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1.
Phys Med Biol ; 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460261

RESUMO

Motivation and objective:For each institute, the selection and calibration of the most suitable approach to assign material properties for Monte Carlo (MC) patient simulation in proton therapy is a major challenge. Current conventional approaches based on computed tomography (CT) depend on CT acquisition and reconstruction settings. This study proposes a material assignment approach, referred to as MATA (MATerialAssignment), which is independent of CT scanner properties and, therefore, universally applicable by any institute.Materials and methods:The MATA approach assigns material properties to the physical quantity stopping-power ratio (SPR) using a set of 40 material compositions specified for human tissues and linearly determined mass density. The application of clinically available CT-number-to-SPR conversion avoids the need for any further calibration. The MATA approach was validated with homogeneous and heterogeneous SPR datasets by assessing the SPR accuracy after material assignment obtained either based on dose scoring or determination of water-equivalent thickness. Finally, MATA was applied on patient datasets to evaluate dose differences induced by different approaches for material assignment and SPR prediction.Results:The deviation between the SPR after material assignment and the input SPR was close to zero in homogeneous datasets and below 0.002 (0.2% relative to water) in heterogeneous datasets, which was within the systematic uncertainty in SPR estimation. The comparison of different material assignment approaches revealed relevant differences in dose distribution and SPR. The comparison between two SPR prediction approaches, a standard look-up table and direct SPR determination from dual-energy CT, resulted in patient-specific mean proton range shifts between 1.3 mm and 4.8 mm.Conclusion:MATA eliminates the need for institution-specific adaptations of the material assignment. It allows for using any SPR dataset and thus facilitates the implementation of more accurate SPR prediction approaches. Hence, MATA provides a universal solution for patient modeling in MC-based proton treatment planning.

2.
J Am Chem Soc ; 142(16): 7647-7654, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32233470

RESUMO

Post-translational modifications of proteins are widespread in eukaryotes. To elucidate the functional role of these modifications, detection methods need to be developed that provide information at atomic resolution. Here, we report on the development of a novel Arg-specific NMR experiment that detects the methylation status and symmetry of each arginine side chain even in highly repetitive RGG amino acid sequence motifs found in numerous proteins within intrinsically disordered regions. The experiment relies on the excellent resolution of the backbone H,N correlation spectra even in these low complexity sequences. It requires 13C, 15N labeled samples.

3.
Science ; 367(6478): 643-652, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32029621

RESUMO

Homodimeric class I cytokine receptors are assumed to exist as preformed dimers that are activated by ligand-induced conformational changes. We quantified the dimerization of three prototypic class I cytokine receptors in the plasma membrane of living cells by single-molecule fluorescence microscopy. Spatial and spatiotemporal correlation of individual receptor subunits showed ligand-induced dimerization and revealed that the associated Janus kinase 2 (JAK2) dimerizes through its pseudokinase domain. Oncogenic receptor and hyperactive JAK2 mutants promoted ligand-independent dimerization, highlighting the formation of receptor dimers as the switch responsible for signal activation. Atomistic modeling and molecular dynamics simulations based on a detailed energetic analysis of the interactions involved in dimerization yielded a mechanistic blueprint for homodimeric class I cytokine receptor activation and its dysregulation by individual mutations.


Assuntos
Carcinogênese/genética , Membrana Celular/química , Janus Quinase 2/química , Janus Quinase 2/genética , Multimerização Proteica , Receptores da Eritropoetina/química , Receptores da Somatotropina/química , Receptores de Trombopoetina/química , Substituição de Aminoácidos/genética , Células HeLa , Humanos , Janus Quinase 2/antagonistas & inibidores , Ligantes , Microscopia de Fluorescência , Modelos Moleculares , Mutação , Fenilalanina/genética , Pirazóis/farmacologia , Transdução de Sinais , Imagem Individual de Molécula , Valina/genética
4.
Med Phys ; 47(4): 1796-1806, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32037543

