pre-procedural hepatic tumor burden.
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http://dx.doi.org/10.1159/000512744DOI Listing
November 2020

Value Improvement by Assessing IR Care via Time-Driven Activity-Based Costing.

J Vasc Interv Radiol 2021 02 31;32(2):262-269. Epub 2020 Oct 31.

Institute of Clinical Radiology, University Hospital Muenster, Muenster, Germany; Klinik und Poliklinik für Radiologie, Klinikum der Universität München, Munich, Germany.

Purpose: To evaluate time-driven activity-based costing (TDABC) in interventional radiology for image-guided vascular malformation treatment as an example.

Materials And Methods: Retrospective analysis was performed on consecutive vascular malformation treatment cycles [67 venous malformations (VMs) and 11 arteriovenous malformations (AVMs)] in a university hospital in 2018. All activities were integrated with a process map, and spent resources were assigned accordingly. TDABC uses 2 parameters: (i) practical capacity cost rate, calculated as 80% of theoretical capacity, and (ii) time consumption of each resource determined by interviews (23 items). Thereby, the total costs were calculated. Treatment cycles were modified according to identified resource waste and TDABC-guided negotiations with health insurance.

Results: Total personnel time required was higher for AVM (1,191 min) than for VM (637 min) treatment. The interventional procedure comprised the major part (46%) of personnel time required in AVM, whereas it comprised 19% in VM treatment. Materials represented the major cost type in AVM (75%) and VM (45%) treatments. TDABC-based treatment process modification led to a decrease in personnel time need of 16% and 30% and a cost reduction of 5.5% and 15.7% for AVM and VM treatments, respectively. TDABC-guided cost reduction and TDABC-informed negotiations improved profit from -56% to +40% and from +41% to +69% for AVM and VM treatments, respectively.

Conclusions: TDABC facilitated the precise costing of interventional radiologic treatment cycles and optimized internal processes, cost reduction, and revenues. Hence, TDABC is a promising tool to determine the denominator of interventional radiology's value.
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http://dx.doi.org/10.1016/j.jvir.2020.09.017DOI Listing
February 2021

CT-Guided Percutaneous Drainage of Pneumoperitoneum Presenting as Acute Abdomen.

J Vasc Interv Radiol 2021 02 28;32(2):271-276. Epub 2020 Oct 28.

Institute of Clinical Radiology, University Hospital Muenster, Muenster, Germany.

Purpose: To evaluate the feasibility and effectiveness of computed tomography (CT)-guided percutaneous drainage (PD) in patients with iatrogenic pneumoperitoneum presenting as acute abdomen.

Materials And Methods: In this retrospective, single-center cohort study, 16 consecutive patients (9 males, 7 females; median age, 67.5 [51-85] years) undergoing PD for managing acute abdomen caused by iatrogenic pneumoperitoneum between 2013 and 2019 were analyzed. Inclusion criteria were clinical signs of acute abdomen that was unresponsive to conservative management and pneumoperitoneum due to an iatrogenic cause after PD, observed using CT imaging. Volumetry of pneumoperitoneum was performed using computer-aided image segmentation. To evaluate the clinical outcome, the paired t-test was performed to analyze the course of pain intensity on the numerical pain rating scale (NPRS, 0-10). Patient records were reviewed to determine PD-related adverse events and median drain duration.

Results: The median pneumoperitoneum volume was 891.1 (127.7-3,677.0) mL. All PD procedures were successfully performed, with symptom relief and immediate abdominal decompression (mean segmental volume reduction, 79.8% ± 13.5). Acute abdomen symptoms were resolved, with significant improvement in pain intensity between the day of the PD procedure and the first day after the procdure (mean NPRS scores, 3.3 ± 1.9 vs 0.8 ± 1.0; P < .001). The median drain duration was 2 (1-3) days. No PD-associated adverse events were observed. After PD, 14 patients required only conservative management, whereas 2 patients with anastomotic leakage required additional surgery as they showed signs of persisting sepsis and generalized peritonitis.

Conclusions: PD is a safe and suitable procedure for the management of symptoms in patients with iatrogenic pneumoperitoneum presenting as acute abdomen.
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http://dx.doi.org/10.1016/j.jvir.2020.09.018DOI Listing
February 2021

Evaluation of 311 contemporary cases of stereotactic biopsies in patients with neoplastic and non-neoplastic lesions-diagnostic yield and management of non-diagnostic cases.

Neurosurg Rev 2020 Sep 20. Epub 2020 Sep 20.

