@article{GuckenbergerAlexandrowFlentje2012,
  author    = {Guckenberger, Matthias and Alexandrow, Nikolaus and Flentje, Michael},
  title     = {Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75702},
  year      = {2012},
  abstract  = {Background: To analyze long-term results of radiotherapy alone for stage I-III low grade follicular lymphoma and to compare outcome after extended field irradiation (EFI) and total nodal irradiation (TNI). Methods and materials: Between 1982 and 2007, 107 patients were treated with radiotherapy alone for low grade follicular lymphoma at Ann Arbor stage I (n = 50), II (n = 36) and III (n = 21); 48 and 59 patients were treated with EFI and TNI, respectively. The median total dose in the first treatment series of the diaphragmatic side with larger lymphoma burden was 38 Gy (25 Gy - 50 Gy) and after an interval of median 30 days, a total dose of 28 Gy (12.6 Gy - 45 Gy) was given in the second treatment series completing TNI. Results: After a median follow-up of 14 years for living patients, 10-years and 15-years overall survival (OS) were 64\% and 50\%, respectively. Survival was not significantly different between stages I, II and III. TNI and EFI resulted in 15-years OS of 65\% and 34\% but patients treated with TNI were younger, had better performance status and higher stage of disease compared to patients treated with EFI. In multivariate analysis, only age at diagnosis (p<0.001, relative risk [RR] 1.06) and Karnofsky performance status (p = 0.04, RR = 0.96) were significantly correlated with OS. Freedom from progression (FFP) was 58\% and 56\% after 10-years and 15-years, respectively. Recurrences outside the irradiated volume were significantly reduced after TNI compared to EFI; however, increased rates of in-field recurrences and extra-nodal out-of-field recurrence counterbalanced this effect resulting in no significant difference in FFP between TNI and EFI. In univariate analysis, FFP was significantly improved in stage I compared to stage II but no differences were observed between stages I/II and stage III. In multivariate analysis no patient or treatment parameter was correlated with FFP. Acute toxicity was significantly increased after TNI compared to EFI with a trend to increased late toxicity as well. Conclusions: Radiotherapy alone for stage I and II follicular lymphoma resulted in long-term OS with high rates of disease control; no benefit of TNI over EFI was observed. For stage III follicular lymphoma, TNI achieved promising OS and FFP and should be considered as a potentially curative treatment option.},
  subject      = {Medizin},
  language  = {en}
}
@article{SaidPolatSteinetal.2012,
  author    = {Said, Harun M. and Polat, Buelent and Stein, Susanne and Guckenberger, Mathias and Hagemann, Carsten and Staab, Adrian and Katzer, Astrid and Anacker, Jelena and Flentje, Michael and Vordermark, Dirk},
  title     = {Inhibition of N-Myc down regulated gene 1 in in vitro cultured human glioblastoma cells},
  series = {World Journal of Clinical Oncology},
  volume    = {3},
  journal   = {World Journal of Clinical Oncology},
  number    = {7},
  doi       = {10.5306/wjco.v3.i7.104},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123385},
  pages     = {104-110},
  year      = {2012},
  abstract  = {AIM: To study short dsRNA oligonucleotides (siRNA) as a potent tool for artificially modulating gene expression of N-Myc down regulated gene 1 (NDRG1) gene induced under different physiological conditions (Normoxia and hypoxia) modulating NDRG1 transcription, mRNA stability and translation. METHODS: A cell line established from a patient with glioblastoma multiforme. Plasmid DNA for transfections was prepared with the Endofree Plasmid Maxi kit. From plates containing 5 x 10(7) cells, nuclear extracts were prepared according to previous protocols. The pSUPER-NDRG1 vectors were designed, two sequences were selected from the human NDRG1 cDNA (5'-GCATTATTGGCATGGGAAC-3' and 5'-ATGCAGAGTAACGTGGAAG-3'. reverse transcription polymerase chain reaction was performed using primers designed using published information on -actin and hypoxia-inducible factor (HIF)-1 mRNA sequences in GenBank. NDRG1 mRNA and protein level expression results under different conditions of hypoxia or reoxygenation were compared to aerobic control conditions using the Mann-Whitney U test. Reoxygenation values were also compared to the NDRG1 levels after 24 h of hypoxia (P < 0.05 was considered significant). RESULTS: siRNA- and iodoacetate (IAA)-mediated downregulation of NDRG1 mRNA and protein expression in vitro in human glioblastoma cell lines showed a nearly complete inhibition of NDRG1 expression when compared to the results obtained due to the inhibitory role of glycolysis inhibitor IAA. Hypoxia responsive elements bound by nuclear HIF-1 in human glioblastoma cells in vitro under different oxygenation conditions and the clearly enhanced binding of nuclear extracts from glioblastoma cell samples exposed to extreme hypoxic conditions confirmed the HIF-1 Western blotting results. CONCLUSION: NDRG1 represents an additional diagnostic marker for brain tumor detection, due to the role of hypoxia in regulating this gene, and it can represent a potential target for tumor treatment in human glioblastoma. The siRNA method can represent an elegant alternative to modulate the expression of the hypoxia induced NDRG1 gene and can help to monitor the development of the cancer disease treatment outcome through monitoring the expression of this gene in the patients undergoing the different therapeutic treatment alternatives available nowadays.},
