A sub-analysis of multi-center planning radiosurgery for intracranial metastases through automation (MC-PRIMA) comparing UK and international centers

Objectives: A sub-analysis of the MC-PRIMA study was performed to compare the plan quality of stereotactic radiosurgery (SRS) to multiple brain metastases (MBM) between UK and other international centres.Methods and materials: Six centres from the UK and nineteen from other international centres autoplanned using Multiple Brain Mets™ (AutoMBM; Brainlab, Munich, Germany) software for a five MBM study case from a prior planning competition that was originally organized by the Trans-Tasmania Radiation Oncology Group (TROG). Twenty-three dosimetric metrics and the resulting composite plan score per the TROG planning competition were compared between the UK and other international centres. Planning experience and planning time from each planner were recorded and statistically compared.Results: Planning experiences between two groups are equal. Except for mean dose to the hippocampus, all other 22 dosimetric metrics were comparable between two groups. The inter-planner variations in these 23 dosimetric metrics and the composite plan score were also statistically equivalent. Planning time is slightly longer in the UK group (mean = 86.8 min) with a mean difference of 50.3 min.Conclusions: AutoMBM effectively achieves standardization of the plan quality of SRS to MBM within UK and further against the other international centres. Significant planning efficiency gain by AutoMBM both among the UK and other international centres may help to increase the capacity of SRS service by alleviating the clinical and technical loadings

Usability and accuracy of high-resolution detectors for daily quality assurance for robotic radiosurgery

For daily CyberKnife QA a Winston-Lutz-Test (Automated-Quality-Assurance, AQA) is used to determine sub-millimeter deviations in beam delivery accuracy. This test is performed using gafchromic film, an extensive and user-dependent method requiring the use of disposables. We therefore analyzed the usability and accuracy of high-resolution detector arrays. We analyzed a liquid-filled ionization-chamber array (Octavius 1000SRS, PTW, Germany), which has a central resolution of 2.5mm. To test sufficient sensitivity, beam profiles with robot shifts of 0.1mm along the arrays' axes were measured. The detected deviation between the shifted and central profile were compared to the real robot's position. We then compared the results to the SRS-Profiler (SunNuclear, USA) with 4.0mm resolution and to the Nonius (QUART, Germany), a single-line diode detector with 2.8mm resolution. Finally, AQA variance and usability were analyzed performing a number of AQA tests over time, which required the use of specially designed fixtures for each array, and the results were compared to film. Concerning sensitivity, the 1000SRS detected the beam profile shifts with a maximum difference of 0.11mm (mean deviation = 0.03mm) compared to the actual robot shift. The Nonius and SRS-Profiler showed differences of up to 0.15mm and 0.69mm with mean deviation of 0.05mm and 0.18mm, respectively. Analyzing the variation of AQA results over time, the 1000SRS showed a comparable standard deviation to film (0.26mm vs. 0.18mm). The SRS-Profiler and the Nonius showed a standard deviation of 0.16mm and 0.24mm, respectively. The 1000SRS seems to provide equivalent accuracy and sensitivity to the gold standard film when performing daily AQA tests. Compared to other detectors in our study the sensitivity as well as the accuracy of the 1000SRS appears to be superior and more user-friendly. Furthermore, no significant modification of the standard AQA procedure is required when introducing 1000SRS for CyberKnife AQA

Does surrounding greenness moderate the relationship between apparent temperature and physical activity? Findings from the PHENOTYPE project

Background: Physical activity can be affected by both meteorological conditions and surrounding greenness, but few studies have evaluated the effects of these environmental factors on physical activity simultaneously. This multi-city comparative study aimed to assess the synergetic effects of apparent temperature and surrounding greenness on physical activity in four European cities. Specifically, we aimed to identify an interaction between surrounding greenness and apparent temperature in the effects on physical activity. Methods: Data were collected from 352 adult residents of Barcelona (Spain), Stoke-on-Trent (United Kingdom), Doetinchem (The Netherlands), and Kaunas (Lithuania) as part of the PHENOTYPE study. Participants wore a smartphone for seven consecutive days between May-December 2013 and provided additional sociodemographic survey data. Hourly average physical activity (Metabolic Equivalent of Task (MET)) and surrounding greenness (NDVI) were derived from the Calfit mobile application collecting accelerometer and location data. Hourly apparent temperature was calculated from temperature and relative humidity, which were obtained from local meteorological stations along with other meteorological covariates (rainfall, windspeed, and sky darkness). We assessed the interaction effects of apparent temperature and surrounding greenness on hourly physical activity for each city using linear mixed models, while adjusting for meteorological, demographic, and time-related variables. Results: We found significant interactions between apparent temperature and surrounding greenness on hourly physical activity in all four cities. Significant quadratic effects of apparent temperature were found in the highest level of surrounding greenness for Stoke-on-Trent and Doetinchem, with 4% decrease in median MET observed for a 10°C departure from optimal temperature (15.2°C and 14.6°C, respectively). On the other hand, significant linear effects were found for higher levels of surrounding greenness in Barcelona and Kaunas, whereby an increase of 10°C was associated with ∼4% increase in median MET. Conclusion: Apparent temperature and surrounding greenness interacted in the effect on hourly physical activity across the four European cities, with varying effect between cities. While quadratic effects of temperature suggest diminishing levels of physical activity in the highest greenness levels in cities of temperate climates, the variation in surrounding greenness between cities could be further explored, particularly by looking at indoor-outdoor locations. The study findings support the need for evidence-based physical activity promotion and urban design

The Genetic Basis of Hepatosplenic T-cell Lymphoma

Hepatosplenic T cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy number alterations in the disease. Chromatin modifying genes including SETD2, INO80 and ARID1B were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%) for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates novel gene mutations linked to HSTL pathogenesis and potential treatment targets

Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis

Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat