23192
2021
eng
599–612
413
article
1
2021-03-25
--
--
Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma
A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.
Analytical and Bioanalytical Chemistry
1618-2642
10.1007/s00216-020-03031-7
urn:nbn:de:bvb:20-opus-231925
publish
Analytical and Bioanalytical Chemistry (2021) 413:599–612. https://doi.org/10.1007/s00216-020-03031-7
true
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Fatemeh Aghai
Sebastian Zimmermann
Max Kurlbaum
Pius Jung
Theo Pelzer
Hartwig Klinker
Nora Isberner
Oliver Scherf-Clavel
eng
uncontrolled
kinase inhibitors
eng
uncontrolled
therapeutic drug monitoring
eng
uncontrolled
liquid chromatography tandem mass spectrometry (LC-MS/MS
eng
uncontrolled
afatinib
eng
uncontrolled
osimertinib
Chemie und zugeordnete Wissenschaften
Medizin und Gesundheit
open_access
Medizinische Klinik und Poliklinik I
Medizinische Klinik und Poliklinik II
Institut für Pharmazie und Lebensmittelchemie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23192/216_2020_Article_3031.pdf
17542
2016
eng
77807-77814
47
7
article
1
2019-01-28
--
--
Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI
Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with \(^{18}\)F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR–PET/CT for detecting cardiac sarcoidosis in comparison to CMR.
15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUV\(_{mean}\)) and maximum standardized uptake values (SUV\(_{max}\)) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.
SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up.
In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUV\(_{mean}\) and SUV\(_{max}\) in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUV\(_{mean}\) and 2.0±0.3 and 1.7±0.3 for SUV\(_{max}\), respectively.
Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.
Oncotarget
10.18632/oncotarget.12799
urn:nbn:de:bvb:20-opus-175423
Oncotarget 2016, 7:47, 77807-77814. DOI: 10.18632/oncotarget.12799
true
true
Constantin Lapa
Theresa Reiter
Malte Kircher
Andreas Schirbel
Rudolf A. Werner
Theo Pelzer
Carmen Pizarro
Dirk Skowasch
Lena Thomas
Ulrike Schlesinger-Irsch
Daniel Thomas
Ralph A. Bundschuh
Wolfgang R. Bauer
Florian C. Gartner
eng
uncontrolled
sarcoidosis
eng
uncontrolled
PET
eng
uncontrolled
SSTR
eng
uncontrolled
somatostatin receptor
eng
uncontrolled
DOTATOC
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17542/Lapa_Oncotarget.pdf
16998
2017
eng
96732-96737
57
8
article
1
2018-10-25
--
--
Targeting CXCR4 with [\(^{68}\)Ga]Pentixafor: a suitable theranostic approach in pleural mesothelioma?
C-X-C motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using [\(^{68}\)Ga]Pentixafor in malignant pleural mesothelioma.
Six patients with pleural mesothelioma underwent [\(^{68}\)Ga]Pentixafor-PET/CT. 2′-[\(^{18}\)F]fluoro-2′-deoxy-D-glucose ([\(^{18}\)F]FDG)-PET/CT (4/6 patients) and immunohistochemistry obtained from biopsy or surgery (all) served as standards of reference. Additionally, 9 surgical mesothelioma samples were available for histological work-up.
Whereas [\(^{18}\)F]FDG-PET depicted active lesions in all patients, [\(^{68}\)Ga]Pentixafor-PET/CT recorded physiologic tracer distribution and none of the 6 patients presented [\(^{68}\)Ga]Pentixafor-positive lesions. This finding paralleled results of immunohistochemistry which also could not identify relevant CXCR4 surface expression in the samples analyzed.
In contrast to past reports, our data suggest widely absence of CXCR4 expression in pleural mesothelioma. Hence, robust cell surface expression should be confirmed prior to targeting this chemokine receptor for diagnosis and/or therapy.