RESUMO

BACKGROUND AND PURPOSE: Proton treatment planning relies on an accurate determination of stopping-power ratio (SPR) from x-ray computed tomography (CT). A refinement of the heuristic CT-based SPR prediction using a state-of-the-art Hounsfield look-up table (HLUT) is proposed, which incorporates patient SPR information obtained from dual-energy CT (DECT) in a retrospective patient-cohort analysis. MATERIAL AND METHODS: SPR datasets of 25 brain-tumor patients, 25 prostate-cancer patients, and three nonsmall cell lung-cancer (NSCLC) patients were calculated from clinical DECT scans with the comprehensively validated DirectSPR approach. Based on the median frequency distribution of voxelwise correlations between CT number and SPR within the irradiated volume, a piecewise linear function was specified (DirectSPR-based adapted HLUT). Differences in dose distribution and proton range were assessed for the nonadapted and adapted HLUT in comparison to the DirectSPR method, which has been shown to be an accurate and reliable SPR estimation method. RESULTS: The application of the DirectSPR-based adapted HLUT instead of the nonadapted HLUT reduced the systematic proton range differences from 1.2% (1.1 mm) to -0.1% (0.0 mm) for brain-tumor patients, 1.7% (4.1 mm) to 0.2% (0.5 mm) for prostate-cancer patients, and 2.0% (2.9 mm) to -0.1% (0.0 mm) for NSCLC patients. Due to the large intra- and inter-patient tissue variability, range differences to DirectSPR larger than 1% remained for the adapted HLUT. CONCLUSIONS: The incorporation of patient-specific correlations between CT number and SPR, derived from a retrospective application of DirectSPR to a broad patient cohort, improves the SPR accuracy of the current state-of-the-art HLUT approach. The DirectSPR-based adapted HLUT has been clinically implemented at the University Proton Therapy Dresden (Dresden, Germany) in 2017. This already facilitates the benefits of an improved DECT-based tissue differentiation within clinical routine without changing the general approach for range prediction (HLUT), and represents a further step toward full integration of the DECT-based DirectSPR method for treatment planning in proton therapy.

6.
Chembiochem ; 21(1-2): 149-156, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31161645

RESUMO

Past sequencing campaigns overlooked small proteins as they seemed to be irrelevant due to their small size. However, their occurrence is widespread, and there is growing evidence that these small proteins are in fact functionally very important in organisms found in all kingdoms of life. Within a global proteome analysis for small proteins of the archaeal model organism Haloferax volcanii, the HVO_2922 protein has been identified. It is differentially expressed in response to changes in iron and salt concentrations, thus suggesting that its expression is stress-regulated. The protein is conserved among Haloarchaea and contains an uncharacterized domain of unknown function (DUF1508, UPF0339 family protein). We elucidated the NMR solution structure, which shows that the isolated protein forms a symmetrical dimer. The dimerization is found to be concentration-dependent and essential for protein stability and most likely for its functionality, as mutagenesis at the dimer interface leads to a decrease in stability and protein aggregation.

