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- Klinik und Poliklinik für Strahlentherapie (14) (remove)
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.
Krebs ist die zweithäufigste Todesursache in Deutschland. Für die Behandlung von Tumorerkrankungen wird unter anderen die Strahlentherapie angewendet. Allerdings ist die Wirkung der Bestrahlung durch die Radiotoxizität auf normalem Gewebe sowie durch die Radioresistenz vieler Tumoren bei klinisch relevanten Dosen limitiert. Ein vielversprechendes Target für die Radiosensibilisierung von Tumorzellen scheint das Hitzeschockprotein HSP90 zu sein, ein wichtiges molekulares Chaperon, das für die Faltung, Aktivierung, Translokation und Degradation der so genannten Klientenproteine zuständig ist. Durch die pharmakologische Blockierung seiner Funktion wird die simultane Degradation multipler HSP90 Klientenproteine eingeleitet, darunter Radioresistenz-assoziierte Proteine wie RAF-1, AKT, EGFR, Survivin, DNA-Reparaturproteine. Verschiedene Studien belegen das Potential der HSP90 Inhibitoren Geldanamycin und seiner Derivaten als Radiosensibilisatoren. Im Gegensatz zu diesen Substanzen sind die neuartigen HSP90 Inhibitoren NVP-AUY922 und NVP-BEP800 wasserlöslich und nicht hepatotoxisch. Im ersten Teil der Arbeit wurde die Wirkung von NVP-AUY922 und NVP-BEP800 (200 nM, 24 h vor der Bestrahlung) auf die Strahlenempfindlichkeit humaner Tumorzelllinien unterschiedlicher Entitäten, darunter eine Lungenkarzinomzellinie A549, eine Fibrosarkomzelllinie HT1080, sowie zwei Glioblastomzelllinien GaMG und SNB19, untersucht. Die neuartigen HSP90 Inhibitoren zeigten in Kolonietest eine strahlensensibilisierende Wirkung in allen getesteten Tumorzelllinien. Weiterhin wurde mit diversen Methoden den Mechanismus der Radiosensibilisierung untersucht. Die HSP90 Inhibition erhöhte den Anteil der Zellen mit hypodiploiden DNA-Gehalt in den meisten untersuchten Tumorzelllinien. Außerdem induzierte die HSP90 Inhibition die Depletion der anti-apoptotischen Proteine AKT, pAKT und RAF-1 in allen Tumorzelllinien. Wie die erhöhte Expression von beiden Apoptosemarkern, aktivierte Caspase-3 und inaktiviertes PARP, nahe legt, wurde verstärkt die Caspase-abhängige Apoptose in den meisten untersuchten Tumorzelllinien nach HSP90 Inhibition eingeleitet. Laut Comet Assay induzierte die HSP90 Inhibition eine geringere DNA-Fragmentierung in bestrahlten Tumorzellen, gleichzeitig konnte aber eine langsamere Restitution der chromosomalen DNA festgestellt werden. Über die Messungen der γH2AX-Expression als Marker für DNA-Doppelstrangbrüche konnte eine erhöhte Induktion von DNA-Schäden nach HSP90 Inhibition und Bestrahlung sowie eine verlangsamte Reparatur der induzierten DNA-Schäden gemessen werden. Diese korrelierte mit der Depletion der DNA-Reparaturproteine KU70/KU80. Die HSP90 Inhibition führte zusätzlich zu einem ausgeprägten G2/M-Arrest, der durch die Bestrahlung verstärkt werden konnte. NVP-AUY922 induzierte außerdem eine Depletion der S-Phase. Die Depletion der Zellzyklus-regulierenden Proteine CDK1 und CDK4 sowie pRB korrelierte mit den beobachteten Zellzyklusstörungen. Die hier gewonnenen Ergebnisse verdeutlichen, dass der komplexe Mechanismus der Radiosensibilisierung nach HSP90 Inhibition die simultane Degradation diverser HSP90 Klientenproteine involviert, was verschiedene zelluläre Auswirkungen hat: verlangsamte Zellteilung durch anhaltende Zellzyklusstörungen, erhöhte DNA-Schäden und Verlangsamung der Reparatur der DNA-Schäden nach Bestrahlung sowie Apoptoseinduktion. Die HSP90 Inhibition induzierte gleichzeitig die Expression der Hitzeschockproteine HSP90 und HSP70, deren anti-apoptotischen Funktionen die radiosensibilisierenden Effekte der HSP90 Inhibitoren vermindern können. In dieser Arbeit wurden zwei Strategien getestet, um die Hochregulation von HSP90/HSP70 nach HSP90 Inhibition in den Tumorzelllinien A549 und GaMG zu unterdrücken. Zum einen wurden siRNAs gegen die stressinduzierbare α-Isoform von HSP90 angewendet, zum anderen wurde KNK437, eine Substanz die die Expression der HSP auf Transkriptionsebene unterdrückt, eingesetzt. Im zweiten Teil der Arbeit konnte gezeigt werden, dass die Transfektion mit siRNA gegen HSP90α gefolgt von NVP-AUY922 die Hochregulation von HSP90α um circa 50% unterdrückte. Allerdings wurde dadurch keine Erhöhung der NVP-AUY922-vermittelten Radiosensibilisierung erreicht. Es wurden außerdem keine signifikanten Veränderungen betreffend der Induktion und Reparatur der DNA-Schäden, Zellzyklusverteilung, Apoptoseinduktion sowie Expression der getesteten HSP90 Klientenproteine im Vergleich zu alleiniger HSP90 Inhibition festgestellt. Im dritten Teil der Arbeit konnte gezeigt werden, dass die simultane Behandlung mit NVP-AUY922 und KNK437 die NVP-AUY922-vermittelte Hochregulation von HSP90 und HSP70 in beiden Tumorzelllinien temporär unterdrückt. Obwohl die alleinige Behandlung mit KNK437 in der A549-Tumorzelllinie laut Kolonietest radiosensibilisierend wirkte, konnte die simultane Behandlung mit beiden Inhibitoren die NVP-AUY922-vermittelte Radiosensibilisierung nicht erhöhen. Obwohl die Unterdrückung der Stressantwort nach HSP90 Inhibition mittels KNK437 in beiden Tumorzelllinien einen anhaltenden G2/M-Arrest induzierte, blieb die Expression der anti-apoptotischen HSP90-Klientenproteine AKT und RAF-1 unverändert im Vergleich zu NVP-AUY922. Außerdem wurde die inhibierende Wirkung von NVP-AUY922 auf die Reparatur der strahleninduzierten DNA-Schäden nicht erhöht. Die hier gezeigten in vitro Ergebnisse unterstützen die Anwendung von NVP-AUY922 und NVP-BEP800 für in vivo Studien sowie in klinischen Studien alleine oder in Kombination mit der Bestrahlung. Unsere Arbeit ist von besonderem Interesse für die Strahlentherapie, da NVP-AUY922 bereits in klinischen Studien getestet wird.
Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information.
Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months.
Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival.
Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.
Klinische Ergebnisse und Lebensqualität nach neoadjuvanter Radiochemotherapie von Rektumkarzinomen
(2012)
Die derzeitige Standardtherapie bei fortgeschrittenen Rektumkarzinomen der UICC Stadien II und III besteht aus der neoadjuvanten Radio(chemo)therapie mit nachfolgender chirurgischer Intervention. Hierbei werden die beiden Therapiemodalitäten, der Kurzzeit-Radiotherapie(5x5Gy) und unmittelbare Operation von der Langzeit-Radiochemotherpaie (28x1,8Gy) mit einem Intervall von 4-6 Wochen bis zur Operation, unterschieden. Im Hinblick auf das Auftreten von Lokalrezidiven sowie auf das Gesamtüberleben sprechen die Ergebnisse für eine bessere Wirksamkeit der LZ-RChT. Dennoch gibt es klinische Situation, bei denen eine KZ-Radiotherapie sinnvoller sein kann. Somit kann als Konsequenz eine differenzierte Indikationsstellung für diese beiden Therapiemodalitäten abgeleitet werden.
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.
Background: Ga-[1,4,7,10-tetraazacyclododecane-N,N0,N00,N000-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors. Methods: Sixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed. Results: The mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2%) had a colocalized 68Ga-DOTATATE accumulation. Conclusions: In this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga-DOTATATE and 18F-FDG does not colocalize in a significant number of lesions.
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.
Age is one of the most salient aspects in faces and of fundamental cognitive and social relevance. Although face processing has been studied extensively, brain regions responsive to age have yet to be localized. Using evocative face morphs and fMRI, we segregate two areas extending beyond the previously established face-sensitive core network, centered on the inferior temporal sulci and angular gyri bilaterally, both of which process changes of facial age. By means of probabilistic tractography, we compare their patterns of functional activation and structural connectivity. The ventral portion of Wernicke’s understudied perpendicular association fasciculus is shown to interconnect the two areas, and activation within these clusters is related to the probability of fiber connectivity between them. In addition, post-hoc age-rating competence is found to be associated with high response magnitudes in the left angular gyrus. Our results provide the first evidence that facial age has a distinct representation pattern in the posterior human brain. We propose that particular face-sensitive nodes interact with additional object-unselective quantification modules to obtain individual estimates of facial age. This brain network processing the age of faces differs from the cortical areas that have previously been linked to less developmental but instantly changeable face aspects. Our probabilistic method of associating activations with connectivity patterns reveals an exemplary link that can be used to further study, assess and quantify structure-function relationships.
Background: Adaptive Radiotherapy aims to identify anatomical deviations during a radiotherapy course and modify the treatment plan to maintain treatment objectives. This requires regions of interest (ROIs) to be defined using the most recent imaging data. This study investigates the clinical utility of using deformable image registration (DIR) to automatically propagate ROIs.
Methods: Target (GTV) and organ-at-risk (OAR) ROIs were non-rigidly propagated from a planning CT scan to a per-treatment CT scan for 22 patients. Propagated ROIs were quantitatively compared with expert physician-drawn ROIs on the per-treatment scan using Dice scores and mean slicewise Hausdorff distances, and center of mass distances for GTVs. The propagated ROIs were qualitatively examined by experts and scored based on their clinical utility.
Results: Good agreement between the DIR-propagated ROIs and expert-drawn ROIs was observed based on the metrics used. 94% of all ROIs generated using DIR were scored as being clinically useful, requiring minimal or no edits. However, 27% (12/44) of the GTVs required major edits.
Conclusion: DIR was successfully used on 22 patients to propagate target and OAR structures for ART with good anatomical agreement for OARs. It is recommended that propagated target structures be thoroughly reviewed by the treating physician.
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.