Vibrational line broadening in the solid system N2-Kr:a molecular dynamics study

The vibrational band shapes and the related parameters of N2N2 in Kr have been calculated by molecular dynamics simulations as a function of the nitrogen concentration. Most of the simulations have been applied to the solid hcp phase at 5 GPa and 296 K. The calculated spectra have been obtained by full analysis of the relaxation function. Due to the limited size of the system, the particles remain near the same lattice point throughout a simulation run (no N2-KrN2-Kr exchange). Upon dilution, the vibrational frequency of nitrogen in krypton shows a red shift. The full width at half maximum is extremely composition dependent, with a maximum value of 3.5 cm−1 at equal mole fractions. In addition, for the 50 and 75 mol % systems, a few special configurations with ordered distributions have been simulated. On the basis of these results together with earlier experimental data it is suggested that, in the real solid system, the nitrogen and krypton particles exchange places rapidly so that in time, each N2N2 molecule vibrates with all possible frequencies. To make an estimation of the exchange rate, several simulations have been performed during which the particles exchange randomly at various rates. The calculated widths depend strongly on the exchange rate. By comparison of the calculated and the experimental width of the spectra, an estimation of the exchange rate in the real system is made

Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. Methods: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0–1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous recombination deficiencies (BRCA mutant or BRCA wild-type and high loss of heterozygosity), and the intention-to-treat population, assessed at screening and every 12 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01968213; enrolment is complete. Findings: Between April 7, 2014, and July 19, 2016, we randomly allocated 564 patients: 375 (66%) to rucaparib and 189 (34%) to placebo. Median progression-free survival in patients with a BRCA-mutant carcinoma was 16·6 months (95% CI 13·4–22·9; 130 [35%] patients) in the rucaparib group versus 5·4 months (3·4–6·7; 66 [35%] patients) in the placebo group (hazard ratio 0·23 [95% CI 0·16–0·34]; p<0·0001). In patients with a homologous recombination deficient carcinoma (236 [63%] vs 118 [62%]), it was 13·6 months (10·9–16·2) versus 5·4 months (5·1–5·6; 0·32 [0·24–0·42]; p<0·0001). In the intention-to-treat population, it was 10·8 months (8·3–11·4) versus 5·4 months (5·3–5·5; 0·36 [0·30–0·45]; p<0·0001). Treatment-emergent adverse events of grade 3 or higher in the safety population (372 [99%] patients in the rucaparib group vs 189 [100%] in the placebo group) were reported in 209 (56%) patients in the rucaparib group versus 28 (15%) in the placebo group, the most common of which were anaemia or decreased haemoglobin concentration (70 [19%] vs one [1%]) and increased alanine or aspartate aminotransferase concentration (39 [10%] vs none). Interpretation: Across all primary analysis groups, rucaparib significantly improved progression-free survival in patients with platinum-sensitive ovarian cancer who had achieved a response to platinum-based chemotherapy. ARIEL3 provides further evidence that use of a poly(ADP-ribose) polymerase inhibitor in the maintenance treatment setting versus placebo could be considered a new standard of care for women with platinum-sensitive ovarian cancer following a complete or partial response to second-line or later platinum-based chemotherapy. Funding: Clovis Oncology

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Vibrational line broadening in the solid system N2-Kr: a molecular dynamics study

The vibrational band shapes and the related parameters of N2N2 in Kr have been calculated by molecular dynamics simulations as a function of the nitrogen concentration. Most of the simulations have been applied to the solid hcp phase at 5 GPa and 296 K. The calculated spectra have been obtained by full analysis of the relaxation function. Due to the limited size of the system, the particles remain near the same lattice point throughout a simulation run (no N2-KrN2-Kr exchange). Upon dilution, the vibrational frequency of nitrogen in krypton shows a red shift. The full width at half maximum is extremely composition dependent, with a maximum value of 3.5 cm−1 at equal mole fractions. In addition, for the 50 and 75 mol % systems, a few special configurations with ordered distributions have been simulated. On the basis of these results together with earlier experimental data it is suggested that, in the real solid system, the nitrogen and krypton particles exchange places rapidly so that in time, each N2N2 molecule vibrates with all possible frequencies. To make an estimation of the exchange rate, several simulations have been performed during which the particles exchange randomly at various rates. The calculated widths depend strongly on the exchange rate. By comparison of the calculated and the experimental width of the spectra, an estimation of the exchange rate in the real system is made

Reproducibility of the bladder shape and bladder shape changes during filling.

The feasibility of high precision radiotherapy to the bladder region is limited by bladder motion and volume changes. In the near future, we plan to begin treatment delivery of bladder cancer patients with the acquisition of a cone beam CT image on which the complete bladder will be semi-automatically localized. Subsequently, a bladder shape model that was developed in a previous study will be used for bladder localization and for the prediction of shape changes in the time interval between acquisition and beam delivery. For such predictions, knowledge about urinary inflow rate is required. Therefore, a series of MR images was acquired over 1 h with time intervals of 10 min for 18 healthy volunteers. To gain insight in the reproducibility of the bladder shape over longer periods of time, two additional MRI series were recorded for 10 of the volunteers. To a good approximation, the bladder volume increased linearly in time for all individuals. Despite receiving drinking instructions, we found a large variation in the inflow rate between individuals, ranging from 2.1 to 15 cc/min (mean value: 9 +/- 3 cc/min). In contrast, the intravolunteer variation was much smaller, with a mean standard deviation (SD) of 0.4 cc/min. The inflow rate was linearly correlated with age (negative slope). To study the reproducibility of the bladder shape, we compared bladder shapes of equal volume. For all individuals, the caudal part of the bladder was the most reproducible (variations <0.3 cm in all cases). The cranial and posterior parts of the bladder was much less reproducible, with local SD values up to approximately 1.2 cm for bladders with a volume of 200 cc. These large long-term variations were primarily caused by changes in position and filling of the small bowel and rectum. However, for short time intervals, the rectal filling was (nearly) constant. Therefore, the reproducibility of urinary inflow, combined with the previously developed shape model gives us an excellent tool to predict short-term shape changes. We intend to use this tool for further improvement of image-guided radiotherapy for bladder cancer patient

A model to predict bladder shapes from changes in bladder and rectal filling.