Department of Neurosurgery, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Stereotactic biopsies are an established tool for obtaining diagnosis of unclear brain lesions. However, non-diagnostic biopsies still occur. We aimed to analyze the contemporary diagnostic yield of stereotactic biopsies, predictors for non-diagnostic biopsies, outcome, and follow-up strategy after non-diagnostic biopsy. We conducted a single-center retrospective study of 311 adult patients undergoing stereotactic biopsies due to a newly diagnosed lesion at our department between 2012 and 2018. Patient data regarding comorbidities, presenting symptoms, imaging features, and non-invasive diagnostic procedures were obtained. The overall diagnostic yield was 86.2% and differed significantly between the various suspected diagnosis groups and was the highest when suspecting primary brain tumor compared with non-neoplastic lesions (91.2% vs. 73.3%, p > 0.001). Predicators for non-diagnostic biopsies were small lesion size, lack of contrast-enhancement, presence of sepsis, or underlying hemato-oncological disease. In case of non-diagnostic biopsy, a re-biopsy was performed in 12 cases, revealing a final diagnosis in 75%. In 16 cases, empiric therapy was started based on the suspected underlying disease. Close follow-up was performed in the remaining 15 cases. We showed that stereotactic biopsy is a safe procedure with reasonable diagnostic yield even for non-neoplastic lesions, when non-invasive diagnostic was inconclusive. In addition, we developed treatment recommendations for cases of non-diagnostic biopsies.
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http://dx.doi.org/10.1007/s10143-020-01394-0DOI Listing
September 2020

Tracking of Tumor Cell-Derived Extracellular Vesicles In Vivo Reveals a Specific Distribution Pattern with Consecutive Biological Effects on Target Sites of Metastasis.

Mol Imaging Biol 2020 12 31;22(6):1501-1510. Epub 2020 Jul 31.

Institute of Clinical Radiology, University Hospital Münster, Münster, Germany.

Purpose: Extracellular vesicles, small vesicles carrying inter alia proteins, miRNA and RNA, are important mediators of intercellular communication. The purpose of this study was to assess the distribution of extracellular vesicles from highly malignant breast cancer and their subsequent effect on the immune cell infiltrate in target organs of metastasis.

Procedures: Extracellular vesicles were isolated from the tissue culture supernatant of highly malignant 4T1 breast cancer cells or the serum of healthy BALB/c mice. The purity of the isolate was verified by electron microscopy and western blotting. Extracellular vesicles were additionally subjected to proteome analysis. After labeling with the fluorescent dye DiR, extracellular vesicles were injected into healthy BALB/c mice and their in vivo distribution was assessed using fluorescence reflectance imaging (FRI). Following ex vivo imaging of the organs, lung tissue samples were analyzed for extracellular vesicle-mediated changes of myeloid cells and T cell numbers, using flow cytometry. Proteome analysis revealed major differences in the cargo of tumor cell-derived versus extracellular vesicles from healthy serum.

Results: In contrast to control extracellular vesicles, DiR-labeled extracellular vesicles from tumor cells preferentially accumulated in lung, liver, and spine. Subsequent flow cytometry of the immune cell composition of lung tissue samples revealed an increase of cytotoxic CD8+ T cells and a decrease of CD4+ T-helper cells as well as an increase in mature macrophages in response to tumor cell EV.

Conclusions: In conclusion, distribution of tumor cell-derived extracellular vesicles follows a specific pattern and can be monitored, using dedicated imaging. Extracellular vesicles alter the immune cell composition in target organs of metastasis, using a specific proteome cargo.
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http://dx.doi.org/10.1007/s11307-020-01521-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666295PMC
December 2020

Soft ultrasound priors in optoacoustic reconstruction: Improving clinical vascular imaging.

Photoacoustics 2020 Sep 10;19:100172. Epub 2020 Mar 10.

Institute of Biological and Medical Imaging (IBMI), Helmholtz Zentrum München, Ingolstädter Landstr. 1, D-85764, Neuherberg, Germany.

Using the same ultrasound detector, hybrid optoacoustic-ultrasound (OPUS) imaging provides concurrent scans of tissue slices or volumes and visualizes complementary sound- and light-based contrast at similar resolutions. In addition to the benefit of hybrid contrast, spatial co-registration enables images from one modality to be employed as prior information for improving an aspect of the performance of the other modality. We consider herein a handheld OPUS system and utilize structural information from ultrasound images to guide regional Laplacian regularization-based reconstruction of optoacoustic images. Using phantoms and data from OPUS scans of human radial and carotid arteries, we show that ultrasound-driven optoacoustic inversion reduces limited-view artefacts and improves image contrast. In phantoms, prior-integrated reconstruction leads to a 50 % higher contrast-to-noise ratio (CNR) of the image than standard reconstruction, and a 17 % higher structural similarity (SSIM) index. In clinical data, prior-integrated reconstruction detects deep-seated radial arteries with higher CNR than the standard method at three different depths. In this way, the prior-integrated method offers unique insights into atherosclerotic carotid plaques in humans (with p<0.01 between patients and healthy volunteers), potentially paving the way for new abilities in vascular imaging and more generally in optoacoustic imaging.
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http://dx.doi.org/10.1016/j.pacs.2020.100172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139114PMC
September 2020

TIPS Modification in the Management of Shunt-Induced Hepatic Encephalopathy: Analysis of Predictive Factors and Outcome with Shunt Modification.

J Clin Med 2020 Feb 19;9(2). Epub 2020 Feb 19.

Institute of Clinical Radiology, University Hospital Muenster, D-48149 Muenster, Germany.

Purpose: To evaluate predictive parameters for the development of Hepatic Encephalopathy (HE) after Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement and for success of shunt modification in the management of shunt-induced HE.

