Framework for quality assurance of ultrahigh dose rate clinical trials investigating FLASH effects and current technology gaps

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials

WFPC2 Images of the Central Regions of Early-Type Galaxies - I. The Data

We present high resolution R-band images of the central regions of 67 early-type galaxies obtained with the Wide Field and Planetary Camera 2 (WFPC2) aboard the Hubble Space Telescope (HST). Our sample strikingly confirms the complex morphologies of the central regions of early-type galaxies. In particular, we detect dust in 43 percent of all galaxies, and evidence for embedded stellar disks in a remarkably large fraction of 51 percent. In 14 of those galaxies the disk-like structures are misaligned with the main galaxy, suggesting that they correspond to stellar bars in S0 galaxies. We analyze the luminosity profiles of the galaxies in our sample, and classify galaxies according to their central cusp slope. To a large extent we confirm the clear dichotomy found in previous HST surveys: bright, boxy ellipticals with shallow inner cusps (`core' galaxies) on one hand and faint, disky ellipticals with steep central cusps (`power-law' galaxies) on the other hand. The advantages and shortcomings of classification schemes utilizing the extrapolated central cusp slope are discussed, and it is shown that this cusp slope might be an inadequate representation for galaxies whose luminosity profile slope changes smoothly with radius rather than resembling a broken power-law. In fact, we find evidence for an `intermediate' class of galaxies, that cannot unambiguously be classified as either core or power-law galaxies, and which have central cusp slopes and absolute magnitudes intermediate between those of core and power-law galaxies.Comment: 44 pages, 7 Postscript figures. Accepted for publication in the Astronomical Journal. The associated Appendix with figures of luminosity profiles, contour plots and isophotal parameters for all galaxies is available at http://www.astro.washington.edu/rest/centralpro

Dosimetric evaluation of heterogeneity corrections for RTOG 0236: stereotactic body radiotherapy of inoperable stage I-II non-small-cell lung cancer.

PURPOSE: Using a retrospective analysis of treatment plans submitted from multiple institutions accruing patients to the Radiation Therapy Oncology Group (RTOG) 0236 non-small-cell stereotactic body radiotherapy protocol, the present study determined the dose prescription and critical structure constraints for future stereotactic body radiotherapy lung protocols that mandate density-corrected dose calculations. METHOD AND MATERIALS: A subset of 20 patients from four institutions participating in the RTOG 0236 protocol and using superposition/convolution algorithms were compared. The RTOG 0236 protocol required a prescription dose of 60 Gy delivered in three fractions to cover 95% of the planning target volume. Additional requirements were specified for target dose heterogeneity and the dose to normal tissue/structures. The protocol required each site to plan the patient\u27s treatment using unit density, and another plan with the same monitor units and applying density corrections was also submitted. These plans were compared to determine the dose differences. Two-sided, paired Student\u27s t tests were used to evaluate these differences. RESULTS: With heterogeneity corrections applied, the planning target volume receiving \u3e/=60 Gy decreased, on average, 10.1% (standard error, 2.7%) from 95% (p = .001). The maximal dose to any point \u3e/=2 cm away from the planning target volume increased from 35.2 Gy (standard error, 1.7) to 38.5 Gy (standard error, 2.2). CONCLUSION: Statistically significant dose differences were found with the heterogeneity corrections. The information provided in the present study is being used to design future heterogeneity-corrected RTOG stereotactic body radiotherapy lung protocols to match the true dose delivered for RTOG 0236

NRG Oncology/RTOG 0921: A phase 2 study of postoperative intensity-modulated radiotherapy with concurrent cisplatin and bevacizumab followed by carboplatin and paclitaxel for patients with endometrial cancer.

