TY - JOUR
A1 - Klammert, Uwe
A1 - Müller, Thomas D.
A1 - Hellmann, Tina V.
A1 - Wuerzler, Kristian K.
A1 - Kotzsch, Alexander
A1 - Schliermann, Anna
A1 - Schmitz, Werner
A1 - Kuebler, Alexander C.
A1 - Sebald, Walter
A1 - Nickel, Joachim
T1 - GDF-5 can act as a context-dependent BMP-2 antagonist
JF - BMC Biology
N2 - Background
Bone morphogenetic protein (BMP)-2 and growth and differentiation factor (GDF)-5 are two related transforming growth factor (TGF)-β family members with important functions in embryonic development and tissue homeostasis. BMP-2 is best known for its osteoinductive properties whereas GDF-5—as evident from its alternative name, cartilage derived morphogenetic protein 1—plays an important role in the formation of cartilage. In spite of these differences both factors signal by binding to the same subset of BMP receptors, raising the question how these different functionalities are generated. The largest difference in receptor binding is observed in the interaction with the type I receptor BMPR-IA. GDF-5, in contrast to BMP-2, shows preferential binding to the isoform BMPR-IB, which is abrogated by a single amino acid (A57R) substitution. The resulting variant, GDF-5 R57A, represents a “BMP-2 mimic” with respect to BMP receptor binding. In this study we thus wanted to analyze whether the two growth factors can induce distinct signals via an identically composed receptor.
Results
Unexpectedly and dependent on the cellular context, GDF-5 R57A showed clear differences in its activity compared to BMP-2. In ATDC-5 cells, both ligands induced alkaline phosphatase (ALP) expression with similar potency. But in C2C12 cells, the BMP-2 mimic GDF-5 R57A (and also wild-type GDF-5) clearly antagonized BMP-2-mediated ALP expression, despite signaling in both cell lines occurring solely via BMPR-IA. The BMP-2- antagonizing properties of GDF-5 and GDF-5 R57A could also be observed in vivo when implanting BMP-2 and either one of the two GDF-5 ligands simultaneously at heterotopic sites.
Conclusions
Although comparison of the crystal structures of the GDF-5 R57A:BMPR-IAEC- and BMP-2:BMPR-IAEC complex revealed small ligand-specific differences, these cannot account for the different signaling characteristics because the complexes seem identical in both differently reacting cell lines. We thus predict an additional component, most likely a not yet identified GDF-5-specific co-receptor, which alters the output of the signaling complexes. Hence the presence or absence of this component then switches GDF-5′s signaling capabilities to act either similar to BMP-2 or as a BMP-2 antagonist. These findings might shed new light on the role of GDF-5, e.g., in cartilage maintenance and/or limb development in that it might act as an inhibitor of signaling events initiated by other BMPs.
KW - growth and differentiation factor 5
KW - ligand-receptor complex
KW - crystal structure
KW - antagonist
Y1 - 2015
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125550
VL - 13
IS - 77
ER -
TY - JOUR
A1 - Weich, Alexander
A1 - Werner, Rudolf A.
A1 - Buck, Andreas K.
A1 - Hartrampf, Philipp E.
A1 - Serfling, Sebastian E.
A1 - Scheurlen, Michael
A1 - Wester, Hans-Jürgen
A1 - Meining, Alexander
A1 - Kircher, Stefan
A1 - Higuchi, Takahiro
A1 - Pomper, Martin G.
A1 - Rowe, Steven P.
A1 - Lapa, Constantin
A1 - Kircher, Malte
T1 - CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas
JF - Diagnostics
N2 - We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT.
KW - CXCR4
KW - NET
KW - NEC
KW - 68Ga-Pentixafor
KW - 18F-FDG
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234231
SN - 2075-4418
VL - 11
IS - 4
ER -
TY - JOUR
A1 - Harter, Philipp
A1 - Hauke, Jan
A1 - Heitz, Florian
A1 - Reuss, Alexander
A1 - Kommoss, Stefan
A1 - Marmé, Frederik
A1 - Heimbach, André
A1 - Prieske, Katharina
A1 - Richters, Lisa
A1 - Burges, Alexander
A1 - Neidhardt, Guido
A1 - de Gregorio, Nikolaus
A1 - El-Balat, Ahmed
A1 - Hilpert, Felix
A1 - Meier, Werner
A1 - Kimmig, Rainer
A1 - Kast, Karin
A1 - Sehouli, Jalid
A1 - Baumann, Klaus
A1 - Jackisch, Christian
A1 - Park-Simon, Tjoung-Won
A1 - Hanker, Lars
A1 - Kröber, Sandra
A1 - Pfisterer, Jacobus
A1 - Gevensleben, Heidrun
A1 - Schnelzer, Andreas
A1 - Dietrich, Dimo
A1 - Neunhöffer, Tanja
A1 - Krockenberger, Mathias
A1 - Brucker, Sara Y.
A1 - Nürnberg, Peter
A1 - Thiele, Holger
A1 - Altmüller, Janine
A1 - Lamla, Josefin
A1 - Elser, Gabriele
A1 - du Bois, Andreas
A1 - Hahnen, Eric
A1 - Schmutzler, Rita
T1 - Prevalence of deleterious germline variants in risk genes including \(BRCA1/2\) in consecutive ovarian cancer patients (AGO-TR-1)
JF - PLoS ONE
N2 - Background
Identification of families at risk for ovarian cancer offers the opportunity to consider prophylactic surgery thus reducing ovarian cancer mortality. So far, identification of potentially affected families in Germany was solely performed via family history and numbers of affected family members with breast or ovarian cancer. However, neither the prevalence of deleterious variants in \(BRCA1/2\) in ovarian cancer in Germany nor the reliability of family history as trigger for genetic counselling has ever been evaluated.
Methods
Prospective counseling and germline testing of consecutive patients with primary diagnosis or with platinum-sensitive relapse of an invasive epithelial ovarian cancer. Testing included 25 candidate and established risk genes. Among these 25 genes, 16 genes (\(ATM\), \(BRCA1\), \(BRCA2\), \(CDH1\), \(CHEK2\), \(MLH1\), \(MSH2\), \(MSH6\), \(NBN\), \(PMS2\), \(PTEN\), \(PALB2\), \(RAD51C\), \(RAD51D\), \(STK11\), \(TP53\)) were defined as established cancer risk genes. A positive family history was defined as at least one relative with breast cancer or ovarian cancer or breast cancer in personal history.