7.
Br J Radiol ; 93(1107): 20190573, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31778315

RESUMO

OBJECTIVE: Classical robust optimization (cRO) in intensity-modulated proton therapy (IMPT) considers isocenter position and particle range uncertainties; anatomical robust optimization (aRO) aims to consider additional non-rigid positioning variations. This work compares the influence of different uncertainty sources on the robustness of cRO and aRO IMPT plans for head and neck squamous cell carcinoma (HNSCC). METHODS: Two IMPT plans were optimized for 20 HNSCC patients who received weekly control CTs (cCT): cRO, using solely the planning CT, and aRO, including 2 additional cCTs. The robustness of the plans in terms of clinical target volume (CTV) coverage and organ at risk (OAR) sparing was analyzed considering stepwise the influence of (1) non-rigid anatomical variations given by the weekly cCT, (2) with fraction-wise added rigid random setup errors and (3) additional systematic proton range uncertainties. RESULTS: cRO plans presented significantly higher nominal CTV coverage but are outperformed by aRO plans when considering non-rigid anatomical variations only, as cRO and aRO plans presented a median target coverage (D98%) decrease for the low-risk/high-risk CTV of 1.8/1.1 percentage points (pp) and -0.2 pp/-0.3 pp, respectively. Setup and range uncertainties had larger influence on cRO CTV coverage, but led to similar OAR dose changes in both plans. Considering all error sources, 10/2 cRO/aRO patients missed the CTV coverage and a limited number exceeded some OAR constraints in both plans. CONCLUSION: Non-rigid anatomical variations are mainly responsible for critical target coverage loss of cRO plans, whereas the aRO approach was robust against such variations. Both plans provide similar robustness of OAR parameters. ADVANCES IN KNOWLEDGE: The influence of different uncertainty sources was quantified for robust IMPT HNSCC plans.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Terapia com Prótons/métodos , Planejamento da Radioterapia Assistida por Computador , Radioterapia de Intensidade Modulada/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Incerteza , Humanos , Órgãos em Risco/efeitos da radiação , Posicionamento do Paciente , Lesões por Radiação/prevenção & controle , Erros de Configuração em Radioterapia , Radioterapia de Intensidade Modulada/normas , Estudos Retrospectivos
8.
Br J Radiol ; 93(1107): 20190590, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31642709

RESUMO

Pre-treatment CT imaging is a topic of growing importance in particle therapy. Improvements in the accuracy of stopping-power prediction are demanded to allow for a dose conformality that is not inferior to state-of-the-art image-guided photon therapy. Although range uncertainty has been kept practically constant over the last decades, recent technological and methodological developments, like the clinical application of dual-energy CT, have been introduced or arise at least on the horizon to improve the accuracy and precision of range prediction. This review gives an overview of the current status, summarizes the innovations in dual-energy CT and its potential impact on the field as well as potential alternative technologies for stopping-power prediction.


Assuntos
Terapia com Prótons , Radioterapia Guiada por Imagem/métodos , Tomografia Computadorizada por Raios X/métodos , Incerteza , Algoritmos , Humanos , Imagem por Ressonância Magnética , Fótons/uso terapêutico , Imagem Radiográfica a Partir de Emissão de Duplo Fóton/instrumentação , Imagem Radiográfica a Partir de Emissão de Duplo Fóton/métodos , Radioterapia Guiada por Imagem/instrumentação , Tomografia Computadorizada por Raios X/instrumentação
9.
Angew Chem Int Ed Engl ; 59(6): 2304-2308, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31730253

RESUMO

Current metabolomics approaches utilize cellular metabolite extracts, are destructive, and require high cell numbers. We introduce here an approach that enables the monitoring of cellular metabolism at lower cell numbers by observing the consumption/production of different metabolites over several kinetic data points of up to 48 hours. Our approach does not influence cellular viability, as we optimized the cellular matrix in comparison to other materials used in a variety of in-cell NMR spectroscopy experiments. We are able to monitor real-time metabolism of primary patient cells, which are extremely sensitive to external stress. Measurements are set up in an interleaved manner with short acquisition times (approximately 7 minutes per sample), which allows the monitoring of up to 15 patient samples simultaneously. Further, we implemented our approach for performing tracer-based assays. Our approach will be important not only in the metabolomics fields, but also in individualized diagnostics.