Methods: A retrospective analysis of all patients with TIPS ( = 344) has been performed since 2011 in our university liver center. = 45 patients with HE after TIPS were compared to = 48 patients without HE after TIPS (case-control-matching). Of = 45 patients with TIPS-induced HE, = 20 patients received a reduction stent ( = 18) or TIPS occlusion ( = 2) and were differentiated into responders (improvement by at least one HE grade according to the West Haven classification) and non-responders (no improvement).

Results: Older patient age, increased serum creatinine and elevated International Normalized Ratio (INR) immediately after TIPS placement were independent predictors for the development of HE. In 11/20 patients (responders, 55%) undergoing shunt modification, the HE grade was improved compared with nine non-responders (45%), with no relevant recurrence of refractory ascites or variceal bleeding. A high HE grade after TIPS insertion was the only positive predictor of treatment response ( = 0.019). A total of 10/11 responders (91%) survived the 6 months follow-up after modification but only 6/9 non-responders (67%) survived.

Discussion: Older patient age as well as an increased serum creatinine and INR after TIPS are potential predictors for the development of HE. TIPS reduction for the treatment of TIPS-induced HE is safe, with particular benefit for patients with pronounced HE.
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http://dx.doi.org/10.3390/jcm9020567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073830PMC
February 2020

[Generation Y in surgery-the competition battle for talent in times of talent shortage].

Chirurg 2020 Nov;91(11):955-961

WWU Weiterbildung, Universität Münster, Münster, Deutschland.

Background: Surgical disciplines are fighting with a critical and escalating shortage of recruits. Potential young professionals belong to the Generation Y, a generation that is constantly challenging senior consultants and human resources departments. The aim of this study was the analysis of various measures of personnel acquisition with respect to motivating factors of young medical students.

Material And Methods: A survey was carried out among students of the first and ninth semesters of a medical faculty on individual motivating factors, aspiration for medical specialist training and professional experience gained in surgery.

Results: Results from 179 out of 269 medical students were available for analysis (66.5% response rate). The interest in a specialist training in surgery was high in the first semester of medical school (21%) but dropped noticeably up to the ninth semester (13%, p = 0.23). Medical students in the ninth semester, who favored professional advancement and appreciation over flexible working hours showed a significantly higher interest in a specialist training in surgery (p = 0.022). Surgical experience gained was valued with an average grade of 2+ (1 = best, 6 = worst).

Conclusion: The high fundamental interest in a surgical residency during the beginning of medical studies is a competitive advantage of surgical disciplines; however, the diverse recruiting efforts are mainly aimed at later stages of studies. Timely hands-on courses in the core working area of surgery, the operating theatre, have proven to be particularly successful for the long-term acquisition and retention of junior doctors.
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http://dx.doi.org/10.1007/s00104-020-01138-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581597PMC
November 2020

Gorham-Stout disease: good results of bisphosphonate treatment in 6 of 7 patients.

Acta Orthop 2020 04 13;91(2):209-214. Epub 2020 Jan 13.

Department of Orthopaedics and Tumor Orthopaedics, University Hospital of Münster, Germany.

Background and purpose - Gorham-Stout disease (GSD) is a rare mono- or polyostotic condition characterized by idiopathic intraosseous proliferation of angiomatous structures resulting in progressive destruction and resorption of bone. Little is known about the course of disease and no previous study has evaluated patients' quality of life (QoL).Patients and methods - This is a retrospective analysis of 7 consecutive patients (5 males) with a median age at diagnosis of 14 years and a median follow-up of 7 years who were diagnosed with GSD in our department between 1995 and 2018. Data regarding clinical, radiographic, and histopathological features, and treatment, as well as sequelae and their subsequent therapy, were obtained. QoL was assessed by Musculoskeletal Tumor Society Score (MSTS), Toronto Extremity Salvage Score (TESS), and Reintegration to Normal Living (RNL) Index.Results - 3 patients had a monoostotic and 4 patients a polyostotic disease. Besides a diagnostic biopsy, 4 of the 7 patients had to undergo 8 surgeries to treat evolving sequelae. Using an off-label therapy with bisphosphonates in 6 patients, a stable disease state was achieved in 5 patients after a median of 20 months. The median MSTS, TESS, and RNL Index at last follow-up was between 87% and 79%.Interpretation - Due to its rare occurrence, diagnosis and treatment of GSD remain challenging. Off-label treatment with bisphosphonates appears to lead to a stable disease state in the majority of patients. QoL varies depending on the individual manifestations but good to excellent results can be achieved even in complex polyostotic cases with a history of possibly life-threatening sequelae.
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http://dx.doi.org/10.1080/17453674.2019.1709716DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144312PMC
April 2020

Introducing Specificity to Iron Oxide Nanoparticle Imaging by Combining Fe-Based MRI and Mass Spectrometry.

Nano Lett 2019 11 2;19(11):7908-7917. Epub 2019 Oct 2.

Translational Research Imaging Center, Institute of Clinical Radiology , University Hospital Muenster , 48149 Muenster , Germany.