Results
In total, we analyzed 523 patients: 281 patients with primary diagnosis of ovarian cancer and 242 patients with relapsed disease. Median age at primary diagnosis was 58 years (range 16–93) and 406 patients (77.6%) had a high-grade serous ovarian cancer. In total, 27.9% of the patients showed at least one deleterious variant in all 25 investigated genes and 26.4% in the defined 16 risk genes. Deleterious variants were most prevalent in the \(BRCA1\) (15.5%), \(BRCA2\) (5.5%), \(RAD51C\) (2.5%) and \(PALB2\) (1.1%) genes. The prevalence of deleterious variants did not differ significantly between patients at primary diagnosis and relapse. The prevalence of deleterious variants in \(BRCA1/2\) (and in all 16 risk genes) in patients <60 years was 30.2% (33.2%) versus 10.6% (18.9%) in patients \(\geq\)60 years. Family history was positive in 43% of all patients. Patients with a positive family history had a prevalence of deleterious variants of 31.6% (36.0%) versus 11.4% (17.6%) and histologic subtype of high grade serous ovarian cancer versus other showed a prevalence of deleterious variants of 23.2% (29.1%) and 10.2% (14.8%), respectively. Testing only for \(BRCA1/2\) would miss in our series more than 5% of the patients with a deleterious variant in established risk genes.
Conclusions
26.4% of all patients harbor at least one deleterious variant in established risk genes. The threshold of 10% mutation rate which is accepted for reimbursement by health care providers in Germany was observed in all subgroups analyzed and neither age at primary diagnosis nor histo-type or family history sufficiently enough could identify a subgroup not eligible for genetic counselling and testing. Genetic testing should therefore be offered to every patient with invasive epithelial ovarian cancer and limiting testing to \(BRCA1/2\) seems to be
not sufficient.
KW - medicine
KW - Genetic causes of cancer
KW - ovarian cancer
KW - cancer risk factors
KW - histology
KW - cancer detection and diagnosis
KW - breast cancer
KW - genetic testing
KW - human genetics
Y1 - 2017
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173553
VL - 12
IS - 10
ER -
TY - JOUR
A1 - Schmidt, Uwe
A1 - Werner, Luis
A1 - Arrowsmith, Merle
A1 - Deissenberger, Andrea
A1 - Hermann, Alexander
A1 - Hofmann, Alexander
A1 - Ullrich, Stefan
A1 - Mattock, James D.
A1 - Vargas, Alfredo
A1 - Braunschweig, Holger
T1 - Trans‐selektive Dihydroborierung eines cis‐Diborens durch Insertion: Synthese eines linearen sp\(^3\)‐sp\(^2\)‐sp\(^3\)‐Triborans und anschließende Kationisierung
JF - Angewandte Chemie
N2 - Die Reaktion zwischen Aryl‐ und Amino(dihydro)boranen und Dibora[2]ferrocenophan 1 führt zur Bildung von 1,3‐trans‐Dihydrotriboranen durch formale Hydrierung und Insertion eines Borylens in die B=B Doppelbindung. Die Aryltriboran‐Derivate unterliegen einer reversiblen Photoisomerisierung zugunsten eines cis‐1,2‐μ‐H‐3‐Hydrotriborans, während eine Hydridabstraktion zu kationischen Triboranen führt, welche die ersten doppelt basenstabilisierten B\(_3\)H\(_4\)\(^+\)‐Analoga darstellen.
KW - Diboren
KW - Hydroborierung
KW - Kation
KW - Photoisomerisierung
KW - Triboran
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219713
VL - 132
IS - 1
ER -
TY - JOUR
A1 - Schmidt, Uwe
A1 - Werner, Luis
A1 - Arrowsmith, Merle
A1 - Deissenberger, Andrea
A1 - Hermann, Alexander
A1 - Hofmann, Alexander
A1 - Ullrich, Stefan
A1 - Mattock, James D.
A1 - Vargas, Alfredo
A1 - Braunschweig, Holger
T1 - trans-Selective Insertional Dihydroboration of a cis-Diborene: Synthesis of Linear sp\(^3\)-sp\(^2\)-sp\(^3\)-Triboranes and Subsequent Cationization
JF - Angewandte Chemie International Edition
N2 - The reaction of aryl‐ and amino(dihydro)boranes with dibora[2]ferrocenophane 1 leads to the formation 1,3‐trans ‐dihydrotriboranes by formal hydrogenation and insertion of a borylene unit into the B=B bond. The aryltriborane derivatives undergo reversible photoisomerization to the cis ‐1,2‐μ‐H‐3‐hydrotriboranes, while hydride abstraction affords cationic triboranes, which represent the first doubly base‐stabilized B3H4\(^+\) analogues.
KW - cations
KW - hydroboration
KW - photoisomerization
KW - triboranes
KW - diborenes
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208090
VL - 59
IS - 1
ER -
TY - JOUR
A1 - Werner, Rudolf
A1 - Solnes, Lilja
A1 - Javadi, Mehrbod
A1 - Weich, Alexander
A1 - Gorin, Michael
A1 - Pienta, Kenneth
A1 - Higuchi, Takahiro
A1 - Buck, Andreas
A1 - Pomper, Martin
A1 - Rowe, Steven
A1 - Lapa, Constantin
T1 - SSTR-RADS Version 1.0 as a Reporting System for SSTR-PET Imaging and Selection of Potential PRRT Candidates: A Proposed Standardization Framework
JF - Journal of Nuclear Medicine
N2 - Reliable standards and criteria for somatostatin receptor (SSTR) positron emission tomography (PET) are still lacking. We herein propose a structured reporting system on a 5-point scale for SSTR-PET imaging, titled SSTR-RADS version 1.0, which might serve as a standardized assessment for both diagnosis and treatment planning in neuroendocrine tumors (NET). SSTR-RADS could guide the imaging specialist in interpreting SSTR-PET scans, facilitate communication with the referring clinician so that appropriate work-up for equivocal findings is pursued, and serve as a reliable tool for patient selection for planned Peptide Receptor Radionuclide Therapy.
KW - Radionuclide Therapy
KW - Standardisierung
KW - Positronen-Emissions-Tomografie
KW - 68Ga-DOTATATE/-TOC
KW - Gastrointestinal
KW - Neuroendocrine
KW - Neuroendocrine Tumor
KW - Oncology
KW - GI
KW - PET
KW - PET/CT
KW - PRRT
KW - RADS
KW - SSTR
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161298
SN - 0161-5505
N1 - This research was originally published in JNM. Rudolf A. Werner, Lilja B. Solnes, Mehrbod Som Javadi, Alexander Weich, Michael A. Gorin, Kenneth J. Pienta, Takahiro Higuchi, Andreas K. Buck, Martin G. Pomper, Steven P. Rowe, Constantin Lapa. SSTR-RADS Version 1.0 as a Reporting System for SSTR-PET Imaging and Selection of Potential PRRT Candidates: A Proposed Standardization Framework. J. Nucl. Med. July 1, 2018, vol. 59, no. 7, 1085-1091. © SNMMI
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Weich, Alexander
A1 - Higuchi, Takahiro
A1 - Schmid, Jan S.
A1 - Schirbel, Andreas
A1 - Lassmann, Michael
A1 - Wild, Vanessa
A1 - Rudelius, Martina
A1 - Kudlich, Theodor
A1 - Herrmann, Ken
A1 - Scheurlen, Michael
A1 - Buck, Andreas K.
A1 - Kropf, Saskia
A1 - Wester, Hans-Jürgen
A1 - Lapa, Constantin
T1 - Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach
JF - Theranostics
N2 - C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors.
KW - SSTR
KW - peptide receptor radionuclide therapy
KW - neuroendocrine tumor
KW - [\(^{68}\)Ga]Pentixafor
KW - CXCR4
KW - chemokine receptor
KW - PET/CT
KW - DOTATOC
KW - PRRT
KW - Positronen-Emissions-Tomografie
Y1 - 2017
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158008
VL - 7
IS - 6
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Beykan, Seval
A1 - Higuchi, Takahiro
A1 - Lückerath, Katharina
A1 - Weich, Alexander
A1 - Scheurlen, Michael
A1 - Bluemel, Christina
A1 - Herrmann, Ken
A1 - Buck, Andreas K.
A1 - Lassmann, Michael
A1 - Lapa, Constantin
A1 - Hänscheid, Heribert
T1 - The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy
JF - Oncotarget
N2 - Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy.
KW - renal scintigraphy
KW - neuroendocrine tumor
KW - 177Lu
KW - MAG3
KW - PRRT
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177318
VL - 7
IS - 27
ER -
TY - INPR
A1 - Löffler, Mona C.
A1 - Mayer, Alexander E.
A1 - Trujillo Viera, Jonathan
A1 - Loza Valdes, Angel
A1 - El-Merahib, Rabih
A1 - Ade, Carsten P.
A1 - Karwen, Till
A1 - Schmitz, Werner
A1 - Slotta, Anja
A1 - Erk, Manuela
A1 - Janaki-Raman, Sudha
A1 - Matesanz, Nuria
A1 - Torres, Jorge L.
A1 - Marcos, Miguel
A1 - Sabio, Guadalupe
A1 - Eilers, Martin
A1 - Schulze, Almut
A1 - Sumara, Grzegorz
T1 - Protein kinase D1 deletion in adipocytes enhances energy dissipation and protects against adiposity
T2 - The EMBO Journal
N2 - Nutrient overload in combination with decreased energy dissipation promotes obesity and diabetes. Obesity results in a hormonal imbalance, which among others, activates G-protein coupled receptors utilizing diacylglycerol (DAG) as secondary messenger. Protein kinase D1 (PKD1) is a DAG effector which integrates multiple nutritional and hormonal inputs, but its physiological role in adipocytes is unknown. Here, we show that PKD1 promotes lipogenesis and suppresses mitochondrial fragmentation, biogenesis, respiration, and energy dissipation in an AMP-activated protein kinase (AMPK)-dependent manner. Moreover, mice lacking PKD1 in adipocytes are resistant to diet-induced obesity due to elevated energy expenditure. Beiging of adipocytes promotes energy expenditure and counteracts obesity. Consistently, deletion of PKD1 promotes expression of the β3-adrenergic receptor (ADRB3) in a CCAAT/enhancerbinding protein (C/EBP)-α and δ-dependent manner, which leads to the elevated expression of beige markers in adipocytes and subcutaneous adipose tissue. Finally, deletion of PKD1 in adipocytes improves insulin sensitivity and ameliorates liver steatosis. Thus, loss of PKD1 in adipocytes increases energy dissipation by several complementary mechanisms and might represent an attractive strategy to treat obesity and its related complications.
KW - AMP-activated protein kinase (AMPK)
KW - Beige adipocytes
KW - β3 adrenergic receptor (ADRB3)
KW - C/EBP
KW - Protein kinase D1 (PKD1)
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176093
ER -
TY - JOUR
A1 - Lapa, Constantin
A1 - Werner, Rudolf A.
A1 - Bluemel, Christina
A1 - Lueckerath, Katharina
A1 - Muegge, Dirk O.
A1 - Strate, Alexander
A1 - Haenscheid, Heribert
A1 - Schirbel, Andreas
A1 - Allen-Auerbach, Martin S.
A1 - Bundschuh, Ralph A.
A1 - Buck, Andreas K.
A1 - Herrmann, Ken
T1 - Prediction of clinically relevant hyperkalemia in patients treated with peptide receptor radionuclide therapy
JF - EJNMMI Research
N2 - Background
Peptide receptor radionuclide therapy (PRRT) is applied in patients with advanced neuroendocrine tumors. Co-infused amino acids (AA) should prevent nephrotoxicity. The aims of this study were to correlate the incidence of AA-induced hyperkalemia (HK) (≥5.0 mmol/l) and to identify predictors of AA-induced severe HK (>6.0).
Methods
In 38 patients, standard activity of \(^{177}Lu\)-labelled somatostatin analogs was administered. Pre-therapeutic kidney function was assessed by renal scintigraphy and laboratory tests. For kidney protection, AA was co-infused. Biochemical parameters (potassium, glomerular filtration rate, creatinine, blood urea nitrogen (BUN), sodium, phosphate, chloride, and lactate dehydrogenase (LDH)) were obtained prior to 4 and 24 h after the AA infusion. Incidence of HK (≥5.0) was correlated with pre-therapeutic kidney function and serum parameters. Formulas for the prediction of severe hyperkalemia (>6.0) were computed and prospectively validated.
Results
At 4 h, HK (≥5.0) was present in 94.7% with severe HK (>6.0) in 36.1%. Values normalized after 24 h in 84.2%. Pre-therapeutic kidney function did not correlate with the incidence of severe HK.
Increases in K+ were significantly correlated with decreases in phosphate (r = −0.444, p < 0.005) and increases in BUN (r = 0.313, p = 0.056). A baseline BUN of >28 mg/dl had a sensitivity of 84.6% and a specificity of 60.0% (AUC = 0.75) in predicting severe HK of >6.0 (phosphate, AUC = 0.37).
Computing of five standard serum parameters (potassium, BUN, sodium, phosphate, LDH) resulted in a sensitivity of 88.9% and a specificity of 79.3% for the prediction of severe HK >6.0 (accuracy = 81.6%).
Conclusions
A combination of serum parameters predicted prospectively the occurrence of relevant HK with an accuracy of 81.6% underlining its potential utility for identifying ‘high-risk’ patients prone to PRRT.
KW - amino acids
KW - kidney function
KW - hyperkalemia
KW - PRRT
KW - NET
KW - MAG3
Y1 - 2014
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124963
VL - 4
IS - 74
ER -
TY - JOUR
A1 - Duhr, Carolin D.
A1 - Kenn, Werner
A1 - Kickuth, Ralph
A1 - Kerscher, Alexander G.
A1 - Germer, Christoph-Thomas
A1 - Hahn, Dietbert
A1 - Pelz, Joerg O. W.