  language  = {en}
}
@article{GuckenbergerHawkinsFlentjeetal.2012,
  author    = {Guckenberger, Matthias and Hawkins, Maria and Flentje, Michael and Sweeney, Reinhart A.},
  title     = {Fractionated radiosurgery for painful spinal metastases: DOSIS - a phase II trial},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75853},
  year      = {2012},
  abstract  = {Background One third of all cancer patients will develop bone metastases and the vertebral column is involved in approximately 70 \% of these patients. Conventional radiotherapy with of 1-10 fractions and total doses of 8-30 Gy is the current standard for painful vertebral metastases; however, the median pain response is short with 3-6 months and local tumor control is limited with these rather low irradiation doses. Recent advances in radiotherapy technology - intensity modulated radiotherapy for generation of highly conformal dose distributions and image-guidance for precise treatment delivery - have made dose-escalated radiosurgery of spinal metastases possible and early results of pain and local tumor control are promising. The current study will investigate efficacy and safety of radiosurgery for painful vertebral metastases and three characteristics will distinguish this study. 1) A prognostic score for overall survival will be used for selection of patients with longer life expectancy to allow for analysis of long-term efficacy and safety. 2) Fractionated radiosurgery will be performed with the number of treatment fractions adjusted to either good (10 fractions) or intermediate (5 fractions) life expectancy. Fractionation will allow inclusion of tumors immediately abutting the spinal cord due to higher biological effective doses at the tumor - spinal cord interface compared to single fraction treatment. 3) Dose intensification will be performed in the involved parts of the vertebrae only, while uninvolved parts are treated with conventional doses using the simultaneous integrated boost concept. Methods / Design It is the study hypothesis that hypo-fractionated image-guided radiosurgery significantly improves pain relief compared to historic data of conventionally fractionated radiotherapy. Primary endpoint is pain response 3 months after radiosurgery, which is defined as pain reduction of ≥2 points at the treated vertebral site on the 0 to 10 Visual Analogue Scale. 60 patients will be included into this two-centre phase II trial. Conclusions Results of this study will refine the methods of patient selection, target volume definition, treatment planning and delivery as well as quality assurance for radiosurgery. It is the intention of this study to form the basis for a future randomized controlled trial comparing conventional radiotherapy with fractionated radiosurgery for palliation of painful vertebral metastases. Trial registration ClinicalTrials.gov Identifier: NCT01594892},
  subject      = {Medizin},
  language  = {en}
}
@article{GuckenbergerRoeschBaieretal.2012,
  author    = {Guckenberger, Matthias and Roesch, Johannes and Baier, Kurt and Sweeney, Reinhart A. and Flentje, Michael},
  title     = {Dosimetric consequences of translational and rotational errors in frame-less image-guided radiosurgery},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75669},
  year      = {2012},
  abstract  = {Background: To investigate geometric and dosimetric accuracy of frame-less image-guided radiosurgery (IG-RS) for brain metastases. Methods and materials: Single fraction IG-RS was practiced in 72 patients with 98 brain metastases. Patient positioning and immobilization used either double- (n = 71) or single-layer (n = 27) thermoplastic masks. Pre-treatment set-up errors (n = 98) were evaluated with cone-beam CT (CBCT) based image-guidance (IG) and were corrected in six degrees of freedom without an action level. CBCT imaging after treatment measured intra-fractional errors (n = 64). Pre- and posttreatment errors were simulated in the treatment planning system and target coverage and dose conformity were evaluated. Three scenarios of 0 mm, 1 mm and 2 mm GTV-to-PTV (gross tumor volume, planning target volume) safety margins (SM) were simulated. Results: Errors prior to IG were 3.9 mm± 1.7 mm (3D vector) and the maximum rotational error was 1.7° ± 0.8° on average. The post-treatment 3D error was 0.9 mm± 0.6 mm. No differences between double- and single-layer masks were