Iron oxide nanoparticles (ION) are highly sensitive probes for magnetic resonance imaging (MRI) that have previously been used for in vivo cell tracking and have enabled implementation of several diagnostic tools to detect and monitor disease. However, the in vivo MRI signal of ION can overlap with the signal from endogenous iron, resulting in a lack of detection specificity. Therefore, the long-term fate of administered ION remains largely unknown, and possible tissue deposition of iron cannot be assessed with established methods. Herein, we combine nonradioactive Fe-ION MRI with ex vivo laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging, enabling unambiguous differentiation between endogenous iron (Fe) and iron originating from applied ION in mice. We establish Fe-ION as an in vivo MRI sensor for cell tracking in a mouse model of subcutaneous inflammation and for assessing the long-term fate of Fe-ION. Our approach resolves the lack of detection specificity in ION imaging by unambiguously recording a Fe signature.
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http://dx.doi.org/10.1021/acs.nanolett.9b03016DOI Listing
November 2019

Imaging of root canal treatment using ultra high field 9.4T UTE-MRI - a preliminary study.

Dentomaxillofac Radiol 2020 Jan 23;49(1):20190183. Epub 2019 Sep 23.

Central Interdisciplinary Ambulance in the School of Dentistry, University Hospital Muenster, Germany.

Objectives: To investigate the potential of 9.4T ultrashort echo time (UTE) technology visualizing tooth anatomy and root canal treatment . In particular, it was evaluated whether the currently achievable resolution is suited presenting all anatomical structures and whether the root canal filling materials are distinguishable in UTE-MRI.

Methods: Four extracted human teeth were examined using 9.4T UTE-MRI prior endodontic treatment (native teeth), after preparation and after obturation procedure. Root canal obturation was performed using warm vertical compaction (Schilder technique) with an epoxy-resin-based sealer. A single gutta-percha cone measured by MRI served as intensity-reference. MRI results were validated with corresponding histologic sections of the teeth. In addition, all teeth were examined at the different stages with CBCT and conventional X-ray.

Results: 9.4T UTE-MRI enabled a precise visualization of root canal anatomy of all teeth at a resolution of 66 µm. After obturation, dentin, sealer and gutta-percha cones showed distinct MRI signal changes that allowed clear differentiation of the obturation materials from surrounding tooth structure. The filling materials, isthmal root canal connections and even dentin-cracks that were identified in the MR-images could be verified in histological sections.

Conclusions: 9.4T UTE-MRI is suitable for visualization of root canal anatomy, the evaluation of root canal preparation and obturation with a high spatial resolution and may provide a versatile tool for dental material research in endodontics.
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http://dx.doi.org/10.1259/dmfr.20190183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957070PMC
January 2020

Intraosseous contrast administration for emergency computed tomography: A case-control study.

PLoS One 2019 31;14(5):e0217629. Epub 2019 May 31.

Institute of Clinical Radiology, University Hospital Muenster, Muenster, Germany.

Objective: The aim of the study was to evaluate the feasibility of intraosseous (i.o.) contrast media injection (CMI) for emergency computed tomography (CT) of severe trauma and the associated image quality compared to intravenous (i.v.) CMI.

Materials And Methods: The authors retrospectively analysed objective (contrast-to-noise ratio (CNR)) and subjective (4-point Likert scale) image quality of CTs after i.o. (n = 4, mean age (y) 57.0±11.0) versus i.v. (n = 20, mean age (y) 58.8±4.4) CMI. All patients underwent a native head CT scan, a cerebral CT angiography (CTA) and CTA of the supra-aortic vasculature as well as a chest and abdominal CT scan in the venous phase; one patient with an i.o. access additionally received a CTA of the lower limbs. Electronic patient records have been reviewed to determine i.o. access related complications.

Results: Both groups were consistent in age, heart rate, scan parameters including the flow rate of the contrast agent, resulting in comparable radiation dose levels. The image noise and CNR had no significant difference between the two groups. Scoring the delineation of the main vessels after i.o. CMI showed no significant difference to the i.v. group. There were no CT or i.o. access related complications observed.

Conclusion: The i.o. access is a safe and suitable alternative for emergency CMI in CT. Using established protocols good to very good image quality can be achieved, comparable to i.v. CMI. We show for the first time, that i.o. CMI is also feasible for CTA imaging of the head and neck region as well as of pelvic and leg vessels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217629PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544258PMC
January 2020

Target-Specific Imaging of Cathepsin and S100A8/A9 Reflects Specific Features of Malignancy and Enables Estimation of Tumor Malignancy.

Mol Imaging Biol 2020 02;22(1):66-72

Translational Research Imaging Center, Institute of Clinical Radiology, Medical Faculty, University of Muenster and University Hospital Muenster, Muenster, Germany.

Purpose: Tumor development and metastasis are dependent on tumor infiltrating immune cells which form a characteristic tumor microenvironment (TME). Activated monocytes secrete the protein heterodimer S100A8/A9 promoting TME formation. Monocyte-dependent proteases facilitate local tumor cell invasion by degradation of the extracellular matrix. We aimed for target specific in vivo imaging of S100A8 and proteases to provide differentiating biomarkers for local tumor growth and metastatic potential.