T1 - Optimizing of preoperative computed tomography for diagnosis in patients with peritoneal carcinomatosis
JF - World Journal of Surgical Oncology
N2 - Background and Objective
This study evaluates whether Computer Tomography is an effective procedure for preoperative staging of patients with Peritoneal Carcinomatosis.
Method
A sample of 37 patients was analyzed with contrast enhanced abdominal Computer Tomography, followed by surgical staging. All Computer Tomography scans were evaluated 3 times by 2 radiologists with one radiologist reviewing 2 times. The efficacy of Computer Tomography was evaluated using the Spearman correlation coefficient. Correlations were analyzed by abdominopelvic region to assess results of the Peritoneal Carcinomatosis Index (PCI) aggregating the 13 regions. Surgical findings were compared to radiological findings.
Results
Results indicate high correlations between the surgical and radiological Peritoneal Carcinomatosis Indices. Analyses of the intra-class correlation between the first and second reading of one radiologist suggest high intra-observer reliability. Correlations by abdominopelvic region show higher values in the upper and middle regions and relatively lower values in the lower regions and the small bowel (correlation coefficients range between 0.418 and 0.726, p < 0.010; sensitivities range between 50% and 96%; and specificities range between 62% and 100%).
Conclusion
Computer Tomography represents an effective procedure in the preoperative staging of patients with PC. However, results by abdominopelvic region show lower correlation, therefore suggest lower efficacy. These results are supported by analyses of sensitivity and accuracy by lesion size. This suggests that Computer Tomography is an effective procedure for pre-operative staging but less for determining a tumor's accurate extent.
KW - Carcinomatosis
KW - diagnosis
KW - PCI
Y1 - 2011
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138024
VL - 9
IS - 171
ER -
TY - THES
A1 - Werner, Alexander
T1 - Vergleich verschiedener Kontrastmittelkonzentrationen für die Computertomographie des Abdomens
T1 - Comparison of different iodine concentrations for multidetector row CT of the upper abdomen
N2 - Das Ziel der vorliegenden Arbeit war es, die Auswirkungen von drei unter-schiedlichen Jodkonzentrationen eines Kontrastmittels sowohl bei gleicher In-jektionsgeschwindigkeit als auch bei gleicher Jodmenge/Zeiteinheit auf den Dichteanstieg in Leber, Pankreas, Milz und Aorta bei der Mehrzeilendetektor-Spiral-CT zu untersuchen. In die prospektive Studie wurden 120 Patienten im Alter von 706 Jahren mit einer bekannten oder vermuteten Leberraumforderung aufgenommen, die sich einer triphasischen Mehrzeilendetektor-Spiral-CT-Untersuchung des Abdomens unterzogen. Als Kontrastmittel wurde das nicht-ionische Iopromid verwendet. Die Patienten wurden in sechs gleich große Gruppen eingeteilt. Die Gruppen waren wie folgt charakterisiert: Gruppe I: 150 ml (KM-Volumen), 240 mg/ml (Jodkonzentration) bei 4 ml/s (Injektionsgeschwindigkeit); Gruppe II: 120 ml, 300 mg/ml bei 4 ml/s; Gruppe III: 100 ml, 370 mg/ml bei 4 ml/s; Gruppe IV: 150 ml, 240 mg/ml bei 5 ml/s; Gruppe V: 120 ml, 300 mg/ml, 60 ml bei 6 ml/s, 60 ml bei 3 ml/s; Gruppe VI: 100 ml, 370 mg/ml bei 3,3 ml/s. Die Gesamtjodmenge war stets konstant und betrug 36 g. Der Dichteanstieg wurde in der Leber (kra-nial, Mitte, kaudal, linker Leberlappen), im Pankreas, in der Milz und in der Aorta (kranial und kaudal) in der nativen, arteriellen, portal-venösen und Paren-chymphase mit Hilfe einer ROI gemessen. Für den statistischen Vergleich der Gruppen wurden der Kruskal-Wallis-Test (Vergleich von mehr als zwei Grup-pen) und der Mann-Whitney-Test (Vergleich von zwei Gruppen) verwendet. Beim Vergleich der Gruppen, die das Kontrastmittel mit gleicher Injektionsge-schwindigkeit erhielten (Gruppe I-III), zeigte sich ein signifikant höheres En-hancement (p=0,02) des Pankreas in der arteriellen Phase bei Gabe des Kon-trastmittels mit einer Konzentration von 370 mg/ml (7420 HE) im Vergleich zur Gabe von Kontrastmitteln mit Konzentrationen von 240 mg/ml (5815 HE) und 300 mg/ml (6212 HE). Sowohl beim Vergleich der Gruppen, die das Kon-trastmittel mit gleicher Jodmenge/Zeiteinheit erhielten (Gruppe II, IV und VI) als auch beim Vergleich aller Gruppen zeigten sich keine signifikanten Grup-penunterschiede hinsichtlich des Dichteanstiegs in den untersuchten Organen. Mit Hilfe der vorliegenden Arbeit konnte auf der einen Seite gezeigt werden, dass bei konstanter Jodgesamtmenge und konstanter Injektionsgeschwindig-keit das Kontrastmittel mit der höheren Jodkonzentration das Enhancement des Pankreas in der arteriellen Phase signifikant verbessert. Auf der anderen Seite konnte gezeigt werden, dass bei konstanter Jodgesamtmenge und konstanter Jodmenge/Zeiteinheit keine signifikanten Unterschiede zwischen den Jodkon-zentrationen hinsichtlich des Enhancements von Oberbauchorganen bestehen.
N2 - The effect of different iodine concentrations at either constant injection or iodine administration rates but constant total iodine load on contrast enhancement of liver, pancreas and spleen by multidetector row CT was investigated. 120 consecutive patients (70±6 years) underwent triphasic liver CT at a 4-channel multidetector row CT using the non-ionic contrast medium iopromide. Patients were divided into six equal groups: I:150ml, 240mg/ml@4ml/s; II:120ml, 300mg/ml@4ml/s; III:97.3ml, 370mg/ml@4ml/s; IV:150ml, 240mg/ml@5ml/s; V:120ml, 300mg/ml, 60ml@6ml/s, 60ml@3ml/s; VI:97.3ml, 370mg/ml@3.3ml/s. ROIs were measured in the liver, the pancreas, and the spleen in unenhanced, arterial, portal venous, and equilibrium phase. At a constant injection rate of 4ml/s, pancreatic enhancement over baseline only in the arterial phase was significantly higher at 370mg/ml (58±15HU vs. 59±18HU vs. 74±20HU for group I-III, respectively (p<0.02)). Comparison of different iodine concentrations at constant iodine administration rate (group II, IV, VI) and of all six protocols revealed no significant differences at either phase. At a constant iodine load and constant injection rates, the high-iodinated contrast agent iopromide at 370 mg/ml improves pancreatic enhancement in the arterial phase. At constant iodine load and constant iodine administration rates, there is no significant effect of different iodine concentrations.