BACKGROUND: The current study was conducted to assess acute and late adverse events (AEs), overall survival (OS), pelvic failure, regional failure, distant failure, and disease-free survival in a prospective phase 2 clinical trial of bevacizumab and pelvic intensity-modulated radiotherapy (IMRT) with chemotherapy in patients with high-risk endometrial cancer. METHODS: Patients underwent a hysterectomy and lymph node removal, and had ≥1 of the following high-risk factors: grade 3 carcinoma with \u3e50% myometrial invasion, grade 2 or 3 disease with any cervical stromal invasion, or known extrauterine extension confined to the pelvis. Treatment included pelvic IMRT and concurrent cisplatin on days 1 and 29 of radiation and bevacizumab (at a dose of 5 mg/kg on days 1, 15, and 29 of radiation) followed by adjuvant carboplatin and paclitaxel for 4 cycles. The primary endpoint was grade ≥3 AEs occurring within the first 90 days (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). RESULTS: A total of 34 patients were accrued from November 2009 through December 2011, 30 of whom were eligible and received study treatment. Seven of 30 patients (23.3%; 1-sided 95% confidence interval, 10.6%-36.0%) developed grade ≥3 treatment-related nonhematologic toxicities within 90 days; an additional 6 patients experienced grade ≥3 toxicities between 90 and 365 days after treatment. The 2-year OS rate was 96.7% and the disease-free survival rate was 79.1%. No patient developed a within-field pelvic failure and no patients with International Federation of Gynecology and Obstetrics stage I to IIIA disease developed disease recurrence after a median follow-up of 26 months. CONCLUSIONS: Postoperative bevacizumab added to chemotherapy and pelvic IMRT appears to be well tolerated and results in high OS rates at 2 years for patients with high-risk endometrial carcinoma

A dozen colliding wind X-ray binaries in the star cluster R136 in the 30Doradus region

We analyzed archival Chandra X-ray observations of the central portion of the 30 Doradus region in the Large Magellanic Cloud. The image contains 20 X-ray point sources with luminosities between $5 \times 10^{32}$ and $2 \times 10^{35}$ erg s$^{-1}$ (0.2 -- 3.5 keV). A dozen sources have bright WN Wolf-Rayet or spectral type O stars as optical counterparts. Nine of these are within $\sim 3.4$pc of R136, the central star cluster of NGC2070. We derive an empirical relation between the X-ray luminosity and the parameters for the stellar wind of the optical counterpart. The relation gives good agreement for known colliding wind binaries in the Milky Way Galaxy and for the identified X-ray sources in NGC2070. We conclude that probably all identified X-ray sources in NGC2070 are colliding wind binaries and that they are not associated with compact objects. This conclusion contradicts Wang (1995) who argued, using ROSAT data, that two earlier discovered X-ray sources are accreting black-hole binaries. Five of the eighteen brightest stars in R136 are not visible in our X-ray observations. These stars are either single, have low mass companions or very wide orbits. The resulting binary fraction among early type stars is then unusually high (at least 70%).Comment: 23 pages, To appear in August in Ap

Future vision for the quality assurance of oncology clinical trials

The National Cancer Institute clinical cooperative groups have been instrumental over the past 50 years in developing clinical trials and evidence-based process improvements for clinical oncology patient care. The cooperative groups are undergoing a transformation process as we further integrate molecular biology into personalized patient care and move to incorporate international partners in clinical trials. To support this vision, data acquisition and data management informatics tools must become both nimble and robust to support transformational research at an enterprise level. Information, including imaging, pathology, molecular biology, radiation oncology, surgery, systemic therapy, and patient outcome data needs to be integrated into the clinical trial charter using adaptive clinical trial mechanisms for design of the trial. This information needs to be made available to investigators using digital processes for real-time data analysis. Future clinical trials will need to be designed and completed in a timely manner facilitated by nimble informatics processes for data management. This paper discusses both past experience and future vision for clinical trials as we move to develop data management and quality assurance processes to meet the needs of the modern trial

The Atomic to Molecular Transition and its Relation to the Scaling Properties of Galaxy Disks in the Local Universe