Procedures: Murine breast cancer cells of the 4T1 model with graduated metastatic potential (4T1 and 4T07: both hematogenous metastasis > 168FAR: lymph-node metastasis > 67NR: no metastasis) were orthotopically implanted into female BALB/c mice. At 4 mm size, tumors were investigated by injecting the protease-specific probe ProSense 750EX (PerkinElmer, 4T1 n = 7, 4T07 n = 10, 168FAR n = 16, 67NR n = 15) and anti-S100A8-Cy5.5 (n = 6 each) and performing fluorescence reflectance imaging at 0 and 24 h after injection. In vivo imaging was validated with immunohistochemistry.

Results: At 24 h, S100A8-specific signals in 4T1 and 4T07 were significantly higher (1714.05/1683.45 AU) as compared to 168FAR and 67NR (174.85/167.95 AU, p = 0.0012/p = 0.0003), reflecting the capability of hematogenous spread. Protease-specific signals were significantly higher in 4T1 and 4T07 (348.01/409.93 AU) as compared to 168FAR (214.91 AU) and 67NR (129.78 AU p < 0.0001 each), reflecting local vessel invasion and tumor cell shedding. Immunohistology supported the in vivo imaging results.

Conclusions: Non-invasive in vivo imaging of S100A8 and monocytic proteases allows for differentiation of the tumors' local invasive and systemic metastatic potential in reflecting the TME formation. While proteases augment local tumor cell invasion, solid metastases seem to be dependent on a pro-tumoral microenvironment.
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http://dx.doi.org/10.1007/s11307-019-01370-1DOI Listing
February 2020

Multispectral Optoacoustic Tomography of Benign and Malignant Thyroid Disorders: A Pilot Study.

J Nucl Med 2019 10 8;60(10):1461-1466. Epub 2019 Mar 8.

Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.

This study aimed at evaluating hybrid multispectral optoacoustic tomography/ultrasound for imaging of thyroid disorders, including Graves' disease and thyroid nodules. The functional biomarkers and tissue parameters deoxygenated hemoglobin, oxygenated hemoglobin, total hemoglobin, saturation of hemoglobin, fat content, and water content were analyzed in thyroid lobes affected by Graves' disease ( = 6), thyroid lobes with healthy tissue ( = 8), benign thyroid nodules ( = 13), and malignant thyroid nodules ( = 3). In Graves' disease, significantly higher deoxygenated hemoglobin (3.18 ± 0.52 vs. 2.13 ± 0.62; = 0.0055) and total hemoglobin (8.34 ± 0.88 vs. 6.59 ± 1.16; = 0.0084) and significantly lower fat content (0.64 ± 0.37 vs. 1.69 ± 1.25; = 0.0293) were found than in healthy controls. Malignant thyroid nodules showed significantly lower saturation of hemoglobin (55.4% ± 2.6% vs. 60.8% ± 7.2%; = 0.0393) and lower fat content (0.62 ± 0.19 vs. 1.46 ± 0.87; = 0.1295) than benign nodules. This pilot study showed the applicability and the potential of hybrid multispectral optoacoustic tomography/ultrasound to semiquantitatively provide tissue characterization and functional parameters in thyroid disorders for improved noninvasive diagnostics of thyroid diseases.
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http://dx.doi.org/10.2967/jnumed.118.222174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785793PMC
October 2019

Multispectral Optoacoustic Tomography: Intra- and Interobserver Variability Using a Clinical Hybrid Approach.

J Clin Med 2019 Jan 9;8(1). Epub 2019 Jan 9.

Institute of Clinical Radiology, Medical Faculty, University of Muenster, and University Hospital Muenster, 48149 Muenster, Germany.

Multispectral optoacoustic tomography (MSOT) represents a new imaging approach revealing functional tissue information without extrinsic contrast agents. Using a clinical combined ultrasound (US)/MSOT device, we investigated the interindividual robustness and impact of intra- and interobserver variability of MSOT values in soft tissue (muscle and subcutaneous fat) of healthy volunteers. Semiquantitative MSOT values for deoxygenated (Hb), oxygenated (HbO₂) and total hemoglobin (HbT), as well as oxygen saturation (sO₂), were calculated for both forearms in transversal and longitudinal probe orientation ( = 3, 8 measurements per subject). For intraobserver reproducibility, the same examiner investigated three subjects twice. Mean values of left vs. right forearm and transversal vs. longitudinal probe orientation were compared using an unpaired Student's test. Bland Altmann plots with 95% limits of agreement for absolute averages and differences were calculated. Intraclass correlation coefficients (ICC 2,k) were computed for three different examiners. We obtained reproducible and consistent MSOT values with small-to-moderate deviation for muscle and subcutaneous fat tissue. Probe orientation and body side had no impact on calculated MSOT values ( > 0.05 each). Intraobserver reproducibility revealed equable mean values with small-to-moderate deviation. For muscular tissue, good ICC was obtained for sO₂. Measurements of subcutaneous tissue revealed good-to-excellent ICCs for all calculated values. Thus, in this preliminary study on healthy individuals, clinical MSOT provided consistent and reproducible functional soft tissue characterization, independent on the investigating personnel.
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http://dx.doi.org/10.3390/jcm8010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352009PMC
January 2019

Use of Multispectral Optoacoustic Tomography to Diagnose Vascular Malformations.