10.
Biochim Biophys Acta Bioenerg ; 1861(1): 148091, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31669489

RESUMO

F1FO ATP synthase, also known as complex V, is a key enzyme of mitochondrial energy metabolism that can synthesize and hydrolyze ATP. It is not known whether the ATP synthase and ATPase function are correlated with a different spatio-temporal organisation of the enzyme. In order to analyze this, we tracked and localized single ATP synthase molecules in situ using live cell microscopy. Under normal conditions, complex V was mainly restricted to cristae indicated by orthogonal trajectories along the cristae membranes. In addition confined trajectories that are quasi immobile exist. By inhibiting glycolysis with 2-DG, the activity and mobility of complex V was altered. The distinct cristae-related orthogonal trajectories of complex V were obliterated. Moreover, a mobile subpopulation of complex V was found in the inner boundary membrane. The observed changes in the ratio of dimeric/monomeric complex V, respectively less mobile/more mobile complex V and its activity changes were reversible. In IF1-KO cells, in which ATP hydrolysis is not inhibited by IF1, complex V was more mobile, while inhibition of ATP hydrolysis by BMS-199264 reduced the mobility of complex V. Taken together, these data support the existence of different subpopulations of complex V, ATP synthase and ATP hydrolase, the latter with higher mobility and probably not prevailing at the cristae edges. Obviously, complex V reacts quickly and reversibly to metabolic conditions, not only by functional, but also by spatial and structural reorganization.


Assuntos
Trifosfato de Adenosina/metabolismo , Mitocôndrias/enzimologia , Membranas Mitocondriais/enzimologia , Proteínas Mitocondriais/metabolismo , ATPases Mitocondriais Próton-Translocadoras/metabolismo , ATPases Translocadoras de Prótons/metabolismo , Trifosfato de Adenosina/genética , Células HeLa , Humanos , Mitocôndrias/genética , Proteínas Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , ATPases Translocadoras de Prótons/genética
11.
Front Microbiol ; 10: 2544, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824440

RESUMO

In 2006 several yeast-like fungi were isolated from apples that showed a postharvest disorder named "white haze." These strains were morphologically and molecularly assigned to the genus Tilletiopsis. Following the recent reclassification of yeasts in Ustilaginomycotina and the genus Tilletiopsis in particular, species that caused "white haze" disorder were re-identified based on the phylogenetic analysis of five DNA-loci (ITS, LSU, SSU, RPB2, and TEF1) and analysis of D1/D2 domains of the 26S/28S rRNA (LSU). Six novel species belonging to three orders in the Exobasidiomycetes, namely Entyloma belangeri (holotype: CBS 111600; ex-type: DSM 29114) MB 823155, Entyloma davenportii (holotype: CBS 111604; ex-type: DSM 100135) MB 823154, Entyloma elstari (holotype: CBS 111593; ex-type: DSM 29113) MB 823153, Entyloma randwijkense (holotype: CBS 111606; ex-type: DSM 100136) MB 823156, Jamesdicksonia mali (holotype: CBS 111625; ex-type: DSM 29121) MB 823151 and Golubevia heteromorpha (holotype: CBS 111610; ex-type: DSM 100176) MB 823152 are proposed to accommodate these strains. In addition, sequences representing phylogenetically related but yet undescribed fungi were obtained from GenBank in order to show the diversity of Tilletiopsis-like yeast states in Exobasidiomycetes.

