@article{WernerWeichHiguchietal.2017, author = {Werner, Rudolf A. and Weich, Alexander and Higuchi, Takahiro and Schmid, Jan S. and Schirbel, Andreas and Lassmann, Michael and Wild, Vanessa and Rudelius, Martina and Kudlich, Theodor and Herrmann, Ken and Scheurlen, Michael and Buck, Andreas K. and Kropf, Saskia and Wester, Hans-J{\"u}rgen and Lapa, Constantin}, title = {Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach}, series = {Theranostics}, volume = {7}, journal = {Theranostics}, number = {6}, doi = {10.7150/thno.18754}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158008}, pages = {1489-1498}, year = {2017}, abstract = {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.}, subject = {Positronen-Emissions-Tomografie}, language = {en} } @article{BluemelLinkeHerrmannetal.2016, author = {Bluemel, Christina and Linke, Fraenze and Herrmann, Ken and Simunovic, Iva and Eiber, Matthias and Kestler, Christian and Buck, Andreas K. and Schirbel, Andreas and Bley, Thorsten A. and Wester, Hans-Juergen and Vergho, Daniel and Becker, Axel}, title = {Impact of \(^{68}\)Ga-PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy}, series = {EJNMMI Research}, volume = {6}, journal = {EJNMMI Research}, number = {78}, doi = {10.1186/s13550-016-0233-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147798}, year = {2016}, abstract = {Background Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced \(^{68}\)Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent \(^{68}\)Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of \(^{68}\)Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity. Results Suspicious lesions were detected in 24/45 (53.3 \%) patients. In 62.5 \% of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 \%) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 \%) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 \%) within a mean follow-up of 8.12 ± 5.23 months. Conclusions \(^{68}\)Ga-PSMA PET/CT impacts treatment planning in more than 40 \% of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.}, language = {en} } @article{WernerBeykanHiguchietal.2016, author = {Werner, Rudolf A. and Beykan, Seval and Higuchi, Takahiro and L{\"u}ckerath, Katharina and Weich, Alexander and Scheurlen, Michael and Bluemel, Christina and Herrmann, Ken and Buck, Andreas K. and Lassmann, Michael and Lapa, Constantin and H{\"a}nscheid, Heribert}, title = {The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy}, series = {Oncotarget}, volume = {7}, journal = {Oncotarget}, number = {27}, doi = {10.18632/oncotarget.9775}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177318}, pages = {41233-41241}, year = {2016}, abstract = {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.}, language = {en} } @article{HerrmannBuckSchusteretal.2014, author = {Herrmann, Ken and Buck, Andreas K. and Schuster, Tibor and Abbrederis, Kathrin and Bl{\"u}mel, Christina and Santi, Ivan and Rudelius, Martina and Wester, Hans-J{\"u}rgen and Peschel, Christian and Schwaiger, Markus and Dechow, Tobias and Keller, Ulrich}, title = {Week one FLT-PET response predicts complete remission to R-CHOP and survival in DLBCL}, series = {Oncotarget}, volume = {5}, journal = {Oncotarget}, number = {12}, issn = {1949-2553}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120659}, pages = {4050-59}, year = {2014}, abstract = {Despite improved survival in the Rituximab (R) era, a considerable number of patients with diffuse large B-cell lymphoma (DLBCL) ultimately die from the disease. Functional imaging using [18F]fluorodeoxyglucose-PET is suggested for assessment of residual viable tumor very early during treatment but is compromised by non-specific tracer retention in inflammatory lesions. The PET tracer [18F]fluorodeoxythymidine (FLT) as surrogate marker of tumor proliferation may overcome this limitation. We present results of a prospective clinical study testing FLT-PET as superior and early predictor of response to chemotherapy and outcome in DLBCL. 54 patients underwent FLT-PET prior to and one week after the start of R-CHOP chemotherapy. Repetitive FLT-PET imaging was readily implemented into the diagnostic work-up. Our data demonstrate that the reduction of FLT standard uptake valuemean (SUVmean) and SUVmax one week after chemotherapy was significantly higher in patients achieving complete response (CR, n=48; non-CR, n=6; p<0.006). Martingale-residual and Cox proportional hazard analyses showed a significant monotonous decrease of mortality risk with increasing change in SUV. Consistent with these results, early FLT-PET response showed relevant discriminative ability in predicting CR. In conclusion, very early FLT-PET in the course of R-CHOP chemotherapy is feasible and enables identification of patients at risk for treatment failure.