JAMA Dermatol 2018 12;154(12):1457-1462

Department of Clinical Radiology, University Hospital Muenster, Muenster, Germany.

Importance: Differential diagnosis of congenital vascular anomalies is challenging, and misdiagnosis is frequent. Vascular malformations are considered one of the most difficult vascular diseases to treat. A new imaging approach that visualizes anatomical features and quantitatively assesses molecular biomarkers noninvasively would aid diagnosis and monitoring of treatment response of vascular malformations.

Objective: To evaluate multispectral optoacoustic tomography (MSOT) for noninvasive assessment of molecular biomarkers for diagnosis and therapeutic monitoring of vascular malformations.

Design, Setting, And Participants: This pilot study examined 6 patients with arteriovenous malformation (AVM) and 6 patients with venous malformation (VM) diagnosed according to the classification system of the International Society for the Study of Vascular Anomalies. All patients underwent clinical hybrid MSOT/ultrasonographic (US) imaging before and after treatment at an interdisciplinary vascular malformations clinic by trained MSOT and US examiners. Examiners were blinded to the patient history and stage of disease. Data were collected from April 11 to 25, 2017, and analyzed from May 1 to October 31, 2017.

Interventions: Clinical hybrid MSOT/US imaging was performed before or within 1 week after endovascular embolization (for AVM) or percutaneous sclerotherapy (for VM).

Main Outcomes And Measures: Region-of-interest analysis of the lesion and contralateral healthy tissue revealed quantitative values for oxygenated (HbO2) and deoxygenated (HbR) hemoglobin by spectral unmixing of optoacoustic data acquired at multiple wavelengths. The HbO2:HbR ratio was calculated for healthy tissue and for AVM and VM before and after treatment.

Results: Twelve patients (9 female and 3 male; mean [SD] age, 23 [18] years; age range, 6-59 years) with vascular malformations (6 with AVMs and 6 with VMs) were included. Significantly higher HbO2:HbR ratios for AVMs (mean [SEM], 1.82 [0.08] vs 0.89 [0.03]; P < .001) and for VMs (mean [SEM], 1.12 [0.04] vs 0.89 [0.03]; P = .001) were found on MSOT tissue compared with healthy tissue. Significantly higher HbO2:HbR ratios for AVMs compared with VMs (mean [SEM], 1.82 [0.08] vs 1.12 [0.04]; P < .001) were also found. Therefore, MSOT provided intrinsic biomarker patterns to distinguish both vascular malformations. After therapy, the HbO2:HbR ratio dropped in correlation to treatment success validated by magnetic resonance imaging or angiography.

Conclusions And Relevance: This study suggests that different types of vascular malformations are clearly distinguished by MSOT-based, noninvasive assessment of hemoglobin levels in vascular malformations. The therapy effects found in this study could be instantly visualized, and this may offer a new tool for noninvasive diagnosis and monitoring of vascular malformations.
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http://dx.doi.org/10.1001/jamadermatol.2018.3269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583374PMC
December 2018

Multispectral optoacoustic tomography of systemic sclerosis.

J Biophotonics 2018 11 18;11(11):e201800155. Epub 2018 Jul 18.

Department of Clinical Radiology, University Hospital Muenster, Münster, Germany.

The study aimed to evaluate the clinical feasibility of hybrid ultrasound/multispectral optoacoustic tomography (MSOT) for assessing microvascular dysfunction in systemic sclerosis (SSc). A handheld US/MSOT imaging system was applied for imaging patients diagnosed with SSc (n = 7) and healthy volunteers (n = 8). Semiquantitative MSOT values for deoxygenated (HbR), oxygenated (HbO ) and total haemoglobin (HbT) were analysed for subcutaneous finger tissue of both hands (8 fingers per subject, 120 fingers in total) and used to assess disease activity (progressive vs stable). Grouped data were compared by one-way nested analysis of variance, Tukey post-hoc test as well as student's t test were used for statistical analysis.Subcutaneous finger tissue of patients with SSc provided significantly lower MSOT values for HbO (26.16 ± 0.71 vs 38.2 ± 1.54, P = .023) and HbT (55.92 ± 1.62 vs 72.46 ± 1.90, P = .018) compared to healthy volunteers. Patients with progressive SSc had significantly lower MSOT values compared to patients with stable disease and healthy volunteers.This pilot study shows the feasibility of MSOT imaging to resolve microvascular dysfunction in SSc as a marker of disease activity. By providing biological tissue properties not revealed by other imaging modalities, MSOT might help to grade SSc non-invasively and monitor early therapy response.
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http://dx.doi.org/10.1002/jbio.201800155DOI Listing
November 2018

Temporal window for detection of inflammatory disease using dynamic cell tracking with time-lapse MRI.