Oncotarget
10.18632/oncotarget.18235
29228566
urn:nbn:de:bvb:20-opus-169989
Oncotarget, 2017, Vol. 8, No. 57, 96732-96737. DOI: 10.18632/oncotarget.18235
false
true
Constantin Lapa
Stefan Kircher
Andreas Schirbel
Andreas Rosenwald
Saskia Kropf
Theo Pelzer
Thorsten Walles
Andreas K. Buck
Wolfgang A. Weber
Hans-Juergen Wester
Ken Herrmann
Katharina Lückerath
eng
uncontrolled
PET
eng
uncontrolled
CXCR4
eng
uncontrolled
[\(^{68}\)Ga] pentixafor
eng
uncontrolled
pleural mesothelioma
eng
uncontrolled
theranostics
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Pathologisches Institut
Medizinische Klinik und Poliklinik I
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16998/010_Lapa_ONCOTARGET.pdf
17176
2018
eng
17631
8
article
1
2018-11-13
--
--
Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated \(^{18}\)F-FDG PET
In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.
Scientific Reports
10.1038/s41598-018-35986-0
urn:nbn:de:bvb:20-opus-171765
Scientific Reports 8:17631 (2018). DOI: 10.1038/s41598-018-35986-0
701983
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Rudolf A. Werner
Christoph Eissler
Nobuyuki Hayakawa
Paula Arias-Loza
Hiroshi Wakabayashi
Mehrbod S. Javadi
Xinyu Chen
Tetsuya Shinaji
Constantin Lapa
Theo Pelzer
Takahiro Higuchi
eng
uncontrolled
diabetic cardiomyopathy
eng
uncontrolled
personalized treatment
eng
uncontrolled
precision medicine
eng
uncontrolled
ZDF rats
eng
uncontrolled
ECG
eng
uncontrolled
PET
eng
uncontrolled
\(^{18}\)F-fluorodeoxyglucose
eng
uncontrolled
\(^{18}\)F-FDG
eng
uncontrolled
diabetes
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Medizinische Klinik und Poliklinik I
OpenAIRE
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/17176/Werner_Scientific_Reports.pdf
16139
2017
deu
Abstract Nr.: V119
2
56
conferenceobject
Schattauer Verlag
1
2018-05-02
--
--
Bildgebung der frühen linksventrikulären Dysfunktion mit ECG-gated F-18-FDG PET in einem Diabetes-Ratten-Modell
Einleitung: Die linksventrikuläre diastolische Dysfunktion (LVDD) ist bei Diabetikern noch vor Entwicklung einer klinisch apparenten Herzinsuffizienz eines der ersten Anzeichen einer kardialen Beteiligung. Daher soll in dieser Studie untersucht werden, ob die LVDD mit ECG-gated F-18-FDG PET in einem Diabetes-Rattenmodell dargestellt werden kann.
Methodik: Es wurden F-18-FDG PET Scans in einem Typ-2-Diabetes Rattenmodell (ZDF fa/fa, n=6) und in ZL Kontrollen (n=6) vorgenommen (Alter, jeweils 13 Wochen). Unter Hyperinsulinemic-Euglycemic Clamp-Technik wurden 37 MBq 18F-FDG über die Schwanzvene appliziert. 15-35 Minuten nach Tracergabe wurden mittels eines Kleintier-PET-Scanners sowie unter EKG-Ableitung PET Scans angefertigt (16 frames/cardiac cycle). Die linksventrikuläre Ejektionsfraktion (EF) und die Peak Füllrate (PFR) wurden mittels einer geeigneten Software (Heart Function View) gemessen, wobei die Software an die Größe des Rattenherzes angepasst wurde.
