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Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Purpose: Evaluation of dose degradation by anatomic changes for head-and-neck cancer (HNC) intensity-modulated proton therapy (IMPT) relative to intensity-modulated photon therapy (IMRT) and identification of potential indicators for IMPT treatment plan adaptation., Methods: For 31 advanced HNC datasets, IMPT and IMRT plans were recalculated on a computed tomography scan (CT) taken after about 4 weeks of therapy. Dose parameter changes were determined for the organs at risk (OARs) spinal cord, brain stem, parotid glands, brachial plexus, and mandible, for the clinical target volume (CTV) and the healthy tissue outside planning target volume (PTV). Correlation of dose degradation with target volume changes and quality of rigid CT matching was investigated., Results: Recalculated IMPT dose distributions showed stronger degradation than the IMRT doses. OAR analysis revealed significant changes in parotid median dose (IMPT) and near maximum dose (D 1ml ) of spinal cord (IMPT, IMRT) and mandible (IMPT). OAR dose parameters remained lower in IMPT cases. CTV coverage (V 95% ) and overdose (V 107% ) deteriorated for IMPT plans to (93.4 ± 5.4)% and (10.6 ± 12.5)%, while those for IMRT plans remained acceptable. Recalculated plans showed similarly decreased PTV conformity, but considerable hotspots, also outside the PTV, emerged in IMPT cases. Lower CT matching quality was significantly correlated with loss of PTV conformity (IMPT, IMRT), CTV homogeneity and coverage (IMPT). Target shrinkage correlated with increased dose in brachial plexus (IMRT, IMPT), hotspot generation outside the PTV (IMPT) and lower PTV conformity (IMRT)., Conclusions: The study underlines the necessity of precise positioning and monitoring of anatomy changes, especially in IMPT which might require adaptation more often. Since OAR doses remained typically below constraints, IMPT plan adaptation will be indicated by target dose degradations., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: The ExoMars 2016 mission, consisting of the Trace Gas Orbiter and the Schiaparelli lander, was launched on March 14 2016 from Baikonur, Kazakhstan and reached its destination in October 2016. The Schiaparelli lander was subject to strict requirements for microbial cleanliness according to the obligatory planetary protection policy. To reach the required cleanliness, the ExoMars 2016 flight hardware was assembled in a newly built, biocontrolled cleanroom complex at Thales Alenia Space in Turin, Italy. In this study, we performed microbiological surveys of the cleanroom facilities and the spacecraft hardware before and during the assembly, integration and testing (AIT) activities., Methods: Besides the European Space Agency (ESA) standard bioburden assay, that served as a proxy for the microbiological contamination in general, we performed various alternative cultivation assays and utilised molecular techniques, including quantitative PCR and next generation sequencing, to assess the absolute and relative abundance and broadest diversity of microorganisms and their signatures in the cleanroom and on the spacecraft hardware., Results: Our results show that the bioburden, detected microbial contamination and microbial diversity decreased continuously after the cleanroom was decontaminated with more effective cleaning agents and during the ongoing AIT. The studied cleanrooms and change room were occupied by very distinct microbial communities: Overall, the change room harboured a higher number and diversity of microorganisms, including Propionibacterium, which was found to be significantly increased in the change room. In particular, the so called alternative cultivation assays proved important in detecting a broader cultivable diversity than covered by the standard bioburden assay and thus completed the picture on the cleanroom microbiota., Conclusion: During the whole project, the bioburden stayed at acceptable level and did not raise any concern for the ExoMars 2016 mission. The cleanroom complex at Thales Alenia Space in Turin is an excellent example of how efficient microbiological control is performed.