The purpose of this study is to develop a model that quantifies in three dimensions changes in bladder shape due to changes in bladder and/or rectal volume. The new technique enables us to predict changes in bladder shape over a short period of time, based on known urinary inflow. Shortly prior to the treatment, the patient will be scanned using a cone beam CT scanner (x-ray volume imager) that is integrated with the linear accelerator. After (automated) delineation of the bladder, the model will be used to predict the short-term shape changes of the bladder for the time interval between image acquisition and dose delivery. The model was developed using multiple daily CT scans of the pelvic area of 19 patients. For each patient, the rigid bony structure in follow-up scans was matched to that of the planning CT scan, and the outer bladder and rectal wall were delineated. Each bladder wall was subdivided in 2500 domains. A fixed reference point inside the bladder was used to calculate for each bladder structure a "Mercator-like" 2D scalar map (similar to a height map of the globe), containing the distances from this reference point to each domain on the bladder wall. Subsequently, for all bladder shapes of a patient and for all domains on the wall individually, the distance to the reference point was fitted by a linear function of both bladder and rectal volume. The model uses an existing bladder structure to create a new structure via expansion (or contraction), until the expressed volume is reached. To evaluate the predictive power of the model, the jack-knife method was used. The errors in the fitting procedure depended on the part of the bladder and range from 0 to 0.5 cm (0.2 cm on average). It was found that a volume increase of 150 cc can lead to a displacement up to about 2.5 cm of the cranial part of the bladder. With the model, the uncertainty in the position of the bladder wall can be reduced down to a maximum value of about 0.5 cm in case the bladder volume increase is known. Furthermore, it was found that a change in rectal filling causes a shift of the bladder, while its shape is hardly influenced. In conclusion, we developed a model that describes the bladder shape and position as a function of the bladder volume and the rectal filling. The model accurately describes the complex shape of the bladder as it works on each domain of the bladder separatel

Tumor motion and deformation during external radiotherapy of bladder cancer.

Purpose: First, to quantify bladder-tumor motion in 3 dimensions during a 4-week to 5-week course of external radiotherapy. Second, to relate the motion to the tumor location on the bladder wall. Third, to extensively evaluate gross tumor volume (GTV) shape and volume changes during the course of the treatment. Methods and Materials: Multiple repeat computed tomography (CT) images were obtained for 21 bladder cancer patients. These scans were matched to the rigid bony anatomy. For each patient, the main direction and magnitude of the tumor movement was determined by use of principle-component analysis. To study GTV shape changes, all GTVs were registered to the GTV in the planning CT scan, and the residual shape errors were determined by measurement of edge variations perpendicular to the median surface. Results: Gross tumor volume translations were largest in cranial–caudal and anterior–posterior direction (SD, 0.1 to ∼0.9 cm). The translations were strongly correlated with the tumor location on the bladder wall. The average value of the local standard deviations of the GTV shape ranged from 0.1 to approximately 0.35 cm. Conclusions: Despite large differences in bladder filling, variations in GTV shape were small compared with variations in GTV position. Geometric uncertainties in the GTV position depended strongly on the tumor location on the bladder wall

Finite element based bladder modeling for image-guided radiotherapy of bladder cancer.

Purpose: A biomechanical model was constructed to give insight into pelvic organ motion as a result of bladder filling changes. Methods: The authors used finite element (FE) modeling to simulate bladder wall deformation caused by urine inflow. For ten volunteers, a series of MRI scans of the pelvic area was recorded at regular intervals of 10 min over 1 h. For the series of scans, the bladder volume gradually increased while the rectal volume was constant. The MR image with the bladder volume closest to 250 ml was selected as the reference in each volunteer. All pelvic structures were defined from the reference image including bladder wall, small bowel, prostate (male), uterus (female), rectum, pelvic bone, and the rest of the body. These structures were translated to FE meshes. Using appropriate material properties for all organs, deformations of these organs as a response to changing bladder pressure were computed. Results: The computation results showed realistic anisotropic deformation of the bladder wall: The bladder became more elongated in the cranial and anterior directions with increasing bladder volume. After fitting the volume of the computed bladder to the actual bladder volume on the test images, the computed bladder shape agreed well with the real bladder shape (overlap from 0.79 to 0.93). The average mean bladder wall prediction errors of all the volunteers were 0.31 cm average and 0.29 cm SD. Conclusions: In conclusion, a FE based mechanical bladder model shows promise for the prediction of the short-term bladder shape change using only one pelvic scan and volume change of the bladder as input. The accuracy levels achieved with this method are likely mostly limited by inaccuracies in material properties and sliding tissue between organs, which has not been modeled. This model can potentially be used to improve image-guided radiotherapy for bladder cancer patients, i.e., by prediction short-term bladder deformation. (C) 2011 American Association of Physicists in Medicine. [DOI: 10.1118/1.3523624