// Constantin Lapa 1,* , Katharina Lückerath 1,* , Martina Rudelius 2 , Jan-Stefan Schmid 1 , Alexander Schoene 3 , Andreas Schirbel 1 , Samuel Samnick 1 , Theo Pelzer 4 , Andreas K. Buck 1 , Saskia Kropf 5 , Hans-Jürgen Wester 6 and Ken Herrmann 1,7 1 Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany 2 Institute for Pathology, University of Würzburg, Würzburg, Germany 3 Department of Internal Medicine, Caritas Hospital Bad Mergentheim, Bad Mergentheim, Germany 4 Department of Internal Medicine, University Hospital Würzburg, Würzburg, Germany 5 Scintomics GmbH, Fürstenfeldbruck, Germany 6 Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany 7 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA * These authors have contributed equally to this work Correspondence to: Constantin Lapa, email: // Keywords : small cell lung cancer, SCLC, molecular imaging, CXCR4, PET Received : January 11, 2016 Accepted : January 16, 2016 Published : January 28, 2016 Abstract Chemokine receptor 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 of small cell lung cancer (SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [ 68 Ga]Pentixafor. 10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent [ 68 Ga]Pentixafor-PET/CT. 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with [ 68 Ga]DOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference. CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on [ 18 F]FDG-PET were missed by CXCR4-PET, in the remainder [ 68 Ga]Pentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry. Non-invasive imaging of CXCR4 expression in SCLC is feasible. [ 68 Ga]Pentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide therapy.
// Constantin Lapa 1 , Stefan Kircher 2 , Andreas Schirbel 1 , Andreas Rosenwald 2 , Saskia Kropf 3 , Theo Pelzer 4 , Thorsten Walles 5 , Andreas K. Buck 1 , Wolfgang A. Weber 6 , Hans-Juergen Wester 7 , Ken Herrmann 1, 8 and Katharina Lückerath 1 1 Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany 2 Institute of Pathology, University of Würzburg, Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany 3 Scintomics GmbH, Fürstenfeldbruck, Germany 4 Department of Internal Medicine I, Division of Pulmonology, Universitätsklinikum Würzburg, Würzburg, Germany 5 Department of Thoracic Surgery, University Hospital Magdeburg, Magdeburg, Germany 6 Molecular Imaging and Therapy Service, Memorial Sloan-Kettering Cancer Center and Weill-Cornell Medical College, New York, New York, USA 7 Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany 8 Department of Nuclear Medicine, University Hospital Essen, Essen, Germany Correspondence to: Constantin Lapa, email: lapa_c@ukw.de Keywords: PET, CXCR4, [ 68 Ga] pentixafor, pleural mesothelioma, theranostics Received: March 29, 2017 Accepted: May 15, 2017 Published: May 27, 2017 ABSTRACT 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.
Estrogens attenuate cardiac hypertrophy and increase cardiac contractility via their cognate estrogen receptors (ERs) ERα and ERβ. Because female sex hormones enhance global glucose use and because myocardial function and mass are tightly linked to cardiac glucose metabolism, we tested the hypothesis that expression and activation of the ERα might be required and sufficient to maintain physiological cardiac glucose uptake in the murine heart. Cardiac glucose uptake quantified in vivo by 18F-fluorodeoxyglucose positron emission tomography was strongly impaired in ovariectomized compared with gonadal intact female C57BL/6JO mice. The selective ERα agonist 16α-LE2 and the nonselective ERα and ERβ agonist 17β-estradiol completely restored cardiac glucose uptake in ovariectomized mice. Cardiac 18F-fluorodeoxyglucose uptake was strongly decreased in female ERα knockout mice compared with wild-type littermates. Analysis of cardiac mRNA accumulation by quantitative RT-PCR revealed an upregulation of genes involved in glycolisis and tricarboxylic acid cycle by ERα treatment. In conclusion, systemic activation of ERα is sufficient, and its expression is required to maintain physiological glucose uptake in the murine heart, which is likely to contribute to known cardioprotective estrogen effects.
Abstract 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 the application in daily clinical routine has been developed and validated according to the US Food and Drug Administration and European Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples with acetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5 μm (2.1 × 50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A and methanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400 μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stable isotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min per run. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mL for 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 throughput and was successfully applied to monitor concentrations of kinase inhibitors in patients.
251 Objectives
Chemokine receptor 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 of small cell lung cancer (SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [68Ga]Pentixafor.
Methods
10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent [68Ga]Pentixafor-PET/CT. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with [68Ga]DOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference.
Results
CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on [18F]FDG-PET were missed by CXCR4PET, in the remainder [68Ga]Pentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry.
Conclusions
Non-invasive imaging of CXCR4 expression in SCLC seems feasible. [68Ga]Pentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide
therapy.
Die Sarkoidose ist eine häufige seltene Erkrankung unklarer Ursache, bei der eine Vielzahl unterschiedlicher Organe in unterschiedlichem Ausmaß betroffen sein kann 1. Das klinische Beschwerdebild, die Indikation zur medikamentösen Therapie sowie die Prognose weisen daher eine besonders hohe Variabilität auf. Dieser Beitrag fasst die korrekte Diagnosestellung, die individuelle Risikostratifizierung und die Therapie der Lungen- und Herzsarkoidose zusammen.
Experimental and population-based studies indicate that female gender and estrogens protect the cardiovascular system against aldosterone-induced injury. Understanding the function of estrogens in heart disease requires more precise information on the role of both estrogen receptor (ER) subtypes, ERα and ERβ. Therefore, we determined whether selective activation of ERα or of ERβ would confer redundant, specific, or opposing effects on cardiovascular remodeling in aldosterone salt–treated rats. The ERα agonist 16α-LE2, the ERβ agonist 8β-VE2, and the nonselective estrogen receptor agonist 17β-estradiol lowered elevated blood pressure, cardiac mass, and cardiac myocyte cross-sectional areas, as well as increased perivascular collagen accumulation and vascular osteopontin expression in ovariectomized rats receiving chronic aldosterone infusion plus a high-salt diet for 8 weeks. Uterus atrophy was prevented by 16α-LE2 and 17β-estradiol but not by 8β-VE2. Cardiac proteome analyses by 2D gel electrophoresis, mass spectrometry, and peptide sequencing identified specific subsets of proteins involved in cardiac contractility, energy metabolism, cellular stress response and extracellular matrix formation that were regulated in opposite directions by aldosterone salt treatment and by different estrogen receptor agonists. We conclude that activation of either ERα or ERβ protects the cardiovascular system against the detrimental effects of aldosterone salt treatment and confers redundant, as well as specific, effects on cardiac protein expression. Nonfeminizing ERβ agonists such as 8β-VE2 have a therapeutic potential in the treatment of hypertensive heart disease.
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