KW - Computertomographie
KW - Spiral-CT
KW - Abdomen
KW - Bauchspeicheldrüsentumor
KW - Lebertumor
KW - Nichtionisches Kontrastmittel
KW - Liver CT
KW - Pancreas CT
KW - contrast media
Y1 - 2007
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-24425
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Lapa, Constantin
A1 - Bluemel, Christina
A1 - Lückerath, Katharina
A1 - Schirbel, Andreas
A1 - Strate, Alexander
A1 - Buck, Andreas K.
A1 - Herrmann, Ken
T1 - Influence of the amount of co-infused amino acids on post-therapeutic potassium levels in peptide receptor radionuclide therapy
N2 - Background
Peptide receptor radionuclide therapy (PRRT) is routinely used for advanced or metastasized neuroendocrine tumours (NET). To prevent nephrotoxicity, positively charged amino acids (AA) are co-infused. The aim of this study was to correlate the risk for therapy-related hyperkalaemia with the total amount of AA infused.
Methods
Twenty-two patients undergoing PRRT with standard activities of 177Lu-DOTATATE/-TOC were monitored during two following treatment cycles with co-infusion of 75 and 50 g of AA (L-arginine and L-lysine), respectively. Mean serum levels of potassium and other parameters (glomerular filtration rate [GFR], creatinine, blood urea nitrogen [BUN], phosphate, chloride, lactate dehydrogenase) prior to, 4 h and 24 h after AA infusion were compared.
Results
Self-limiting hyperkalaemia (>5.0 mmol/l) resolving after 24 h occurred in 91% (20/22) of patients in both protocols. Potassium levels, BUN, creatinine, GFR, phosphate, chloride and LDH showed a similar range at 4 h after co-infusion of 75 or 50 g of AA, respectively (p > 0.05). Only GFR and creatinine levels at 24 h varied significantly between the two co-infusion protocols (p < 0.05).
Conclusions
Hyperkalaemia is a frequent side effect of AA infusion in PRRT. Varying the dose of co-infused amino acids did not impact on the incidence and severity of hyperkalaemia.
KW - NET
KW - PRRT
KW - Hyperkalaemia
KW - Arginine
KW - Lysine
Y1 - 2014
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110617
ER -
TY - JOUR
A1 - Mayer, Alexander E.
A1 - Löffler, Mona C.
A1 - Loza Valdés, Angel E.
A1 - Schmitz, Werner
A1 - El-Merahbi, Rabih
A1 - Trujillo-Viera, Jonathan
A1 - Erk, Manuela
A1 - Zhang, Thianzhou
A1 - Braun, Ursula
A1 - Heikenwalder, Mathias
A1 - Leitges, Michael
A1 - Schulze, Almut
A1 - Sumara, Grzegorz
T1 - The kinase PKD3 provides negative feedback on cholesterol and triglyceride synthesis by suppressing insulin signaling
JF - Science Signaling
N2 - Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.
KW - Protein kinase D3 (PKD3)
KW - cholesterol
KW - diacylglycerol (DAG)
KW - liver
KW - metabolism
Y1 - 2019
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250025
ET - accepted manuscript
ER -
TY - JOUR
A1 - Kosmala, Aleksander
A1 - Serfling, Sebastian E.
A1 - Dreher, Niklas
A1 - Lindner, Thomas
A1 - Schirbel, Andreas
A1 - Lapa, Constantin
A1 - Higuchi, Takahiro
A1 - Buck, Andreas K.
A1 - Weich, Alexander
A1 - Werner, Rudolf A.
T1 - Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography
JF - Cancers
N2 - (1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs.
KW - PET
KW - [\(^{68}\)Ga]Ga-FAPI
KW - theranostics
KW - radioligand therapy
KW - fibroblast activation protein
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275154
SN - 2072-6694
VL - 14
IS - 11
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Bundschuh, Ralph A.
A1 - Bundschuh, Lena
A1 - Javadi, Mehrbod S.
A1 - Higuchi, Takahiro
A1 - Weich, Alexander
A1 - Sheikhbahaei, Sara
A1 - Pienta, Kenneth J.
A1 - Buck, Andreas K.
A1 - Pomper, Martin G.
A1 - Gorin, Michael A.
A1 - Lapa, Constantin
A1 - Rowe, Steven P.
T1 - MI-RADS: Molecular Imaging Reporting and Data Systems – A Generalizable Framework for Targeted Radiotracers with Theranostic Implications
JF - Annals of Nuclear Medicine
N2 - Both prostate-specific membrane antigen (PSMA)- and somatostatin receptor (SSTR)-targeted positron emission tomography (PET) imaging agents for staging and restaging of prostate carcinoma or neuroendocrine tumors, respectively, are seeing rapidly expanding use. In addition to diagnostic applications, both classes of radiotracers can be used to triage patients for theranostic endoradiotherapy. While interpreting PSMA- or SSTR-targeted PET/computed tomography (CT) scans, the reader has to be aware of certain pitfalls. Adding to the complexity of the interpretation of those imaging agents, both normal biodistribution, and also false-positive and -negative findings differ between PSMA- and SSTR-targeted PET radiotracers. Herein summarized under the umbrella term molecular imaging reporting and data systems (MI-RADS), two novel RADS classifications for PSMA- and SSTR-targeted PET imaging are described (PSMA- and SSTR-RADS). Both framework systems may contribute to increase the level of a reader’s confidence and to navigate the imaging interpreter through indeterminate lesions, so that appropriate workup for equivocal findings can be pursued. Notably, PSMA- and SSTR-RADS are structured in a reciprocal fashion, i.e. if the reader is familiar with one system, the other system can readily be applied as well. In the present review we will discuss the most common pitfalls on PSMA- and SSTR-targeted PET/CT, briefly introduce PSMA- and SSTR-RADS, and define a future role of the umbrella framework MI-RADS compared to other harmonization systems.
KW - PET
KW - Positronen-Emissions-Tomografie
KW - prostate cancer
KW - neuroendocrine tumor
KW - prostate-specific membrane antigen (PSMA)
KW - somatostatin receptor (SSTR)
KW - positron emission tomography
KW - theranostics
KW - standardization
KW - RADS
KW - reporting and data systems
KW - personalized medicine
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166995
SN - 0914-7187
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Weich, Alexander
A1 - Kircher, Malte
A1 - Solnes, Lilja B.
A1 - Javadi, Mehrbod S.
A1 - Higuchi, Takahiro
A1 - Buck, Andreas K.
A1 - Pomper, Martin G.
A1 - Rowe, Steven
A1 - Lapa, Constantin
T1 - The theranostic promise for neuroendocrine tumors in the late 2010s – Where do we stand, where do we go?