}, language = {en} } @article{WondergemHerrmannSyrbuetal.2014, author = {Wondergem, Marielle J. and Herrmann, Ken and Syrbu, Sergei and Zijlstra, Jos{\´e}e M. and Hoetjes, Nikie and Hoekstra, Otto S. and Cillessen, Saskia A. G. M. and Moesbergen, Laura M. and Buck, Andreas K. and Vose, Julie M. and Juweid, Malik E.}, title = {18 F-fluorothymidine uptake in follicular lymphoma and error-prone DNA repair}, series = {EJNMMI Research}, volume = {4}, journal = {EJNMMI Research}, doi = {10.1186/2191-219x-4-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121233}, pages = {3}, year = {2014}, abstract = {BACKGROUND: We observed a disproportional 18 F-fluorothymidine (F-FLT) uptake in follicular lymphoma (FL) relative to its low cell proliferation. We tested the hypothesis that the 'excess' uptake of 18 F-FLT in FL is related to error-prone DNA repair and investigated whether this also contributes to 18 F-FLT uptake in diffuse large B cell lymphoma (DLBCL). METHODS: We performed immunohistochemical stainings to assess the pure DNA replication marker MIB-1 as well as markers of both DNA replication and repair like PCNA, TK-1 and RPA1 on lymph node biopsies of 27 FLs and 35 DLBCLs. In 7 FL and 15 DLBCL patients, 18 F-FLT-PET had been performed. RESULTS: 18 F-FLT uptake was lower in FL than in DLBCL (median SUVmax 5.7 vs. 8.9, p = 0,004), but the ratio of 18 F-FLT-SUVmax to percentage of MIB-1 positive cells was significantly higher in FL compared with DLBCL (p = 0.001). The median percentage of MIB-1 positive cells was 10\% (range, 10\% to 20\%) in FL and 70\% (40\% to 80\%) in DLBCL. In contrast, the median percentages of PCNA, TK-1 and RPA1 positive cells were 90\% (range, 80 to 100), 90\% (80 to 100) and 100\% (80 to 100) in FL versus 90\% (60 to 100), 90\% (60 to 100) and 100\% (80 to 100) in DLBCL, respectively. CONCLUSIONS: This is the first demonstration of a striking discordance between 18 F-FLT uptake in FL and tumour cell proliferation. High expression of DNA replication and repair markers compared with the pure proliferation marker MIB-1 in FL suggests that this discordance might be due to error-prone DNA repair. While DNA repair-related 18 F-FLT uptake considerably contributes to 18 F-FLT uptake in FL, its contribution to 18 F-FLT uptake in highly proliferative DLBCL is small. This apparently high contribution of DNA repair to the 18 F-FLT signal in FL may hamper studies where 18 F-FLT is used to assess response to cytostatic therapy or to distinguish between FL and transformed lymphoma.}, language = {en} } @article{LapaWernerBluemeletal.2014, author = {Lapa, Constantin and Werner, Rudolf A. and Bluemel, Christina and Lueckerath, Katharina and Muegge, Dirk O. and Strate, Alexander and Haenscheid, Heribert and Schirbel, Andreas and Allen-Auerbach, Martin S. and Bundschuh, Ralph A. and Buck, Andreas K. and Herrmann, Ken}, title = {Prediction of clinically relevant hyperkalemia in patients treated with peptide receptor radionuclide therapy}, series = {EJNMMI Research}, volume = {4}, journal = {EJNMMI Research}, number = {74}, doi = {10.1186/s13550-014-0074-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124963}, year = {2014}, abstract = {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.}, language = {en} } @article{LapaLinsenmannLueckerathetal.2015, author = {Lapa, Constantin and Linsenmann, Thomas and L{\"u}ckerath, Katharina and Samnick, Samuel and Herrmann, Ken and Stoffer, Carolin and Ernestus, Ralf-Ingo and Buck, Andreas K. and L{\"o}hr, Mario and Monoranu, Camelia-Maria}, title = {Tumor-Associated Macrophages in Glioblastoma Multiforme—A Suitable Target for Somatostatin Receptor-Based Imaging and Therapy?}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {3}, doi = {10.1371/journal.pone.0122269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125498}, pages = {e0122269}, year = {2015}, abstract = {Background Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Tumor-associated macrophages (TAM) have been shown to promote malignant growth and to correlate with poor prognosis. [1,4,7,10-tetraazacyclododecane-NN′,N″,N′″-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) labeled with Gallium-68 selectively binds to somatostatin receptor 2A (SSTR2A) which is specifically expressed and up-regulated in activated macrophages. On the other hand, the role of SSTR2A expression on the cell surface of glioma cells has not been fully elucidated yet. The aim of this study was to non-invasively assess SSTR2A expression of both glioma cells as well as macrophages in GBM. Methods 15 samples of patient-derived GBM were stained immunohistochemically for macrophage infiltration (CD68), proliferative activity (Ki67) as well as expression of SSTR2A. Anti-CD45 staining was performed to distinguish between resident microglia and tumor-infiltrating macrophages. In a subcohort, positron emission tomography (PET) imaging using \(^{68}Ga-DOTATATE\) was performed and the semiquantitatively evaluated tracer uptake was compared to the results of immunohistochemistry. Results The amount of microglia/macrophages ranged