Background: The Mars500 project was conceived as the first full duration simulation of a crewed return flight to Mars. For 520 days, six crew members lived confined in a specifically designed spacecraft mock-up. The herein described "MIcrobial ecology of Confined Habitats and humAn health" (MICHA) experiment was implemented to acquire comprehensive microbiota data from this unique, confined manned habitat, to retrieve important information on the occurring microbiota dynamics, the microbial load and diversity in the air and on various surfaces. In total, 360 samples from 20 (9 air, 11 surface) locations were taken at 18 time-points and processed by extensive cultivation, PhyloChip and next generation sequencing (NGS) of 16S rRNA gene amplicons., Results: Cultivation assays revealed a Staphylococcus and Bacillus-dominated microbial community on various surfaces, with an average microbial load that did not exceed the allowed limits for ISS in-flight requirements indicating adequate maintenance of the facility. Areas with high human activity were identified as hotspots for microbial accumulation. Despite substantial fluctuation with respect to microbial diversity and abundance throughout the experiment, the location within the facility and the confinement duration were identified as factors significantly shaping the microbial diversity and composition, with the crew representing the main source for microbial dispersal. Opportunistic pathogens, stress-tolerant or potentially mobile element-bearing microorganisms were predicted to be prevalent throughout the confinement, while the overall microbial diversity dropped significantly over time., Conclusions: Our findings clearly indicate that under confined conditions, the community structure remains a highly dynamic system which adapts to the prevailing habitat and micro-conditions. Since a sterile environment is not achievable, these dynamics need to be monitored to avoid spreading of highly resistant or potentially pathogenic microorganisms and a potentially harmful decrease of microbial diversity. If necessary, countermeasures are required, to maintain a healthy, diverse balance of beneficial, neutral and opportunistic pathogenic microorganisms. Our results serve as an important data collection for (i) future risk estimations of crewed space flight, (ii) an optimized design and planning of a spacecraft mission and (iii) for the selection of appropriate microbial monitoring approaches and potential countermeasures, to ensure a microbiologically safe space-flight environment.

Prompt γ-ray imaging with a knife-edge shaped slit camera provides the possibility of verifying proton beam range in tumor therapy. Dedicated experiments regarding the characterization of the camera system have been performed previously. Now, we aim at implementing the prototype into clinical application of monitoring patient treatments. Focused on this goal of translation into clinical operation, we systematically addressed remaining challenges and questions. We developed a robust energy calibration routine and corresponding quality assurance protocols. Furthermore, with dedicated experiments, we determined the positioning precision of the system to 1.1 mm (2σ). For the first time, we demonstrated the application of the slit camera, which was intentionally developed for pencil beam scanning, to double scattered proton beams. Systematic experiments with increasing complexity were performed. It was possible to visualize proton range shifts of 2-5 mm with the camera system in phantom experiments in passive scattered fields. Moreover, prompt γ-ray profiles for single iso-energy layers were acquired by synchronizing time resolved measurements to the rotation of the range modulator wheel of the treatment system. Thus, a mapping of the acquired profiles to different anatomical regions along the beam path is feasible and additional information on the source of potential range shifts can be obtained. With the work presented here, we show that an application of the slit camera in clinical treatments is possible and of potential benefit.

Purpose: Rating both a lung segmentation algorithm and a deformable image registration (DIR) algorithm for subsequent lung computed tomography (CT) images by different evaluation techniques. Furthermore, investigating the relative performance and the correlation of the different evaluation techniques to address their potential value in a clinical setting., Methods: Two to seven subsequent CT images (69 in total) of 15 lung cancer patients were acquired prior, during, and after radiochemotherapy. Automated lung segmentations were compared to manually adapted contours. DIR between the first and all following CT images was performed with a fast algorithm specialized for lung tissue registration, requiring the lung segmentation as input. DIR results were evaluated based on landmark distances, lung contour metrics, and vector field inconsistencies in different subvolumes defined by eroding the lung contour. Correlations between the results from the three methods were evaluated., Results: Automated lung contour segmentation was satisfactory in 18 cases (26%), failed in 6 cases (9%), and required manual correction in 45 cases (66%). Initial and corrected contours had large overlap but showed strong local deviations. Landmark-based DIR evaluation revealed high accuracy compared to CT resolution with an average error of 2.9 mm. Contour metrics of deformed contours were largely satisfactory. The median vector length of inconsistency vector fields was 0.9 mm in the lung volume and slightly smaller for the eroded volumes. There was no clear correlation between the three evaluation approaches., Conclusions: Automatic lung segmentation remains challenging but can assist the manual delineation process. Proven by three techniques, the inspected DIR algorithm delivers reliable results for the lung CT data sets acquired at different time points. Clinical application of DIR demands a fast DIR evaluation to identify unacceptable results, for instance, by combining different automated DIR evaluation methods.

