Combining stereotactic body radiation therapy with immunotherapy: Current data and future directions

Stereotactic body radiation therapy (SBRT) offers excellent local control of early-stage non-small cell lung cancer (NSCLC), but there currently is a need for tolerable systemic therapy to address regional and distant disease progression. One potential option is immunotherapy, which in metastatic NSCLC has shown promise for sustained disease control in a subset of patients. There is also growing evidence for a clinical synergy between radiation and immunotherapy, with several ongoing trials studying the abscopal effect. This review summarizes the current data in the fast-changing field of immuno-radiation therapy, highlighting updates from recent clinical trials

A Multi-Parametric Imaging Investigation of the Response of C6 Glioma Xenografts to MLN0518 (Tandutinib) Treatment.

Angiogenesis, the development of new blood vessels, is essential for tumour growth; this process is stimulated by the secretion of numerous growth factors including platelet derived growth factor (PDGF). PDGF signalling, through its receptor platelet derived growth factor receptor (PDGFR), is involved in vessel maturation, stimulation of angiogenesis and upregulation of other angiogenic factors, including vascular endothelial growth factor (VEGF). PDGFR is a promising target for anti-cancer therapy because it is expressed on both tumour cells and stromal cells associated with the vasculature. MLN0518 (tandutinib) is a potent inhibitor of type III receptor tyrosine kinases that demonstrates activity against PDGFRα/β, FLT3 and c-KIT. In this study a multi-parametric MRI and histopathological approach was used to interrogate changes in vascular haemodynamics, structural response and hypoxia in C6 glioma xenografts in response to treatment with MLN0518. The doubling time of tumours in mice treated with MLN0518 was significantly longer than tumours in vehicle treated mice. The perfused vessel area, number of alpha smooth muscle actin positive vessels and hypoxic area in MLN0518 treated tumours were also significantly lower after 10 days treatment. These changes were not accompanied by alterations in vessel calibre or fractional blood volume as assessed using susceptibility contrast MRI. Histological assessment of vessel size and total perfused area did not demonstrate any change with treatment. Intrinsic susceptibility MRI did not reveal any difference in baseline R2* or carbogen-induced change in R2*. Dynamic contrast-enhanced MRI revealed anti-vascular effects of MLN0518 following 3 days treatment. Hypoxia confers chemo- and radio-resistance, and alongside PDGF, is implicated in evasive resistance to agents targeted against VEGF signalling. PDGFR antagonists may improve potency and efficacy of other therapeutics in combination. This study highlights the challenges of identifying appropriate quantitative imaging response biomarkers in heterogeneous models, particularly considering the multifaceted roles of angiogenic growth factors

Cosmic String Formation from Correlated Fields

We simulate the formation of cosmic strings at the zeros of a complex Gaussian field with a power spectrum $P(k) \propto k^n$, specifically addressing the issue of the fraction of length in infinite strings. We make two improvements over previous simulations: we include a non-zero random background field in our box to simulate the effect of long-wavelength modes, and we examine the effects of smoothing the field on small scales. The inclusion of the background field significantly reduces the fraction of length in infinite strings for $n < -2$. Our results are consistent with the possibility that infinite strings disappear at some $n = n_c$ in the range $-3 \le n_c < -2.2$, although we cannot rule out $n_c = -3$, in which case infinite strings would disappear only at the point where the mean string density goes to zero. We present an analytic argument which suggests the latter case. Smoothing on small scales eliminates closed loops on the order of the lattice cell size and leads to a ``lattice-free" estimate of the infinite string fraction. As expected, this fraction depends on the type of window function used for smoothing.Comment: 24 pages, latex, 10 figures, submitted to Phys Rev

Non-degenerate normal-mode doublets in vibrating flat circular plates

The vibrations of flat circular plates have been studied for hundreds of years, and they are well understood by the scientific community. Unfortunately, when vibrating circular plates are discussed in textbooks, the relationship between pairs of spatially orthogonal vibrational patterns that occur at each of the normal-mode frequencies is often ignored. Usually these orthogonal solutions are presented to the student as being degenerate in frequency; however, in practice the degeneracy of the doublet is often broken and the two spatially orthogonal solutions are separated in frequency. We show theoretically and experimentally that the degeneracy can be broken by a small asymmetry in the plate, and we derive a formula for predicting the magnitude of the frequency-splitting. We have used electronic speckle pattern interferometry to investigate the phenomena of doublet splitting and have confirmed the validity of the theory

Adsorbate-induced surface stress, surface strain and surface reconstruction : S on Cu(100) and Ni(100)

Density functional theory (DFT) calculations have been applied to investigate the known difference in behaviour of S adsorption on Cu(100) and Ni(100). Both surfaces form a 0.25 ML (2 × 2) adsorption phase, but while at higher coverage a 0.5 ML c(2 × 2) phase forms on Ni(100), on Cu(100) only a reconstructed 0.47 ML (√17 × √17)R14° structure occurs. Calculations of the energy, structure, and surface stress of (2 × 2) and c(2 × 2) phases on both substrates show there is an energy advantage on both surfaces to form the higher coverage phase, but that both surfaces show local surface strain around the S atoms in the (2 × 2) phase, a phenomenon previously investigated only on Cu(100). More than forty different structural models of the Cu(100)(√17 × √17)R14°-S phase have been investigated. The pseudo-(100)c(2 × 2) structure previously proposed, containing 16 Cu adatoms per unit mesh in the reconstructed layer, is found to be less energetically favourable than many other possible structures, even after taking account of local structural relaxations. Significantly more favourable is a structure with 12 Cu adatoms per (√17 × √17)R14° unit mesh, previously proposed on the basis of scanning tunnelling microscopy (STM), and found to yield simulated STM images in good agreement with experiment. This model has all S atoms in local 4-fold coordinated hollows relative to the Cu atoms below, half being located above Cu adatoms with the remainder lying above the underlying outermost substrate layer. However, an alternative model with only 4 Cu adatoms and with half the S atoms at 3-fold coordinated sites on the periphery of the Cu adatom cluster, has an even lower energy and gives simulated STM images in excellent agreement with experiment