We extend existing semi-analytic models of galaxy formation to track atomic and molecular gas in disk galaxies. Simple recipes for processes such as cooling, star formation, supernova feedback, and chemical enrichment of the stars and gas are grafted on to dark matter halo merger trees derived from the Millennium Simulation. Each galactic disk is represented by a series of concentric rings. We assume that surface density profile of infalling gas in a dark matter halo is exponential, with scale radius r_d that is proportional to the virial radius of the halo times its spin parameter $\lambda$. As the dark matter haloes grow through mergers and accretion, disk galaxies assemble from the inside out. We include two simple prescriptions for molecular gas formation processes in our models: one is based on the analytic calculations by Krumholz, McKee & Tumlinson (2008), and the other is a prescription where the H_2 fraction is determined by the kinematic pressure of the ISM. Motivated by the observational results of Leroy et al. (2008), we adopt a star formation law in which $\Sigma_{SFR}\propto\Sigma_{H_2}$ in the regime where the molecular gas dominates the total gas surface density, and $\Sigma_{SFR}\propto \Sigma_{gas}^2$ where atomic hydrogen dominates. We then fit these models to the radial surface density profiles of stars, HI and H_2 drawn from recent high resolution surveys of stars and gas in nearby galaxies. We explore how the ratios of atomic gas, molecular gas and stellar mass vary as a function of global galaxy scale parameters, including stellar mass, stellar surface density, and gas surface density. We elucidate how the trends can be understood in terms of three variables that determine the partition of baryons in disks: the mass of the dark matter halo, the spin parameter of the halo, and the amount of gas recently accreted from the external environment.Comment: Made some minor changes according to the reviewer's suggestion. Accepted by MNRA

Orbiting Circum-galactic Gas as a Signature of Cosmological Accretion

We use cosmological SPH simulations to study the kinematic signatures of cool gas accretion onto a pair of well-resolved galaxy halos. Cold-flow streams and gas-rich mergers produce a circum-galactic component of cool gas that generally orbits with high angular momentum about the galaxy halo before falling in to build the disk. This signature of cosmological accretion should be observable using background-object absorption line studies as features that are offset from the galaxy's systemic velocity by ~100 km/s. Accreted gas typically co-rotates with the central disk in the form of a warped, extended cold flow disk, such that the observed velocity offset is in the same direction as galaxy rotation, appearing in sight lines that avoid the galactic poles. This prediction provides a means to observationally distinguish accreted gas from outflow gas: the accreted gas will show large one-sided velocity offsets in absorption line studies while radial/bi-conical outflows will not (except possibly in special polar projections). This rotation signature has already been seen in studies of intermediate redshift galaxy-absorber pairs; we suggest that these observations may be among the first to provide indirect observational evidence for cold accretion onto galactic halos. Cold mode halo gas typically has ~3-5 times more specific angular momentum than the dark matter. The associated cold mode disk configurations are likely related to extended HI/XUV disks seen around galaxies in the local universe. The fraction of galaxies with extended cold flow disks and associated offset absorption-line gas should decrease around bright galaxies at low redshift, as cold mode accretion dies out.Comment: 15 pages, 9 figures, edited to match published version. Includes expanded discussion, with primary results unchange

IGR J17354-3255 as a candidate intermediate SFXT possibly associated with the transient MeV AGL J1734-3310

We present spectral and temporal results from INTEGRAL long-term monitoring of the unidentified X-ray source IGR J17354-3255. We show that it is a weak persistent hard X-ray source spending a major fraction of the time in an out-of-outburst state with average 18-60 keV X-ray flux of about 1.1 mCrab, occasionally interspersed with fast X-ray flares (duration from a few hours to a few days) with a dynamic range as high as 200. From archival Swift/XRT observations, we also show that the dynamic range from non-detection to highest level of measured X-ray activity is >300. Our IBIS timing analysis strongly confirms the 8.4 days orbital period previously detected with Swift/BAT, in addition we show that the shape of the orbital profile is rather smooth and appears to be dominated by low level X-ray emission rather than by bright outbursts, the measured degree of outburst recurrence is about 25 per cent. The spectral and temporal characteristics of IGR J17354-3255 are highly indicative of a Supergiant High Mass X-ray Binary nature (SGXB). However, our inferred dynamic ranges both at soft and hard X-rays are significantly greater than those of classical SGXB systems, but instead are typical of intermediate Supergiant Fast X-ray Transient (SFXTs). Finally, we note for the first time that the observed fast flaring X-ray behaviour of IGR J17354-3255 is very similar to that detected with AGILE from the spatially associated MeV source AGL J1734-3310, suggesting a possible physical link between the two objects.Comment: accepted for publication in MNRAS, 8 pages, 9 figures, 1 tabl