Aim: To study the dose-response of stage I non-small-cell lung cancer (NSCLC) in terms of long-term local tumor control (LC) after conventional and hypofractionated photon radiotherapy, modeled with the linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) approaches and to estimate the clinical α/β ratio within the LQ frame., Material and Methods: We identified studies of curative radiotherapy as single treatment through MedLine search reporting 3-year LC as primary outcome of interest. Logistic models coupled with the biologically effective dose (BED) at isocenter and PTV edge according to both the LQ and LQ-L models with α/β = 10 Gy were fitted. Additionally, α/β was estimated from direct LQ fits., Results: Thirty one studies were included reporting outcome of 2319 patients. The LQ-L fit yielded a significant value of 11.0 ± 5.2 Gy for the dose threshold (Dt) for BED10 at the isocenter. The LQ and LQ-L fits did not differ substantially. Concerning the estimation of α/β, the value obtained from the direct LQ fit for the complete fractionation range was 3.9 [68 % CI: 2.2-9.0] Gy (p > 0.05)., Conclusion: Both LQ and LQ-L fits can model local tumor control after conventionally and hypofractionated irradiation and are robust methods for predicting clinical effects. The observed dose-effect for local control in NSCLC is weaker at high doses due to data dispersion. For BED10 values of 100-150 Gy in ≥3 fractions, the differences in isoeffects predicted by both models can be neglected.

Background and Purpose: To improve precision of particle therapy, in vivo range verification is highly desirable. Methods based on prompt gamma rays emitted during treatment seem promising but have not yet been applied clinically. Here we report on the worldwide first clinical application of prompt gamma imaging (PGI) based range verification., Material and Methods: A prototype of a knife-edge shaped slit camera was used to measure the prompt gamma ray depth distribution during a proton treatment of a head and neck tumor for seven consecutive fractions. Inter-fractional variations of the prompt gamma profile were evaluated. For three fractions, in-room control CTs were acquired and evaluated for dose relevant changes., Results: The measurement of PGI profiles during proton treatment was successful. Based on the PGI information, inter-fractional global range variations were in the range of ±2 mm for all evaluated fractions. This is in agreement with the control CT evaluation showing negligible range variations of about 1.5mm., Conclusions: For the first time, range verification based on prompt gamma imaging was applied for a clinical proton treatment. With the translation from basic physics experiments into clinical operation, the potential to improve the precision of particle therapy with this technique has increased considerably., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Space agencies maintain highly controlled cleanrooms to ensure the demands of planetary protection. To study potential effects of microbiome control, we analyzed microbial communities in two particulate-controlled cleanrooms (ISO 5 and ISO 8) and two vicinal uncontrolled areas (office, changing room) by cultivation and 16S rRNA gene amplicon analysis (cloning, pyrotagsequencing, and PhyloChip G3 analysis). Maintenance procedures affected the microbiome on total abundance and microbial community structure concerning richness, diversity and relative abundance of certain taxa. Cleanroom areas were found to be mainly predominated by potentially human-associated bacteria; archaeal signatures were detected in every area. Results indicate that microorganisms were mainly spread from the changing room (68%) into the cleanrooms, potentially carried along with human activity. The numbers of colony forming units were reduced by up to ~400 fold from the uncontrolled areas towards the ISO 5 cleanroom, accompanied with a reduction of the living portion of microorganisms from 45% (changing area) to 1% of total 16S rRNA gene signatures as revealed via propidium monoazide treatment of the samples. Our results demonstrate the strong effects of cleanroom maintenance on microbial communities in indoor environments and can be used to improve the design and operation of biologically controlled cleanrooms.