JF - Theranostics
N2 - More than 25 years after the first peptide receptor radionuclide therapy (PRRT), the concept of somatostatin receptor (SSTR)-directed imaging and therapy for neuroendocrine tumors (NET) is seeing rapidly increasing use. To maximize the full potential of its theranostic promise, efforts in recent years have expanded recommendations in current guidelines and included the evaluation of novel theranostic radiotracers for imaging and treatment of NET. Moreover, the introduction of standardized reporting framework systems may harmonize PET reading, address pitfalls in interpreting SSTR-PET/CT scans and guide the treating physician in selecting PRRT candidates. Notably, the concept of PRRT has also been applied beyond oncology, e.g. for treatment of inflammatory conditions like sarcoidosis. Future perspectives may include the efficacy evaluation of PRRT compared to other common treatment options for NET, novel strategies for closer monitoring of potential side effects, the introduction of novel radiotracers with beneficial pharmacodynamic and kinetic properties or the use of supervised machine learning approaches for outcome prediction. This article reviews how the SSTR-directed theranostic concept is currently applied and also reflects on recent developments that hold promise for the future of theranostics in this context.
KW - theranostics
KW - Positronen-Emissions-Tomografie
KW - PRRT
KW - somatostatin receptor
KW - peptide receptor radionuclide therapy
KW - neuroendocrine tumor
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170264
VL - 8
IS - 22
ER -
TY - JOUR
A1 - Serfling, Sebastian E.
A1 - Lapa, Constantin
A1 - Dreher, Niklas
A1 - Hartrampf, Philipp E.
A1 - Rowe, Steven P.
A1 - Higuchi, Takahiro
A1 - Schirbel, Andreas
A1 - Weich, Alexander
A1 - Hahner, Stefanie
A1 - Fassnacht, Martin
A1 - Buck, Andreas K.
A1 - Werner, Rudolf A.
T1 - Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT
JF - Molecular Imaging and Biology
N2 - Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.
Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.
Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.
Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.
KW - CXCR4
KW - C-X-C motif chemokine receptor 4
KW - PET
KW - [68Ga]PentixaFor
KW - [177Lu]/[90Y]PentixaTher
KW - theranostics
KW - endoradiotherapy
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324622
VL - 24
IS - 4
ER -
TY - JOUR
A1 - Weich, Alexander
A1 - Higuchi, Takahiro
A1 - Bundschuh, Ralph A.
A1 - Lapa, Constantin
A1 - Serfling, Sebastian E.
A1 - Rowe, Steven P.
A1 - Pomper, Martin G.
A1 - Herrmann, Ken
A1 - Buck, Andreas K.
A1 - Derlin, Thorsten
A1 - Werner, Rudolf A.
T1 - Training on reporting and data system (RADS) for somatostatin-receptor targeted molecular imaging can reduce the test anxiety of inexperienced readers
JF - Molecular Imaging and Biology
N2 - Purpose
For somatostatin receptor (SSTR)-positron emission tomography/computed tomography (PET/CT), a standardized framework termed SSTR-reporting and data system (RADS) has been proposed. We aimed to elucidate the impact of a RADS-focused training on reader’s anxiety to report on SSTR-PET/CT, the motivational beliefs in learning such a system, whether it increases reader’s confidence, and its implementation in clinical routine.
Procedures
A 3-day training course focusing on SSTR-RADS was conducted. Self-report questionnaires were handed out prior to the course (Pre) and thereafter (Post). The impact of the training on the following categories was evaluated: (1) test anxiety to report on SSTR-PET/CT, (2) motivational beliefs, (3) increase in reader’s confidence, and (4) clinical implementation. To assess the effect size of the course, Cohen’s d was calculated (small, d = 0.20; large effect, d = 0.80).
Results
Of 22 participants, Pre and Post were returned by 21/22 (95.5%). In total, 14/21 (66.7%) were considered inexperienced (IR, < 1 year experience in reading SSTR-PET/CTs) and 7/21 (33.3%) as experienced readers (ER, > 1 year). Applying SSTR-RADS, a large decrease in anxiety to report on SSTR-PET/CT was noted for IR (d = − 0.74, P = 0.02), but not for ER (d = 0.11, P = 0.78). For the other three categories motivational beliefs, reader’s confidence, and clinical implementation, agreement rates were already high prior to the training and persisted throughout the course (P ≥ 0.21).
Conclusions
A framework-focused reader training can reduce anxiety to report on SSTR-PET/CTs, in particular for inexperienced readers. This may allow for a more widespread adoption of this system, e.g., in multicenter trials for better intra- and interindividual comparison of scan results.
KW - PET/CT
KW - neuroendocrine tumor
KW - PRRT
KW - peptide receptor radionuclide therapy
KW - reporting and data system
KW - SSTR-RADS
KW - RADS
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324645
VL - 24
IS - 4
ER -
TY - JOUR
A1 - Volland, Julian Manuel
A1 - Kaupp, Johannes
A1 - Schmitz, Werner
A1 - Wünsch, Anna Chiara
A1 - Balint, Julia
A1 - Möllmann, Marc
A1 - El-Mesery, Mohamed
A1 - Frackmann, Kyra
A1 - Peter, Leslie
A1 - Hartmann, Stefan
A1 - Kübler, Alexander Christian
A1 - Seher, Axel
T1 - Mass spectrometric metabolic fingerprinting of 2-Deoxy-D-Glucose (2-DG)-induced inhibition of glycolysis and comparative analysis of methionine restriction versus glucose restriction under perfusion culture in the murine L929 model system
JF - International Journal of Molecular Sciences
N2 - All forms of restriction, from caloric to amino acid to glucose restriction, have been established in recent years as therapeutic options for various diseases, including cancer. However, usually there is no direct comparison between the different restriction forms. Additionally, many cell culture experiments take place under static conditions. In this work, we used a closed perfusion culture in murine L929 cells over a period of 7 days to compare methionine restriction (MetR) and glucose restriction (LowCarb) in the same system and analysed the metabolome by liquid chromatography mass spectrometry (LC-MS). In addition, we analysed the inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) over a period of 72 h. 2-DG induced very fast a low-energy situation by a reduced glycolysis metabolite flow rate resulting in pyruvate, lactate, and ATP depletion. Under perfusion culture, both MetR and LowCarb were established on the metabolic level. Interestingly, over the period of 7 days, the metabolome of MetR and LowCarb showed more similarities than differences. This leads to the conclusion that the conditioned medium, in addition to the different restriction forms, substantially reprogramm the cells on the metabolic level.