12.
Radiother Oncol ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31767470

RESUMO

BACKGROUND AND PURPOSE: Early radiation-induced esophageal toxicity (RIET) is one of the major side effects in patients with non-small cell lung cancer (NSCLC) and can be a reason for treatment interruptions. As the age of patients with NSCLC and corresponding comorbidities continue to increase, primary radiotherapy alone is a commonly used alternative treatment in these cases. The aim of the present study is to compare dosimetric and clinical parameters from the previously reported CHARTWEL trial for their ability to predict esophagitis and investigate potential differences in the accelerated and conventional fractionation arm. MATERIAL AND METHODS: 146 patients of the Dresden cohort of the randomized phase III CHARTWEL trial were included in this post-hoc analysis. Side effects were prospectively scored weekly during the first 8 weeks from start of radiotherapy. To compare both treatment arms, recorded dose-volume parameters were adjusted for the different fractionation schedules. Logistic regression was performed to predict early RIET for the entire study group as well as for the individual treatment arms. Different dosimetric and clinical parameters were tested. RESULTS: Patients receiving the accelerated CHARTWEL schedule experienced earlier and more severe esophagitis (e.g. 20.5% vs. 9.6% ≥grade 2 at week 3, respectively). In contrast, the median time period for recovery of grade 1 esophagitis was significantly longer for patients with conventional fractionation compared to the CHARTWEL group (median [range]: 21 [12-49] days vs. 15 [7-84] days, p = 0.028). In univariable logistic regression none of the dose-volume parameters showed a significant correlation with early RIET grade ≥ 2 in the conventional irradiation group. In contrast, for patients receiving CHARTWEL, the physical dose-volumes parameters V40 and V50; and re-scaled values VEQD2,50 and VEQD2,60 were significant predictors of early RIET grade ≥ 2. Dose-volume parameters remained different between CHARTWEL and conventional fractionation even after biological rescaling. CONCLUSION: Our results show a more dominant dose-volume effect in the CHARTWEL arm compared to conventional fractionation, especially for higher esophageal doses. These findings support the notion that dose-volume parameters for radiation esophagitis determined in a specific and time dependent setting of field arrangements can not be easily transferred to another setting. In clinical practice esophageal volumes receiving 40 Gy or more should be strictly limited in hyperfractionated-accelerated fraction schemes.

13.
Chembiochem ; 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31705614

RESUMO

Proteins encoded by small open reading frames (sORFs) have a widespread occurrence in diverse microorganisms and can be of high functional importance. However, due to annotation biases and their technically challenging direct detection, these small proteins have been overlooked for a long time and were only recently rediscovered. The currently rapidly growing number of such proteins requires efficient methods to investigate their structure-function relationship. Herein, a method is presented for fast determination of the conformational properties of small proteins. Their small size makes them perfectly amenable for solution-state NMR spectroscopy. NMR spectroscopy can provide detailed information about their conformational states (folded, partially folded, and unstructured). In the context of the priority program on small proteins funded by the German research foundation (SPP2002), 27 small proteins from 9 different bacterial and archaeal organisms have been investigated. It is found that most of these small proteins are unstructured or partially folded. Bioinformatics tools predict that some of these unstructured proteins can potentially fold upon complex formation. A protocol for fast NMR spectroscopy structure elucidation is described for the small proteins that adopt a persistently folded structure by implementation of new NMR technologies, including automated resonance assignment and nonuniform sampling in combination with targeted acquisition.

14.
J Org Chem ; 84(17): 11203-11209, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31409073

RESUMO

Two new dimeric compounds of the alternariol class, (±)-alternarlactones A (1) and B (2), were isolated along with 11 known compounds from the fungus Alternaria alternata P1210. Their structures were elucidated with the assistance of long-range HSQMBC to address inadequate cross-peaks in HMBC that result from the highly dense quaternary carbons, as well as theoretical calculations. All isolated altenuisol derivatives were screened for their antiparasitic activities, which provide a preliminary structure-activity relationship of this class of compounds against neglected tropical diseases.