Ergebnisse: Im Alter von 13 Wochen entwickeln ZDF Diabetes-Ratten eine im Vergleich zu Kontrolltieren eine signifikante myokardiale Hypertrophie, bestätigt durch post-mortem Analyse des Herzgewichtes (994±78mg vs. 871±44mg in ZDF Diabetes-Ratten vs. ZL Kontrollen, p<0.01). ECG-gated PET zeigte eine signifikante Abnahme der LV diastolischen PFR (10.4±0.5 vs. 11.8±0.4 EDV/sec in ZDF Diabetes-Ratten vs. ZL Kontrollen, p<0.001), jedoch zeigte sich kein signifikanter Unterschied zwischen LVEF und der Herzfrequenz in den untersuchten ZDF Diabetes-Ratten und Kontrollen (LVEF: 60.0±4.5 vs. 63.7±4.1%, n.s. und HR: 305±25 vs. 323±24 bpm, n.s.).
Schlussfolgerung: Im Diabetes-Ratten-Modell kann unter Verwendung eines ECG-gated FDG-PET Protokolls die diastolische Dysfunktion als Parameter der frühen diabetischen Kardiomyopathie nachgewiesen werden.
Nuklearmedizin
http://www.nuklearmedizin.de/jahrestagungen/abstr_online2017/print_abstract_pdf.php
0029-5566
10.3413/Nukmed-0880-17-02
urn:nbn:de:bvb:20-opus-161396
This article is not an exact copy of the original published article in Nuklearmedizin.
The definitive publisher-authenticated version of „Bildgebung der frühen linksventrikulären Dysfunktion mit ECG-gated F-18-FDG PET in einem Diabetes-Ratten-Modell. Nuklearmedizin 2017; 56 (Abstract Nr.: V119).“ is available online at http://www.nuklearmedizin.de/jahrestagungen/abstr_online2017/print_abstract_pdf.php
Johns Hopkins School of Medicine
701983
Nuklearmedizin 2017 (Vol. 56): Heft 2 (A41-A42). doi:10.3413/Nukmed-0880-17-02
Deutsches Urheberrecht
Rudolf Werner
Nobuyuki Hayakawa
Paula-Anah Arias-Loza
Hiroshi Wakabayashi
Tetsuya Shinaji
Constantin Lapa
Theo Pelzer
Takahiro Higuchi
deu
swd
Positronen-Emissions-Tomografie
deu
uncontrolled
Diabetes
deu
uncontrolled
diabetische Kardiomyopathie
deu
uncontrolled
Positronen-Emissions-Tomografie
deu
uncontrolled
PET
deu
uncontrolled
EKG
deu
uncontrolled
ECG
deu
uncontrolled
ECG-gated
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Medizinische Klinik und Poliklinik I
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16139/Werner_Rudolf_Diabetische Kardiomyopathie_accepted_version.pdf
15898
2018
eng
644–649
3
8
article
1
2018-03-14
--
--
Peptide receptor radionuclide therapy as a new tool in treatment-refractory sarcoidosis - initial experience in two patients
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors.
Methods:
We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT.
Results:
PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively.
Conclusion:
Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted.