from <10\% to >50\% in the tumor samples with the vast majority being resident microglial cells. A strong SSTR2A immunostaining was observed in endothelial cells of proliferating vessels, in neurons and neuropile. Only faint immunostaining was identified on isolated microglial and tumor cells. Somatostatin receptor imaging revealed areas of increased tracer accumulation in every patient. However, retention of the tracer did not correlate with immunohistochemical staining patterns. Conclusion SSTR2A seems not to be overexpressed in GBM samples tested, neither on the cell surface of resident microglia or infiltrating macrophages, nor on the surface of tumor cells. These data suggest that somatostatin receptor directed imaging and treatment strategies are less promising in GBM.}, language = {en} } @article{GrafLiHerrmannetal.2014, author = {Graf, Nicolas and Li, Zhoulei and Herrmann, Ken and Weh, Daniel and Aichler, Michaela and Slawska, Jolanta and Walch, Axel and Peschel, Christian and Schwaiger, Markus and Buck, Andreas K. and Dechow, Tobias and Keller, Ulrich}, title = {Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma}, series = {Oncotargets and Therapy}, volume = {7}, journal = {Oncotargets and Therapy}, doi = {10.2147/OTT.S59314}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117915}, pages = {789-798}, year = {2014}, abstract = {Background: Dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition offers an attractive therapeutic strategy in anaplastic large cell lymphoma depending on oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) signaling. We tested the efficacy of a novel dual PI3K/mTOR inhibitor, NVP-BGT226 (BGT226), in two anaplastic large cell lymphoma cell lines in vitro and in vivo and performed an early response evaluation with positron emission tomography (PET) imaging using the standard tracer, 2-deoxy-2-[F-18] fluoro-D-glucose (FDG) and the thymidine analog, 3'-deoxy-3'-[F-18] fluorothymidine (FLT). Methods: The biological effects of BGT226 were determined in vitro in the NPM-ALK positive cell lines SU-DHL-1 and Karpas299 by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, propidium iodide staining, and biochemical analysis of PI3K and mTOR downstream signaling. FDG-PET and FLT-PET were performed in immunodeficient mice bearing either SU-DHL-1 or Karpas299 xenografts at baseline and 7 days after initiation of treatment with BGT226. Lymphomas were removed for immunohistochemical analysis of proliferation and apoptosis to correlate PET findings with in vivo treatment effects. Results: SU-DHL-1 cells showed sensitivity to BGT226 in vitro, with cell cycle arrest in G0/G1 phase and an IC50 in the low nanomolar range, in contrast with Karpas299 cells, which were mainly resistant to BGT226. In vivo, both FDG-PET and FLT-PET discriminated sensitive from resistant lymphoma, as indicated by a significant reduction of tumor-to-background ratios on day 7 in treated SU-DHL-1 lymphoma-bearing animals compared with the control group, but not in animals with Karpas299 xenografts. Imaging results correlated with a marked decrease in the proliferation marker Ki67, and a slight increase in the apoptotic marker, cleaved caspase 3, as revealed by immunostaining of explanted lymphoma tissue. Conclusion: Dual PI3K/mTOR inhibition using BGT226 is effective in ALK-positive anaplastic large cell lymphoma and can be monitored with both FDG-PET and FLT-PET early on in the course of therapy.}, language = {en} } @article{BuderLapaKreissletal.2014, author = {Buder, Kristina and Lapa, Constantin and Kreissl, Michael C. and Schirbel, Andreas and Herrmann, Ken and Schnack, Alexander and Br{\"o}cker, Eva-Bettina and Goebeler, Matthias and Buck, Andreas K. and Becker, J{\"u}rgen C.}, title = {"Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging"}, doi = {10.1186/1471-2407-14-268}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110326}, year = {2014}, abstract = {Background Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. Methods To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). Results SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73\% for nodal metastases, 100\% for bone, and 67\% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17\%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13\%). Conclusion SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.}, language = {en} } @article{WernerLapaBluemeletal.2014, author = {Werner, Rudolf A. and Lapa, Constantin and Bluemel, Christina and L{\"u}ckerath, Katharina and Schirbel, Andreas and Strate, Alexander and Buck, Andreas K. and Herrmann, Ken}, title = {Influence of the amount of co-infused amino acids on post-therapeutic potassium levels in peptide receptor radionuclide therapy}, doi = {10.1186/s13550-014-0046-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110617}, year = {2014}, abstract = {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.}, language = {en} }