KW - amino acid restriction
KW - glucose restriction
KW - mass spectrometry
KW - low carb
KW - 2-deoxy-D-glucose
KW - 2-DG
KW - methionine
KW - perfusion culture
KW - energy restriction
KW - caloric restriction
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286007
SN - 1422-0067
VL - 23
IS - 16
ER -
TY - JOUR
A1 - Schmitz, Werner
A1 - Koderer, Corinna
A1 - El-Mesery, Mohamed
A1 - Gobik, Sebastian
A1 - Sampers, Rene
A1 - Straub, Anton
A1 - Kübler, Alexander Christian
A1 - Seher, Axel
T1 - Metabolic fingerprinting of murine L929 fibroblasts as a cell-based tumour suppressor model system for methionine restriction
JF - International Journal of Molecular Sciences
N2 - Since Otto Warburg reported in 1924 that cancer cells address their increased energy requirement through a massive intake of glucose, the cellular energy level has offered a therapeutic anticancer strategy. Methionine restriction (MetR) is one of the most effective approaches for inducing low-energy metabolism (LEM) due to the central position in metabolism of this amino acid. However, no simple in vitro system for the rapid analysis of MetR is currently available, and this study establishes the murine cell line L929 as such a model system. L929 cells react rapidly and efficiently to MetR, and the analysis of more than 150 different metabolites belonging to different classes (amino acids, urea and tricarboxylic acid cycle (TCA) cycles, carbohydrates, etc.) by liquid chromatography/mass spectrometry (LC/MS) defines a metabolic fingerprint and enables the identification of specific metabolites representing normal or MetR conditions. The system facilitates the rapid and efficient testing of potential cancer therapeutic metabolic targets. To date, MS studies of MetR have been performed using organisms and yeast, and the current LC/MS analysis of the intra- and extracellular metabolites in the murine cell line L929 over a period of 5 days thus provides new insights into the effects of MetR at the cellular metabolic level.
KW - methionine restriction
KW - caloric restriction
KW - mass spectrometry
KW - LC/MS
KW - liquid chromatography/mass spectrometry
KW - metabolism
KW - L929
KW - amino acid
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259198
SN - 1422-0067
VL - 22
IS - 6
ER -
TY - JOUR
A1 - Schmitz, Werner
A1 - Ries, Elena
A1 - Koderer, Corinna
A1 - Völter, Maximilian Friedrich
A1 - Wünsch, Anna Chiara
A1 - El-Mesery, Mohamed
A1 - Frackmann, Kyra
A1 - Kübler, Alexander Christian
A1 - Linz, Christian
A1 - Seher, Axel
T1 - Cysteine restriction in murine L929 fibroblasts as an alternative strategy to methionine restriction in cancer therapy
JF - International Journal of Molecular Sciences
N2 - Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level.
KW - methionine restriction
KW - cysteine restriction
KW - mass spectrometry
KW - LC/MS
KW - cancer therapy
KW - caloric restriction
KW - homocysteine
KW - amino acid analogues
KW - cysteine synthase inhibitor
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265486
SN - 1422-0067
VL - 22
IS - 21
ER -
TY - JOUR
A1 - Schoffer, Olaf
A1 - Schülein, Stefanie
A1 - Arand, Gerlinde
A1 - Arnholdt, Hans
A1 - Baaske, Dieter
A1 - Bargou, Ralf C.
A1 - Becker, Nikolaus
A1 - Beckmann, Matthias W.
A1 - Bodack, Yves
A1 - Böhme, Beatrix
A1 - Bozkurt, Tayfun
A1 - Breitsprecher, Regine
A1 - Buchali, Andre
A1 - Burger, Elke
A1 - Burger, Ulrike
A1 - Dommisch, Klaus
A1 - Elsner, Gudrun
A1 - Fernschild, Karin
A1 - Flintzer, Ulrike
A1 - Funke, Uwe
A1 - Gerken, Michael
A1 - Göbel, Hubert
A1 - Grobe, Norbert
A1 - Gumpp, Vera
A1 - Heinzerling, Lucie
A1 - Kempfer, Lana Raffaela
A1 - Kiani, Alexander
A1 - Klinkhammer-Schalke, Monika
A1 - Klöcking, Sabine
A1 - Kreibich, Ute
A1 - Knabner, Katrin
A1 - Kuhn, Peter
A1 - Lutze, Stine
A1 - Mäder, Uwe
A1 - Maisel, Tanja
A1 - Maschke, Jan
A1 - Middeke, Martin
A1 - Neubauer, Andreas
A1 - Niedostatek, Antje
A1 - Opazo-Saez, Anabelle
A1 - Peters, Christoph
A1 - Schell, Beatrice
A1 - Schenkirsch, Gerhard
A1 - Schmalenberg, Harald
A1 - Schmidt, Peter
A1 - Schneider, Constanze
A1 - Schubotz, Birgit
A1 - Seide, Anika
A1 - Strecker, Paul
A1 - Taubenheim, Sabine
A1 - Wackes, Matthias
A1 - Weiß, Steffen
A1 - Welke, Claudia
A1 - Werner, Carmen
A1 - Wittekind, Christian
A1 - Wulff, Jörg
A1 - Zettl, Heike
A1 - Klug, Stefanie J.
T1 - Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011
JF - BMC Cancer
N2 - Background
Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients.
Methods
Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival.
Results
The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97–0.97), sex (OR 1.18, 95% CI 1.11–1.25), date of diagnosis (OR 1.05, 95% CI 1.04–1.06), ‘diagnosis during screening’ (OR 3.24, 95% CI 2.50–4.19) and place of residence (OR 1.23, 95% CI 1.16–1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8–83.9%).
Conclusions
No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.
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KW - Malignant melanoma
KW - TNM staging
KW - Survival analysis
KW - Skin cancer screening
KW - Stage distribution
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164544
VL - 16
IS - 936
ER -
TY - JOUR
A1 - Koderer, Corinna
A1 - Schmitz, Werner
A1 - Wünsch, Anna Chiara
A1 - Balint, Julia
A1 - El-Mesery, Mohamed
A1 - Volland, Julian Manuel
A1 - Hartmann, Stefan
A1 - Linz, Christian
A1 - Kübler, Alexander Christian
A1 - Seher, Axel
T1 - Low energy status under methionine restriction is essentially independent of proliferation or cell contact inhibition
JF - Cells
N2 - Nonlimited proliferation is one of the most striking features of neoplastic cells. The basis of cell division is the sufficient presence of mass (amino acids) and energy (ATP and NADH). A sophisticated intracellular network permanently measures the mass and energy levels. Thus, in vivo restrictions in the form of amino acid, protein, or caloric restrictions strongly affect absolute lifespan and age-associated diseases such as cancer. The induction of permanent low energy metabolism (LEM) is essential in this process. The murine cell line L929 responds to methionine restriction (MetR) for a short time period with LEM at the metabolic level defined by a characteristic fingerprint consisting of the molecules acetoacetate, creatine, spermidine, GSSG, UDP-glucose, pantothenate, and ATP. Here, we used mass spectrometry (LC/MS) to investigate the influence of proliferation and contact inhibition on the energy status of cells. Interestingly, the energy status was essentially independent of proliferation or contact inhibition. LC/MS analyses showed that in full medium, the cells maintain active and energetic metabolism for optional proliferation. In contrast, MetR induced LEM independently of proliferation or contact inhibition. These results are important for cell behaviour under MetR and for the optional application of restrictions in cancer therapy.