Understanding microbial diversity in spacecraft assembly clean rooms is of major interest with respect to planetary protection considerations. A coordinated screening of different clean rooms in Europe and South America by three German institutes [Deutsches Zentrum für Luft- und Raumfahrt (DLR), Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), and the Institute of Microbiology and Archaea Center, University of Regensburg] took place during the assembly, test, and launch operations of the Herschel spacecraft in 2006-2009. Through this campaign, we retrieved critical information regarding the microbiome within these clean rooms and on the Herschel spacecraft, which served as a model for upcoming ESA mission preparations. This "lessons learned" document summarizes and discusses the data we obtained during this sampling campaign. Additionally, we have taken the opportunity to create a database that includes all 16S rRNA gene sequences ever retrieved from molecular and cultivable diversity studies of spacecraft assembly clean rooms to compare the microbiomes of US, European, and South American facilities.

In this study, samples from the spacecraft assembly clean room BAF (final assembly building), located at Centre Spatial Guyanais in Kourou, French Guiana, were characterized by qualitative and quantitative methods to determine the bioburden and biodiversity. The cultivation assays mainly focused on extremotolerant microorganisms that have special metabolic skills, such as the ability to grow without oxygen, fix nitrogen, grow autotrophically, or reduce sulfate. A broad range of media and growth conditions were used to simulate possible extraterrestrial environments and clean room buildings. In addition to these alternative cultivation assays, the ESA standard protocol for bioburden estimation was also applied. The phylogenetic analysis of the isolates (mainly facultative anaerobes) showed an extraordinarily broad cultivable biodiversity. Overall, 49 species were isolated and identified as members of the bacterial phyla Actinobacteria, Firmicutes, α-, β-, γ-Proteobacteria, and Bacteroidetes/Chlorobi. In addition to cultivation-based analyses, molecular techniques were also applied, including construction of a 16S rRNA gene clone library. The results indicate a wide-ranging microbial diversity (12 bacterial phyla, 34 families) that not only confirms the results of the cultivation efforts but also deepens our understanding of the noncultivable variety. Our investigations hint at a very broad, mainly uncultivated microbial diversity.

The determination of the microbial load of a spacecraft en route to interesting extraterrestrial environments is mandatory and currently based on the culturable, heat-shock-surviving portion of microbial contaminants. Our study compared these classical bioburden measurements as required by NASA's and ESA's guidelines for the microbial examination of flight hardware, with molecular analysis methods (16S rRNA gene cloning and quantitative PCR) to further develop our understanding of the diversity and abundance of the microbial communities of spacecraft-associated clean rooms. Three samplings of the Herschel Space Observatory and its surrounding clean rooms were performed in two different European facilities. Molecular analyses detected a broad diversity of microbes typically found in the human microbiome with three bacterial genera (Staphylococcus, Propionibacterium, and Brevundimonas) common to all three locations. Bioburden measurements revealed a low, but heterogeneous, abundance of spore-forming and other heat-resistant microorganisms. Total cell numbers estimated by quantitative real-time PCR were typically 3 orders of magnitude greater than those determined by viable counts, which indicates a tendency for traditional methods to underestimate the extent of clean room bioburden. Furthermore, the molecular methods allowed the detection of a much broader diversity than traditional culture-based methods.

The multi-user facility EXPOSE-E was designed by the European Space Agency to enable astrobiology research in space (low-Earth orbit). On 7 February 2008, EXPOSE-E was carried to the International Space Station (ISS) on the European Technology Exposure Facility (EuTEF) platform in the cargo bay of Space Shuttle STS-122 Atlantis. The facility was installed at the starboard cone of the Columbus module by extravehicular activity, where it remained in space for 1.5 years. EXPOSE-E was returned to Earth with STS-128 Discovery on 12 September 2009 for subsequent sample analysis. EXPOSE-E provided accommodation in three exposure trays for a variety of astrobiological test samples that were exposed to selected space conditions: either to space vacuum, solar electromagnetic radiation at >110 nm and cosmic radiation (trays 1 and 3) or to simulated martian surface conditions (tray 2). Data on UV radiation, cosmic radiation, and temperature were measured every 10 s and downlinked by telemetry. A parallel mission ground reference (MGR) experiment was performed on ground with a parallel set of hardware and samples under simulated space conditions. EXPOSE-E performed a successful 1.5-year mission in space.