TY - JOUR A1 - Wondergem, Marielle J. A1 - Herrmann, Ken A1 - Syrbu, Sergei A1 - Zijlstra, Josée M. A1 - Hoetjes, Nikie A1 - Hoekstra, Otto S. A1 - Cillessen, Saskia A. G. M. A1 - Moesbergen, Laura M. A1 - Buck, Andreas K. A1 - Vose, Julie M. A1 - Juweid, Malik E. T1 - 18 F-fluorothymidine uptake in follicular lymphoma and error-prone DNA repair JF - EJNMMI Research N2 - 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. KW - 18-F-fluorothymidine uptake KW - positron emission tomography KW - follicular lymphoma KW - non-Hodgkin's lymphoma KW - DNA repair Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121233 VL - 4 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 - Lückerath, Katharina A1 - Lapa, Constantin A1 - Malzahn, Uwe A1 - Samnick, Samuel A1 - Einsele, Herrmann A1 - Buck, Andreas K. A1 - Herrmann, Ken A1 - Knop, Stefan T1 - 18FDG-PET/CT for prognostic stratification of patients with multiple myeloma relapse after stem cell transplantation N2 - The aim of this study was to investigate the prognostic value of 18F-fluoro-deoxyglucose positron emission tomography–computed tomography (18F-FDG-PET/CT) in 37 patients with a history of multiple myeloma (MM) and suspected or confirmed recurrence after stem cell transplantation (SCT). All patients had been heavily pre-treated. Time to progression (TTP) and overall survival (OS) were correlated to a number of different PET-derived as well as clinical parameters. Impact on patient management was assessed. Absence of FDG-avid MM foci was a positive prognostic factor for both TTP and OS (p<0.01). Presence of >10 focal lesions correlated with both TTP (p<0.01) and OS (p<0.05). Interestingly, presence of >10 lesions in the appendicular skeleton proved to have the strongest association with disease progression. Intensity of glucose uptake and presence of extramedullary disease were associated with shorter TTP (p=0.037 and p=0.049, respectively). Manifestations in soft tissue structures turned out to be a strong negative predictor for both, TTP and OS (p<0.01, respectively). PET resulted in a change of management in 30% of patients. Our data underline the prognostic value of 18F-FDG-PET/CT in MM patients also in the setting of post-SCT relapse. PET/CT has a significant impact on patient management. KW - 18FDG-PET/CT KW - Multiple myeloma KW - molecular imaging KW - FDG-PET/CT Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113107 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 - Herrmann, Ken A1 - Buck, Andreas K. A1 - Schuster, Tibor A1 - Abbrederis, Kathrin A1 - Blümel, Christina A1 - Santi, Ivan A1 - Rudelius, Martina A1 - Wester, Hans-Jürgen A1 - Peschel, Christian A1 - Schwaiger, Markus A1 - Dechow, Tobias A1 - Keller, Ulrich T1 - Week one FLT-PET response predicts complete remission to R-CHOP and survival in DLBCL JF - Oncotarget N2 - 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. KW - [18F]Fluorodeoxythymidine KW - FLT-PET KW - positron emission tomography KW - DLBCL KW - lymphoma Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120659 SN - 1949-2553 VL - 5 IS - 12 ER - TY - JOUR A1 - Graf, Nicolas A1 - Li, Zhoulei A1 - Herrmann, Ken A1 - Weh, Daniel A1 - Aichler, Michaela A1 - Slawska, Jolanta A1 - Walch, Axel A1 - Peschel, Christian A1 - Schwaiger, Markus A1 - Buck, Andreas K. A1 - Dechow, Tobias A1 - Keller, Ulrich T1 - Positron emission tomographic monitoring of dual phosphatidylinositol-3-kinase and mTOR inhibition in anaplastic large cell lymphoma JF - Oncotargets and Therapy N2 - 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. KW - mammalian target of rapamycin KW - phosphatidylinositol-3-kinase KW - lymphoma KW - early response KW - NVP-BGT226 KW - non-hodgkins-lymphoma KW - signaling pathway KW - FDG-PET KW - in-vivo KW - target KW - tumor KW - imaging proliferation KW - inhibition KW - positron emission tomography Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117915 VL - 7 ER - TY - JOUR A1 - Buder, Kristina A1 - Lapa, Constantin A1 - Kreissl, Michael C. A1 - Schirbel, Andreas A1 - Herrmann, Ken A1 - Schnack, Alexander A1 - Bröcker, Eva-Bettina A1 - Goebeler, Matthias A1 - Buck, Andreas K. A1 - Becker, Jürgen C. T1 - "Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging" N2 - 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. KW - Merkel cell carcinoma KW - Molecular imaging KW - Somatostatin receptor expression KW - Positron emission tomography Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110326 ER -