15.
Int J Radiat Oncol Biol Phys ; 105(3): 504-513, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31271828

RESUMO

PURPOSE: Range prediction in particle therapy is associated with an uncertainty originating from calculating the stopping-power ratio (SPR) based on x-ray computed tomography (CT). Here, we assessed the intra- and inter-patient variability of tissue properties in patients with primary brain tumor using dual-energy CT (DECT) and quantified its influence on current SPR prediction. METHODS AND MATERIALS: For 102 patients' DECT scans, SPR distributions were derived from a patient-specific DECT-based approach (DirectSPR). The impact of soft tissue diversity and age-related variations in bone composition on SPR were assessed. Tissue-specific and global deviations between this method and the state-of-the-art CT-number-to-SPR conversion applying a Hounsfield look-up table (HLUT) were quantified. To isolate systematic deviations between the two, the HLUT was also optimized using DECT information. RESULTS: An intra-patient ± inter-patient soft tissue diversity of 5.6% ± 0.7% in SPR (width of 95% confidence interval) was obtained including imaging- and model-related variations of up to 2.9%. This intra-patient SPR variability is associated with a mean absolute SPR deviation of 1.2% between the patient-specific DirectSPR approach and an optimal HLUT. Between adults and children younger than 6 years, age-related variations in bone composition resulted in a median SPR difference of approximately 5%. CONCLUSIONS: Accurate patient-specific DECT-based stopping-power prediction allows for improved handling of tissue mixtures and can intrinsically incorporate most of the SPR variability arising from tissue mixtures as well as inter-patient and intra-tissue variations. Since the state-of-the-art HLUT-even after cohort-specific optimization-cannot fully consider the broad tissue variability, patient-specific DECT-based stopping-power prediction is advisable in particle therapy.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Terapia com Prótons/métodos , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos , Tecido Adiposo/diagnóstico por imagem , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Osso e Ossos/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Imagem Radiográfica a Partir de Emissão de Duplo Fóton , Estudos Retrospectivos , Razão Sinal-Ruído , Incerteza , Adulto Jovem
16.
Clin Transl Radiat Oncol ; 18: 113-119, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31341986

RESUMO

Background and purpose: Previous MRI studies have shown a substantial decrease in normal-tissue uptake of a hepatobiliary-directed contrast agent 6-9 weeks after liver irradiation. In this prospective clinical study, we investigated whether this effect is detectable during the course of proton therapy. Material and methods: Gd-EOB-DTPA enhanced MRI was performed twice during hypo-fractionated proton therapy of liver lesions in 9 patients (plus two patients with only one scan available). Dose-correlated signal changes were qualitatively scored based on difference images from the two scans. We evaluated the correlation between the MRI signal change with the planned dose map. The GTV was excluded from all analyses. In addition, were examined timing, irradiated liver volume, changes in liver function parameters as well as circulating biomarkers of inflammation. Results: Strong, moderate or no dose-correlated signal changes were detected for 2, 3 and 5 patients, respectively. Qualitative scoring was consistent with the quantitative dose to signal change correlation. In an exploratory analysis, the strongest correlation was found between the qualitative scoring and pretreatment IL-6 concentration. For all patients, a clear dose-correlated signal decrease was seen in late follow-up scans. Conclusion: Radiation-induced effects can be detected with Gd-EOB-DTPA enhanced MRI in a subgroup of patients within a few days after proton irradiation. The reason for the large inter-patient variations is not yet understood and will require validation in larger studies.

17.
Angew Chem Int Ed Engl ; 58(27): 9140-9144, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31131949

RESUMO

Up to now, NMR spectroscopic investigations of RNA have utilized imino proton resonances as reporters for base pairing and RNA structure. The nucleobase amino groups are often neglected, since most of their resonances are broadened beyond detection due to rotational motion around the C-NH2 bond. Here, we present 13 C-detected NMR experiments for the characterization of all RNA amino groups irrespective of their motional behavior. We have developed a C(N)H-HDQC experiment that enables the observation of a complete set of sharp amino resonances through the detection of proton-NH2 double quantum coherences. Further, we present an "amino"-NOESY experiment to detect NOEs to amino protons, which are undetectable by any other conventional NOESY experiment. Together, these experiments allow the exploration of additional chemical shift information and inter-residual proton distances important for high-resolution RNA secondary and tertiary structure determination.