Theranostics
10.7150/thno.22161
urn:nbn:de:bvb:20-opus-158983
Theranostics 2018, 8(3), 644-649. DOI: 10.7150/thno.22161
CC BY-NC: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell 4.0 International
Constantin Lapa
Malte Kircher
Heribert Hänscheid
Andreas Schirbel
Götz Ulrich Grigoleit
Erdwine Klinker
Markus Böck
Samuel Samnick
Theo Pelzer
Andreas K Buck
eng
uncontrolled
peptide receptor
eng
uncontrolled
PRRT
eng
uncontrolled
sarcoidosis
eng
uncontrolled
somatostatin receptors
eng
uncontrolled
radionuclide therapy
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II)
Institut für Klinische Transfusionsmedizin und Hämotherapie
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15898/Lapa_Theranostics.pdf
15906
2017
eng
16795
7
article
1
2018-03-16
--
--
Whitening and impaired glucose utilization of brown adipose tissue in a rat model of type 2 diabetes mellitus
Brown adipose tissue (BAT) is an attractive therapeutic target to combat diabetes and obesity due to its ability to increase glucose expenditure. In a genetic rat model (ZDF fa/fa) of type-2 diabetes and obesity, we aimed to investigate glucose utilization of BAT by \(^{18}\)F-FDG PET imaging. Male Zucker diabetic fatty (ZDF) and Male Zucker lean (ZL) control rats were studied at 13 weeks. Three weeks prior to imaging, ZDF rats were randomized into a no-restriction (ZDF-ND) and a mild calorie restriction (ZDF-CR) group. Dynamic \(^{18}\)F-FDG PET using a dedicated small animal PET system was performed under hyperinsulinemic-euglycemic clamp. \(^{18}\)F-FDG PET identified intense inter-scapular BAT glucose uptake in all ZL control rats, while no focally increased \(^{18}\)F-FDG uptake was detected in all ZDF-ND rats. Mild but significant improved BAT tracer uptake was identified after calorie restriction in diabetic rats (ZDF-CR). The weight of BAT tissue and fat deposits were significantly increased in ZDF-CR and ZDF-ND rats as compared to ZL controls, while UCP-1 and mitochondrial concentrations were significantly decreased. Whitening and severely impaired insulin-stimulated glucose uptake in BAT was confirmed in a rat model of type-2 diabetes. Additionally, calorie restriction partially restored the impaired BAT glucose uptake.
Scientific Reports
10.1038/s41598-017-17148-w
urn:nbn:de:bvb:20-opus-159066
Scientific Reports 7:16795 (2017). DOI: 10.1038/s41598-017-17148-w
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Constantin Lapa
Paula Arias-Loza
Nobuyuki Hayakawa
Hiroshi Wakabayashi
Rudolf A. Werner
Xinyu Chen
Tetsuya Shinaji
Ken Herrmann
Theo Pelzer
Takahiro Higuchi
eng
uncontrolled
molecular medicine
eng
uncontrolled
endocrinology
Krankheiten
open_access
Klinik und Poliklinik für Nuklearmedizin
Medizinische Klinik und Poliklinik I
Förderzeitraum 2017
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15906/Lapa_Scientific_Reports.pdf
13006
2013
eng
e68275
8
8
article
1
2016-03-16
--
--
Impact of Thoracic Surgery on Cardiac Morphology and Function in Small Animal Models of Heart Disease: A Cardiac MRI Study in Rats
Background
Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies.
Methods
Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition.
Results
Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5±10.6 vs. 317.0±11.3 g, n<0.05) and 8 weeks (317.0±21.1 vs. 358.7±22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19±0.30/0.83±0.13 vs. 1.85±0.22/0.70±0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31±0.36/1.21±0.31 vs. 1.14±0.20/1.07±0.17 µl left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2±57.2/260.2±33.2 vs. 805.9±84.8/310.4±48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease.
Conclusion
Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients.
PLoS ONE
10.1371/journal.pone.0068275
urn:nbn:de:bvb:20-opus-130064
PLoS ONE 8(8): e68275. doi:10.1371/journal.pone.0068275
Peter Nordbeck
Leoni Bönhof
Karl-Heinz Hiller
Sabine Voll
Paula Arias-Loza
Lea Seidlmaier
Tatjana Williams
Yu-Xiang Ye
Daniel Gensler
Theo Pelzer
Georg Ertl
Peter M. Jakob
Wolfgang R. Bauer
Oliver Ritter
eng
uncontrolled
heart rate
eng
uncontrolled
body weight
eng
uncontrolled
surgical and invasive medical procedures
eng
uncontrolled
magnetic resonance imaging
eng
uncontrolled
blood
eng
uncontrolled
vascular surgery
eng
uncontrolled
myocardial infarction
eng
uncontrolled
cardiac ventricles
Medizin und Gesundheit
open_access
Physikalisches Institut
Medizinische Klinik und Poliklinik I
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13006/093_Impact of Thoracic Surgery.pdf