Sci Rep 2018 06 22;8(1):9563. Epub 2018 Jun 22.

Translational Research Imaging Center, Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, 48149, Muenster, Germany.

Time-lapse MRI was implemented for dynamic non-invasive cell tracking of individual slowly moving intravascular immune cells. Repetitive MRI acquisition enabled dynamic observation of iron oxide nanoparticle (ION) labelled cells. Simulations of MRI contrast indicated that only cells moving slower than 1 µm/s were detectable. Time-lapse MRI of the brain was performed after either IONs or ION-labelled monocytes were injected intravenously into naïve and experimental autoimmune encephalomyelitis (EAE) bearing mice at a presymptomatic or symptomatic stage. EAE mice showed a reduced number of slow moving, i.e. patrolling cells before and after onset of symptoms as compared to naïve controls. This observation is consistent with the notion of altered cell dynamics, i.e. higher velocities of immune cells rolling along the endothelium in the inflamed condition. Thus, time-lapse MRI enables for assessing immune cell dynamics non-invasively in deep tissue and may serve as a tool for detection or monitoring of an inflammatory response.
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http://dx.doi.org/10.1038/s41598-018-27879-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015069PMC
June 2018

Dental Imaging - A basic guide for the radiologist.

Rofo 2019 Mar 18;191(3):192-198. Epub 2018 Jun 18.

Institute of Clinical Radiology, Medical Faculty - University of Muenster - and University Hospital Muenster, Muenster, Germany.

Background:  As dental imaging accounts for approximately 40 % of all X-ray examinations in Germany, profound knowledge of this topic is essential not only for the dentist but also for the clinical radiologist. This review focuses on basic imaging findings regarding the teeth. Therefore, tooth structure, currently available imaging techniques and common findings in conserving dentistry including endodontology, periodontology, implantology and dental trauma are presented.

Methods:  Literature research on the current state of dental radiology was performed using Pubmed.

Results And Conclusion:  Currently, the most frequent imaging techniques are the orthopantomogram (OPG) and single-tooth radiograph, as well as computer tomography (CT) and cone beam CT mainly for implantology (planning or postoperative control) or trauma indications. Especially early diagnosis and correct classification of a dental trauma, such as dental pulp involvement, prevents from treatment delays or worsening of therapy options and prognosis. Furthermore, teeth are commonly a hidden focus of infection.Since radiologists are frequently confronted with dental imaging, either concerning a particular question such as a trauma patient or regarding incidental findings throughout head and neck imaging, further training in this field is more than worthwhile to facilitate an early and sufficient dental treatment.

Key Points:   · This review focuses on dental imaging techniques and the most important pathologies.. · Dental pathologies may not only be locally but also systemically relevant.. · Reporting of dental findings is important for best patient care..

Citation Format: · Masthoff M, Gerwing M, Masthoff M et al. Dental Imaging - A basic guide for the radiologist. Fortschr Röntgenstr 2019; 191: 192 - 198.
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http://dx.doi.org/10.1055/a-0636-4129DOI Listing
March 2019

Multispectral optoacoustic tomography of the human breast: characterisation of healthy tissue and malignant lesions using a hybrid ultrasound-optoacoustic approach.

Eur Radiol 2018 Feb 7;28(2):602-609. Epub 2017 Aug 7.

Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Campus 1, A16, 49149, Muenster, Germany.

Background And Aim: Multispectral optoacoustic tomography (MSOT) represents a new in vivo imaging technique with high resolution (~250 μm) and tissue penetration (>1 cm) using the photoacoustic effect. While ultrasound contains anatomical information for lesion detection, MSOT provides functional information based on intrinsic tissue chromophores. We aimed to evaluate the feasibility of combined ultrasound/MSOT imaging of breast cancer in patients compared to healthy volunteers.

Methods: Imaging was performed using a handheld MSOT system for clinical use in healthy volunteers (n = 6) and representative patients with histologically confirmed invasive breast carcinoma (n = 5) and ductal carcinoma in situ (DCIS, n = 2). MSOT values for haemoglobin and oxygen saturation were assessed at 0.5, 1.0 and 1.5 cm depth and selected wavelengths between 700 and 850 nm.

Results: Reproducible signals were obtained in all wavelengths with consistent MSOT signals in superficial tissue in breasts of healthy individuals. In contrast, we found increased signals for haemoglobin in invasive carcinoma, suggesting a higher perfusion of the tumour and tumour environment. For DCIS, MSOT values showed only little variation compared to healthy tissue.

Conclusions: This preliminary MSOT breast imaging study provided stable, reproducible data on tissue composition and physiological properties, potentially enabling differentiation of solid malignant and healthy tissue.

Key Points: • A handheld MSOT probe enables real-time molecular imaging of the breast. • MSOT of healthy controls provides a reproducible reference for pathology identification. • MSOT parameters allows for differentiation of invasive carcinoma and healthy tissue.
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http://dx.doi.org/10.1007/s00330-017-5002-xDOI Listing
February 2018

Elemental bioimaging of thulium in mouse tissues by laser ablation-ICPMS as a complementary method to heteronuclear proton magnetic resonance imaging for cell tracking experiments.

