Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BackgroundA previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak.MethodsIn order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).ResultsOf the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available.ConclusionOff-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies

Going Straight: The Politics of Time and Space in David Eldridge’s Incomplete and Random Acts of Kindness

Amelia Howe Kritzer states that a contemporary British play is commonly thought of as political if it presents "a political issue or comments on what is already perceived as a political issue" (10). Since 1989, however, the economic and political system in the UK has become increasingly monologic. In such a monologic political system, Shavian dialogic forms of political theatre, which present a dialectical discussion of a political issue, lose their efficacy. As a result, some British playwrights have moved toward more interventionist strategies of political engagement, which involve our lived experience of social structures through their dramaturgy. These plays re-order normative representations of social structures, of offering a symbolic re-ordering of social structures within their form. As such, their form represents what Adorno terms, "and analogy of that other condition which should be" (194). David Harvey argues that in late capitalist society, our experience of time and space has become increasingly compressed. Consequently, our temporary axis of succession, which constitutes the fundamental organisation of Shavian drama, no longer reflects our lived experience of time in the world outside the theatre. Therefore, plays that re-order structures of time and space have political efficacy in that they expose a gap between representations of time and space as linear and concrete and our lived experience of time and space as compressed. This essay argues that David Eldridge's 'Incomplete and Random Acts of Kindness' articulates a complete breakdown in the temporal axis of succession in its structure. Its dramaturgy reflects the experience of space-time compression. Thus, it is a highly political play, not on the basis of its content, but in terms of the way in which its structure mediates and negotiates our lived experience of social structures under the pressures of late capitalism

Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions

A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg−1 of body weight) or over 300 min (0, 5, 10 or 51 μmol kg−1 of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M1) inhibited the formation of R and the last compartment (MN) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC50, of NiAc was 45 nmol L−1, the fractional turnover rate kout was 0.41 L mmol−1 min−1 and the turnover rate of moderator ktol was 0.027 min−1. A lower physiological limit of NEFA was modeled as a NiAc-independent release (kcap) of NEFA into plasma and was estimated to 0.032 mmol L−1 min−1. This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues

State Dependent Effective Interaction for the Hyperspherical Formalism with Noncentral Forces

The recently developed effective interaction method for the hyperspherical harmonic formalism is extended to noncentral forces. Binding energies and radii of three- and four-body nuclei are calculated with AV6 and AV14 NN potentials. Excellent results for the convergence of the expansion are found, particularly for the three-nucleon system. Due to the higher density the convergence rate is a bit slower for the alpha particle. In comparison to central potential models there is only a very slight deterioration of the convergence due the tensor force, while other potential terms have no visible effect on the convergence. The obtained values for binding energy and radii also agree well with the results in the literature obtained with other few-body techniques.Comment: LaTeX, 12 pages, 6 ps figures, Figures in correct order in this replacemen

Low-lying spectrum of the Y-string three-quark potential using hyper-spherical coordinates

We calculate the energies of three-quark states with definite permutation symmetry (i.e. of SU(6) multiplets) in the N=0,1,2 shells, confined by the Y-string three-quark potential. The exact Y-string potential consists of one, so-called three-string term, and three angle-dependent two-string terms. Due to this technical complication we treat the problem at three increasingly accurate levels of approximation: 1) the (approximate) three-string potential expanded to first order in trigonometric functions of hyper-spherical angles; 2) the (approximate) three-string potential to all orders in the power expansion in hyper-spherical harmonics, but without taking into account the transition(s) to two-string potentials; 3) the exact minimal-length string potential to all orders in power expansion in hyper-spherical harmonics, and taking into account the transition(s) to two-string potentials. We show the general trend of improvement %convergence of these approximations: The exact non-perturbative corrections to the total energy are of the order of one per cent, as compared with approximation 2), yet the exact energy differences between the $[20,1^{+}], [70,2^{+}], [56,2^{+}], [70,0^{+}]$-plets are shifted to 2:2:0.9, from the Bowler and Tynemouth separation rule 2:2:1, which is obeyed by approximation 2) at the one per cent level. The precise value of the energy separation of the first radial excitation ("Roper") $[56^{\prime},0^{+}]$-plet from the $[70,1^{-}]$-plet depends on the approximation, but does not become negative, i.e. the "Roper" remains heavier than the odd-parity $[70,1^{-}]$-plet in all of our approximations.Comment: 19 pages, 6 figure

Non-perturbative Gluons and Pseudoscalar Mesons in Baryon Spectroscopy

We study baryon spectroscopy including the effects of pseudoscalar meson exchange and one gluon exchange potentials between quarks, governed by $\alpha_s$. The non-perturbative, hyperspherical method calculations show that one can obtain a good description of the data by using a quark-meson coupling constant that is compatible with the measured pion-nucleon coupling constant, and a reasonably small value of $\alpha_s$.Comment: 12 pages; Submitted to Phys. Rev. C. Rapid Communication

BDM Dark Matter: CDM with a core profile and a free streaming scale

We present a new dark matter model BDM which is an hybrid between hot dark matter HDM and cold dark matter CDM, in which the BDM particles behave as HDM above the energy scale E_c and as CDM below this scale. Evolution of structure formation is similar to that of CDM model but BDM predicts a nonvanishing free streaming l_fs scale and a inner galaxy core radius r_core, both quantities determined in terms of a single parameter E_c, which corresponds to the phase transition energy scale of the subjacent elementary particle model. For energies above E_c or for a scale factor a smaller then a_c, with a<a_c<a_{eq}, the particles are massless and rho redshifts as radiation. However, once the energy becomes E\leq E_c or a>a_c then the BDM particles acquire a large mass through a non perturbative mechanism, as baryons do, and rho redshifts as matter with the particles having a vanishing velocity. Typical energies are E_c=O(10-100) eV giving a l_fs \propto E_c^{-4/3}\lesssim Mpc and m_fs\propto E_c^{-4}\lesssim 10^9 M\odot. A l_fs\neq 0, r_core\neq 0 help to resolve some of the shortcomings of CDM such as overabundance substructure in CDM halos and numerical fit to rotation curves in dwarf spheroidal and LSB galaxies. Finally, our BDM model and the phase transition scale E_c can be derived from particle physics.Comment: 7 pages, 8 figure

On three-manifolds dominated by circle bundles

We determine which three-manifolds are dominated by products. The result is that a closed, oriented, connected three-manifold is dominated by a product if and only if it is finitely covered either by a product or by a connected sum of copies of the product of the two-sphere and the circle. This characterization can also be formulated in terms of Thurston geometries, or in terms of purely algebraic properties of the fundamental group. We also determine which three-manifolds are dominated by non-trivial circle bundles, and which three-manifold groups are presentable by products.Comment: 12 pages; to appear in Math. Zeitschrift; ISSN 1103-467

First and second order optimality conditions for optimal control problems of state constrained integral equations

This paper deals with optimal control problems of integral equations, with initial-final and running state constraints. The order of a running state constraint is defined in the setting of integral dynamics, and we work here with constraints of arbitrary high orders. First and second-order necessary conditions of optimality are obtained, as well as second-order sufficient conditions

Pentaquark spectrum in string dynamics

The masses of $uudd\bar s$ and $uudd\bar d$ pentaquarks are evaluated in a framework of the Effective Hamiltonian approach to QCD using the Jaffe-Wilczek $[ud]^2\bar q$ approximation. The mass of the $[ud]^2\bar s$ state is found to be $\sim 300-500$ MeV higher than the observed $\Theta^+(1540)$ mass.Comment: 6 pages, 1 figure included, LaTeX2e; several references added; misprints corrected; to appear in Physics Letters