Verification of Experimental Techniques for Flow Surface Determination

The concept of a yield surface is central to the mathematical formulation of a classical plasticity theory. However, at elevated temperatures, material response can be highly time-dependent, which is beyond the realm of classical plasticity. Viscoplastic theories have been developed for just such conditions. In viscoplastic theories, the flow law is given in terms of inelastic strain rate rather than the inelastic strain increment used in time-independent plasticity. Thus, surfaces of constant inelastic strain rate or flow surfaces are to viscoplastic theories what yield surfaces are to classical plasticity. The purpose of the work reported herein was to validate experimental procedures for determining flow surfaces at elevated temperatures. Since experimental procedures for determining yield surfaces in axial/torsional stress space are well established, they were employed -- except inelastic strain rates were used rather than total inelastic strains. In yield-surface determinations, the use of small-offset definitions of yield minimizes the change of material state and allows multiple loadings to be applied to a single specimen. The key to the experiments reported here was precise, decoupled measurement of axial and torsional strain. With this requirement in mind, the performance of a high-temperature multi-axial extensometer was evaluated by comparing its results with strain gauge results at room temperature. Both the extensometer and strain gauges gave nearly identical yield surfaces (both initial and subsequent) for type 316 stainless steel (316 SS). The extensometer also successfully determined flow surfaces for 316 SS at 650 C. Furthermore, to judge the applicability of the technique for composite materials, yield surfaces were determined for unidirectional tungsten/Kanthal (Fe-Cr-Al)

Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: A review of the National Cancer Database

For elderly patients with locally advanced esophageal cancer, therapeutic approaches and outcomes in a modern cohort are not well characterized. Patients ≥70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment type. Variables associated with treatment utilization were evaluated using logistic regression and survival evaluated using Cox proportional hazards analysis. Propensity matching (1:1) was performed to help account for selection bias. A total of 21,593 patients were identified. Median and maximum ages were 77 and 90, respectively. Treatment included palliative therapy (24.3%), chemoradiation (37.1%), trimodality therapy (10.0%), esophagectomy alone (5.6%), or no therapy (12.9%). Age ≥80 (OR 0.73), female gender (OR 0.81), Charlson-Deyo comorbidity score ≥2 (OR 0.82), and high-volume centers (OR 0.83) were associated with a decreased likelihood of palliative therapy versus no treatment. Age ≥80 (OR 0.79) and Clinical Stage III (OR 0.33) were associated with a decreased likelihood, while adenocarcinoma histology (OR 1.33) and nonacademic cancer centers (OR 3.9), an increased likelihood of esophagectomy alone compared to definitive chemoradiation. Age ≥80 (OR 0.15), female gender (OR 0.80), and non-Caucasian race (OR 0.63) were associated with a decreased likelihood, while adenocarcinoma histology (OR 2.10) and high-volume centers (OR 2.34), an increased likelihood of trimodality therapy compared to definitive chemoradiation. Each treatment type demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49) to trimodality therapy (HR 0.25) with significance between all groups. Any therapy, including palliative care, was associated with improved survival; however, subsets of elderly patients with locally advanced esophageal cancer are less likely to receive aggressive therapy. Care should be taken to not unnecessarily deprive these individuals of treatment that may improve survival

Time-resolved optical spectroscopy of the pulsating DA white dwarf HS 0507+0434B: New constraints on mode identification and pulsation properties

We present a detailed analysis of time-resolved optical spectra of the ZZ Ceti white dwarf, HS 0507+0434B. Using the wavelength dependence of observed mode amplitudes, we deduce the spherical degree, l, of the modes, most of which have l=1. The presence of a large number of combination frequencies (linear sums or differences of the real modes) enabled us not only to test theoretical predictions but also to indirectly infer spherical and azimuthal degrees of real modes that had no observed splittings. In addition to the above, we measure line-of-sight velocities from our spectra. We find only marginal evidence for periodic modulation associated with the pulsation modes: at the frequency of the strongest mode in the lightcurve, we measure an amplitude of 2.6+/-1.0 km/s, which has a probability of 2% of being due to chance; for the other modes, we find lower values. Our velocity amplitudes and upper limits are smaller by a factor of two compared to the amplitudes found in ZZ Psc. We find that this is consistent with expectations based on the position of HS 0507+0434B in the instability strip. Combining all the available information from data such as ours is a first step towards constraining atmospheric properties in a convectionally unstable environment from an observational perspective.Comment: 16 pages, 12 figs.; accepted for publication in A&

Mode identification of Pulsating White Dwarfs using the HST

We have obtained time-resolved ultraviolet spectroscopy for the pulsating DAV stars G226-29 and G185-32, and for the pulsating DBV star PG1351+489 with the Hubble Space Telescope Faint Object Spectrograph, to compare the ultraviolet to the optical pulsation amplitude and determine the pulsation indices. We find that for essentially all observed pulsation modes, the amplitude rises to the ultraviolet as the theoretical models predict for l=1 non-radial g-modes. We do not find any pulsation mode visible only in the ultraviolet, nor any modes whose phase flips by 180 degrees; in the ultraviolet, as would be expected if high l pulsations were excited. We find one periodicity in the light curve of G185-32, at 141 s, which does not fit theoretical models for the change of amplitude with wavelength of g-mode pulsations.Comment: Accepted for publication in the Astrophysical Journal, Aug 200