Anal Chem 2015 Apr 2;87(8):4225-30. Epub 2015 Apr 2.

†Westfälische Wilhelms-Universität Münster, Institute of Inorganic and Analytical Chemistry, Corrensstr. 30, 48149 Münster, Germany.

Due to the fact that cellular therapies are increasingly finding application in clinical trials and promise success by treatment of fatal diseases, monitoring strategies to investigate the delivery of the therapeutic cells to the target organs are getting more and more into the focus of modern in vivo imaging methods. In order to monitor the distribution of the respective cells, they can be labeled with lanthanide complexes such as thulium-1,4,7,10-tetraazacyclodoecane-α,α,α,α-tetramethyl-1,4,7,10-tetraacetic acid (Tm(DOTMA)). In this study, experiments on a mouse model with two different cell types, namely, tumor cells and macrophages labeled with Tm(DOTMA), were performed. The systemic distribution of Tm(DOTMA) of both cell types was investigated by means of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICPMS). Using the high resolution of 25 μm, distribution maps of Tm in different tissues such as tumor, liver, lung, and spleen as well as in explanted gel pellets were generated and the behavior of the labeled cells inside the tissue was investigated. Additionally, quantitative data were obtained using homemade matrix-matched standards based on egg yolk. Using this approach, limits of detection and quantification of 2.2 and 7.4 ng·g(-1), respectively, and an excellent linearity over the concentration range from 0.01 to 46 μg·g(-1) was achieved. The highest concentration of the label agent, 32.4 μg·g(-1), in tumor tissue was observed in the area of the injection of the labeled tumor cells. Regarding the second experiment with macrophages for cell tracking, Tm was detected in the explanted biogell pellet with relatively low concentrations below 60 ng·g(-1) and in the liver with a relatively high concentration of 10 μg·g(-1). Besides thulium, aluminum was detected with equal distribution behavior in the tumor section due to a contamination resulting from the labeling procedure, which includes the usage of an Al electrode.
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http://dx.doi.org/10.1021/ac504363qDOI Listing
April 2015

Highly shifted proton MR imaging: cell tracking by using direct detection of paramagnetic compounds.

Radiology 2014 Sep 18;272(3):785-95. Epub 2014 May 18.

From the Department of Clinical Radiology (R.S., K.S., M.M., C.H., U.K., C.B., C.F.) and Clinic of Dermatology-General Dermatology and Venerology (N.N., C.S.), University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany; Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, Germany (O.R., U.K.); Department of Molecular Biotechnologies and Health Sciences, University of Torino, Turin, Italy (D.D.C., S.A.); Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany (U.K., C.S., C.B., C.F.); and Bruker Biospin GmbH, Ettlingen, Germany (K.S.).

Purpose: To explore the feasibility of tracking thulium (Tm)-1,4,7,10-tetraazacyclododecane-α,α',α'',α'''-tetramethyl-1,4,7,10-tetraacetic acid (DOTMA)-labeled cells in vivo by means of highly shifted proton magnetic resonance (MR) imaging as a potential alternative to established cell-tracking methods.

Materials And Methods: All animal experiments were approved by the local ethics committee for animal experiments. Highly shifted proton MR imaging is based on the principle that the shifted resonances on Tm and dysprosium (Dy)-DOTMA can be detected separately from the tissue water signal at MR imaging with very short echo time and radial center-out readout (UTE, or "ultrashort echo time"). MR imaging of aqueous solutions and in mice in vivo was performed at 9.4 T. Human fibrosarcoma cells (HT-1080) and murine macrophages were labeled with different amounts of Tm-DOTMA. Labeled fibrosarcoma cells were injected subcutaneously into three mice. For cell tracking, labeled macrophages were administered intravenously into eight mice bearing local granulomatous inflammation. Three-dimensional UTE MR imaging was performed during 1 week. Macrophage viability and activity and fibrosarcoma cell viability were statistically analyzed by performing an unpaired two-tailed t test for labeled versus unlabeled cells by using data of at least six independent experiments.

Results: The strongly shifted MR lines of Tm- and Dy-DOTMA can be separated from the tissue water signal and from each other. A detection limit of about 25 µmol/L of Tm-DOTMA was calculated from in vitro MR measurements. A mean ± standard error of the mean intracellular uptake of (4.19 ± 0.88) × 10(9) (HT-1080) and (10.1 ± 3.0) × 10(10) (macrophages) of Tm-DOTMA molecules per cell was achieved. In vivo, Tm-DOTMA signal was detectable for 1 week in both tumors and macrophages, with a detection limit of approximately 10(4) HT-1080 and 600 macrophages. Histologic examination results and elemental bioimaging confirmed labeled cells as source of MR signal.

Conclusion: Strongly shifted proton three-dimensional UTE MR imaging of Tm-DOTMA-labeled cells is a highly specific and sensitive tool for in vivo cell tracking.
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http://dx.doi.org/10.1148/radiol.14132056DOI Listing
September 2014