KW - methionine restriction
KW - caloric restriction
KW - mass spectrometry
KW - LC/MS
KW - liquid chromatography/mass spectrometry
KW - metabolomics
KW - L929
KW - amino acid
KW - proliferation
KW - contact inhibition
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262329
SN - 2073-4409
VL - 11
IS - 3
ER -
TY - JOUR
A1 - Werner, Rudolf A.
A1 - Derlin, Thorsten
A1 - Lapa, Constantin
A1 - Sheikbahaei, Sara
A1 - Higuchi, Takahiro
A1 - Giesel, Frederik L.
A1 - Behr, Spencer
A1 - Drzezga, Alexander
A1 - Kimura, Hiroyuki
A1 - Buck, Andreas K.
A1 - Bengel, Frank M.
A1 - Pomper, Martin G.
A1 - Gorin, Michael A.
A1 - Rowe, Steven P.
T1 - \(^{18}\)F-labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging
JF - Theranostics
N2 - Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with \(^{68}\)Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from \(^{68}\)Ga- to \(^{18}\)F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite \(^{68}\)Ge/\(^{68}\)Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, \(^{18}\)F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, \(^{18}\)F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging \(^{18}\)F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available \(^{18}\)F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.
KW - Radiofluorine
KW - prostate-specific membrane antigen
KW - prostate cancer
KW - \(^{18}\)F
KW - PSMA
KW - \(^{68}\)Ga
KW - theranostics
KW - radioligand therapy
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202559
SN - 1838-7640
VL - 10
IS - 1
ER -
TY - JOUR
A1 - Fröhlich, Matthias
A1 - Serfling, Sebastian
A1 - Higuchi, Takahiro
A1 - Pomper, Martin G.
A1 - Rowe, Steven P.
A1 - Schmalzing, Marc
A1 - Tony, Hans-Peter
A1 - Gernert, Michael
A1 - Strunz, Patrick-Pascal
A1 - Portegys, Jan
A1 - Schwaneck, Eva-Christina
A1 - Gadeholt, Ottar
A1 - Weich, Alexander
A1 - Buck, Andreas K.
A1 - Bley, Thorsten A.
A1 - Guggenberger, Konstanze V.
A1 - Werner, Rudolf A.
T1 - Whole-Body [\(^{18}\)F]FDG PET/CT Can Alter Diagnosis in Patients with Suspected Rheumatic Disease
JF - Diagnostics
N2 - The 2-deoxy-d-[\(^{18}\)F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely utilized to assess the vascular and articular inflammatory burden of patients with a suspected diagnosis of rheumatic disease. We aimed to elucidate the impact of [\(^{18}\)F]FDG PET/CT on change in initially suspected diagnosis in patients at the time of the scan. Thirty-four patients, who had undergone [\(^{18}\)F]FDG PET/CT, were enrolled and the initially suspected diagnosis prior to [18F]FDG PET/CT was compared to the final diagnosis. In addition, a semi-quantitative analysis including vessel wall-to-liver (VLR) and joint-to-liver (JLR) ratios was also conducted. Prior to [\(^{18}\)F]FDG PET/CT, 22/34 (64.7%) of patients did not have an established diagnosis, whereas in 7/34 (20.6%), polymyalgia rheumatica (PMR) was suspected, and in 5/34 (14.7%), giant cell arteritis (GCA) was suspected by the referring rheumatologists. After [\(^{18}\)F]FDG PET/CT, the diagnosis was GCA in 19/34 (55.9%), combined GCA and PMR (GCA + PMR) in 9/34 (26.5%) and PMR in the remaining 6/34 (17.6%). As such, [\(^{18}\)F]FDG PET/CT altered suspected diagnosis in 28/34 (82.4%), including in all unclear cases. VLR of patients whose final diagnosis was GCA tended to be significantly higher when compared to VLR in PMR (GCA, 1.01 ± 0.08 (95%CI, 0.95–1.1) vs. PMR, 0.92 ± 0.1 (95%CI, 0.85–0.99), p = 0.07), but not when compared to PMR + GCA (1.04 ± 0.14 (95%CI, 0.95–1.13), p = 1). JLR of individuals finally diagnosed with PMR (0.94 ± 0.16, (95%CI, 0.83–1.06)), however, was significantly increased relative to JLR in GCA (0.58 ± 0.04 (95%CI, 0.55–0.61)) and GCA + PMR (0.64 ± 0.09 (95%CI, 0.57–0.71); p < 0.0001, respectively). In individuals with a suspected diagnosis of rheumatic disease, an inflammatory-directed [\(^{18}\)F]FDG PET/CT can alter diagnosis in the majority of the cases, particularly in subjects who were referred because of diagnostic uncertainty. Semi-quantitative assessment may be helpful in establishing a final diagnosis of PMR, supporting the notion that a quantitative whole-body read-out may be useful in unclear cases.
KW - giant cell arteritis
KW - GCA
KW - [18F]FDG PET/CT
KW - vasculature
KW - inflammation
KW - polymyalgia rheumatica
KW - PMR
KW - vasculitis
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250227
SN - 2075-4418
VL - 11
IS - 11
ER -
TY - JOUR
A1 - Kuhlemann, Alexander
A1 - Beliu, Gerti
A1 - Janzen, Dieter
A1 - Petrini, Enrica Maria
A1 - Taban, Danush
A1 - Helmerich, Dominic A.
A1 - Doose, Sören
A1 - Bruno, Martina
A1 - Barberis, Andrea
A1 - Villmann, Carmen
A1 - Sauer, Markus
A1 - Werner, Christian
T1 - Genetic Code Expansion and Click-Chemistry Labeling to Visualize GABA-A Receptors by Super-Resolution Microscopy
JF - Frontiers in Synaptic Neuroscience
N2 - Fluorescence labeling of difficult to access protein sites, e.g., in confined compartments, requires small fluorescent labels that can be covalently tethered at well-defined positions with high efficiency. Here, we report site-specific labeling of the extracellular domain of γ-aminobutyric acid type A (GABA-A) receptor subunits by genetic code expansion (GCE) with unnatural amino acids (ncAA) combined with bioorthogonal click-chemistry labeling with tetrazine dyes in HEK-293-T cells and primary cultured neurons. After optimization of GABA-A receptor expression and labeling efficiency, most effective variants were selected for super-resolution microscopy and functionality testing by whole-cell patch clamp. Our results show that GCE with ncAA and bioorthogonal click labeling with small tetrazine dyes represents a versatile method for highly efficient site-specific fluorescence labeling of proteins in a crowded environment, e.g., extracellular protein domains in confined compartments such as the synaptic cleft.
KW - super-resolution microscopy (SRM)
KW - click-chemistry
KW - dSTORM
KW - GABA-A receptor
KW - genetic code expansion
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251035
SN - 1663-3563
VL - 13
ER -