observed. Intra-fractional errors were significantly correlated with the total treatment time with 0.7mm±0.5mm and 1.2mm±0.7mm for treatment times ≤23 minutes and >23 minutes (p<0.01), respectively. Simulation of RS without image-guidance reduced target coverage and conformity to 75\% ± 19\% and 60\% ± 25\% of planned values. Each 3D set-up error of 1 mm decreased target coverage and dose conformity by 6\% and 10\% on average, respectively, with a large inter-patient variability. Pre-treatment correction of translations only but not rotations did not affect target coverage and conformity. Post-treatment errors reduced target coverage by >5\% in 14\% of the patients. A 1 mm safety margin fully compensated intra-fractional patient motion. Conclusions: IG-RS with online correction of translational errors achieves high geometric and dosimetric accuracy. Intra-fractional errors decrease target coverage and conformity unless compensated with appropriate safety margins.},
  subject      = {Medizin},
  language  = {en}
}
@article{KreisslHaenscheidLoehretal.2012,
  author    = {Kreissl, Michael C. and H{\"a}nscheid, Heribert and L{\"o}hr, Mario and Verburg, Frederik A. and Schiller, Markus and Lassmann, Michael and Reiners, Christoph and Samnick, Samuel S. and Buck, Andreas K. and Flentje, Michael and Sweeney, Reinhart A.},
  title     = {Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75540},
  year      = {2012},
  abstract  = {Background: External beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma. Methods: 10 patients with irresectable meningioma were treated with PRRT (177Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5-6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3-6 months. Side effects were evaluated according to CTCAE 4.0. Results: Median tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects>CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUVmax in the meningiomas was 14.2 (range: 4.3-68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUVmax (median: 37\%; range: 15\%-46\%) to a median value of 23.7 (range: 8.0-119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21\% of the initial volume. Conclusions: The combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated.},
  subject      = {Medizin},
  language  = {en}
}
@article{SweeneySeubertStarketal.2012,
  author    = {Sweeney, Reinhart A. and Seubert, Benedikt and Stark, Silke and Homann, Vanessa and M{\"u}ller, Gerd and Flentje, Michael and Guckenbeger, Matthias},
  title     = {Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75698},
  year      = {2012},
  abstract  = {Background: To analyze the accuracy and inter-observer variability of image-guidance (IG) using 3D or 4D cone-beam CT (CBCT) technology in stereotactic body radiotherapy (SBRT) for lung tumors. Materials and methods: Twenty-one consecutive patients treated with image-guided SBRT for primary and secondary lung tumors were basis for this study. A respiration correlated 4D-CT and planning contours served as reference for all IG techniques. Three IG techniques were performed independently by three radiation oncologists (ROs) and three radiotherapy technicians (RTTs). Image-guidance using respiration correlated 4D-CBCT (IG-4D) with automatic registration of the planning 4D-CT and the verification 4D-CBCT was considered gold-standard. Results were compared with two IG techniques using 3D-CBCT: 1) manual registration of the planning internal target volume (ITV) contour and the motion blurred tumor in the 3D-CBCT (IG-ITV); 2) automatic registration of the planning reference CT image and the verification 3D-CBCT (IG-3D). Image quality of 3D-CBCT and 4D-CBCT images was scored on a scale of 1-3, with 1 being best and 3 being worst quality for visual verification of the IGRT results. Results: Image quality was scored significantly worse for 3D-CBCT compared to 4D-CBCT: the worst score of 3 was given in 19 \% and 7.1 \% observations, respectively. Significant differences in target localization were observed between 4D-CBCT and 3D-CBCT based IG: compared to the reference of IG-4D, tumor positions differed by 1.9 mm± 0.9 mm (3D vector) on average using IG-ITV and by 3.6 mm± 3.2 mm using IG-3D; results of IG-ITV were significantly closer to the reference IG-4D compared to IG-3D. Differences between the 4D-CBCT and 3D-CBCT techniques increased significantly with larger motion amplitude of the tumor; analogously, differences increased with worse 3D-CBCT image quality scores. Inter-observer variability was largest in SI direction and was significantly larger in IG using 3D-CBCT compared to 4D-CBCT: 0.6 mm versus 1.5 mm (one standard deviation). Inter-observer variability was not different between the three ROs compared to the three RTTs. Conclusions: Respiration correlated 4D-CBCT improves the accuracy of image-guidance by more precise target localization in the presence of breathing induced target motion and by reduced inter-observer variability.},
  subject      = {Medizin},
  language  = {en}
}