18.
Phys Med Biol ; 64(10): 105023, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30965311

RESUMO

In proton therapy, patients benefit from the precise deposition of the dose in the tumor volume due to the interaction of charged particles with matter. Currently, the determination of the beam range in the patient's body during the treatment is not a clinical standard. This lack causes broad safety margins around the tumor, which limits the potential of proton therapy. To overcome this obstacle, different methods are under investigation aiming at the verification of the proton range in real time during the irradiation. One approach is the prompt gamma-ray timing (PGT) method, where the range of the primary protons is derived from time-resolved profiles (PGT spectra) of promptly emitted gamma rays, which are produced along the particle track in tissue. After verifying this novel technique in an experimental environment but far away from treatment conditions, the translation of PGT into clinical practice is intended. Therefore, new hardware was extensively tested and characterized using short irradiation times of 70 ms and clinical beam currents of 2 nA. Experiments were carried out in the treatment room of the University Proton Therapy Dresden. A pencil beam scanning plan was delivered to a target without and with cylindrical air cavities of down to 5 mm thickness. The range shifts of the proton beam induced due to the material variation could be identified from the corresponding PGT spectra, comprising events collected during the delivery of a whole energy layer. Additionally, an assignment of the PGT data to the individual pencil beam spots allowed a spot-wise analysis of the variation of the PGT distribution mean and width, corresponding to range shifts produced by the different air cavities. Furthermore, the paper presents a comprehensive software framework which standardizes future PGT analysis methods and correction algorithms for technical limitations that have been encountered in the presented experiments.

19.
Clin Transl Radiat Oncol ; 15: 108-112, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30834349

RESUMO

Purpose: This secondary analysis of the prospective study on repeat [18F]fluoromisonidazole (FMISO)-PET in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) assessed the correlation of hypoxia in the primary tumour and lymph node metastases (LN) prior to and during primary radiochemotherapy. Methods: This analysis included forty-five LN-positive HNSCC patients having undergone FMISO-PET/CTs at baseline, and at week 1, 2 and 5 of radiochemotherapy. The quantitative FMISO-PET/CT parameters maximum standardised uptake value (SUVmax, corrected for partial volume effect) and peak tumour-to-background ratio (TBRpeak) were estimated in the primary tumour as well as in index and large LN, respectively. Statistical analysis was performed using the Spearman correlation coefficient ρ. Results: In 15 patients with large LN (FDG-PET positive volume >5 ml), there was a significant correlation between the hypoxia measured in the primary tumour and the large LN at three out of four time-points using the TBRpeak (baseline: ρ = 0.57, p = 0.006; week 2: ρ = 0.64, p = 0.003 and week 5: ρ = 0.68, p = 0.001). For the entire cohort (N = 45) only assessed prior to the treatment, there was a statistically significant, though weak correlation between FMISO-SUVmax of the primary tumour and the index LN (ρ = 0.36, p = 0.015). Conclusions: We observed a significant correlation between FMISO-based hypoxia in the primary tumour and large lymph node(s) in advanced stage HNSCC patients. However, since most patients only had relatively small hypoxic lymph node metastases, a comprehensive assessment of the primary tumour and lymph node hypoxia is essential.

20.
Sci Rep ; 9(1): 4126, 2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30858409

RESUMO

In radiotherapy, computed tomography (CT) datasets are mostly used for radiation treatment planning to achieve a high-conformal tumor coverage while optimally sparing healthy tissue surrounding the tumor, referred to as organs-at-risk (OARs). Based on CT scan and/or magnetic resonance images, OARs have to be manually delineated by clinicians, which is one of the most time-consuming tasks in the clinical workflow. Recent multi-atlas (MA) or deep-learning (DL) based methods aim to improve the clinical routine by an automatic segmentation of OARs on a CT dataset. However, so far no studies investigated the performance of these MA or DL methods on dual-energy CT (DECT) datasets, which have been shown to improve the image quality compared to conventional 120 kVp single-energy CT. In this study, the performance of an in-house developed MA and a DL method (two-step three-dimensional U-net) was quantitatively and qualitatively evaluated on various DECT-derived pseudo-monoenergetic CT datasets ranging from 40 keV to 170 keV. At lower energies, the MA method resulted in more accurate OAR segmentations. Both the qualitative and quantitative metric analysis showed that the DL approach often performed better than the MA method.

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