Cost Effectiveness of First-Line Treatment with Doxorubicin/Ifosfamide Compared to Trabectedin Monotherapy in the Management of Advanced Soft Tissue Sarcoma in Italy, Spain, and Sweden

BACKGROUND: Doxorubicin/ifosfamide is a first-line systemic chemotherapy for the majority of advanced soft tissue sarcoma (ASTS) subtypes. Trabectedin is indicated for the treatment of ASTS after failure of anthracyclines and/or ifosfamide; however it is being increasingly used off-label as a first-line treatment. This study estimated the cost effectiveness of these two treatments in the first-line management of ASTS in Italy, Spain, and Sweden. METHODS: A Markov model was constructed to estimate the cost effectiveness of doxorubicin/ifosfamide compared to trabectedin monotherapy, defined as the cost per QALY gained, in each country. RESULTS: First-line treatment with doxorubicin/ifosfamide resulted in lower two-year healthcare costs and more QALYs than first-line treatment with trabectedin monotherapy in all three countries. Probabilistic sensitivity analysis showed that at a cost per QALY threshold of €35,000, >90% of a cohort would be cost effectively treated with doxorubicin/ifosfamide compared to trabectedin monotherapy in all three countries. CONCLUSION: Within the model’s limitations, first-line treatment of patients with ASTS with doxorubicin/ifosfamide instead of trabectedin monotherapy affords a cost-effective use of publicly funded healthcare resources in Italy, Spain, and Sweden and is therefore the preferred treatment in all three countries. These findings support the recommendation that trabectedin should remain a second-line treatment

Supergravity loop contributions to brane world supersymmetry breaking

We compute the supergravity loop contributions to the visible sector scalar masses in the simplest 5D `brane-world' model. Supersymmetry is assumed to be broken away from the visible brane and the contributions are UV finite due to 5D locality. We perform the calculation with N = 1 supergraphs, using a formulation of 5D supergravity in terms of N = 1 superfields. We compute contributions to the 4D effective action that determine the visible scalar masses, and we find that the mass-squared terms are negative.Comment: 12 pages, LaTeX 2

Covariant N=2 heterotic string in four dimensions

We construct a covariant formulation of the heterotic superstring on K3 times T^2 with manifest N=2 supersymmetry. We show how projective superspace appears naturally in the hybrid formulation giving a (partially) geometric interpretation of the harmonic parameter. The low-energy effective action for this theory is given by a non-standard form of N=2 supergravity which is intimately related to the N=1 old-minimal formulation. This formalism can be used to derive new descriptions of interacting projective superspace field theories using Berkovits' open string field theory and the the heterotic Berkovits-Okawa-Zwiebach construction.Comment: 11+3 page

Immunophenotypic analysis of cell cycle status in acute myeloid leukaemia: relationship to cytogenetics, genotype and clinical outcome

Cell cycle status may play an important role in directing patient therapy. We therefore determined the cell cycle status of leukaemic cells by immunophenotypic analysis of bone marrow trephine biopsies from 181 patients with acute myeloid leukaemia (AML) and correlated the results with biological features and clinical outcome. There was considerable heterogeneity between patients. The presenting white cell count significantly correlated with the proportion of non-quiescent cells (P < 0·0001), of cycling cells beyond G1 (P < 0·0001) and the speed of cycling (P < 0·0001). Profiles in acute promyelocytic leukaemia (APL) differed from non-APL and were consistent with more differentiated cells with reduced proliferative potential, but no significant differences were observed between non-APL cytogenetic risk groups. NPM1 mutations but not FLT3 internal tandem duplication (FLT3ITD ) were significantly associated with a higher proportion of cells beyond G1 (P = 0·002) and faster speed of cycling (P = 0·003). Resistance to standard cytosine arabinoside and daunorubicin induction chemotherapy was significantly related to a slower speed of cycling (P = 0·0002), as was a higher relapse rate (P = 0·05), but not with the proportion of non-quiescent cells or actively cycling cells. These results show a link between the cycling speed of AML cells and the response to chemotherapy, and help to identify a group with a very poor prognosis

Chiral Supergravitons Interacting with a 0-Brane N-Extended NSR Super-Virasoro Group

We continue the development of the actions, S_{AFF}, by examining the cases where there are N fermionic degrees of freedom associated with a 0-brane. These actions correspond to the interaction of the N-extended super Virasoro algebra with the supergraviton and the associated SO(N) gauge field that accompanies the supermultiplet. The superfield formalism is used throughout so that supersymmetry is explicit.Comment: PACS: 04.65.+e, 11.15.-q, 11.25.-w, 12.60.

Mediation of supersymmetry breaking in extra dimensions

We review the mechanisms of supersymmetry breaking mediation that occur in sequestered models, where the visible and the hidden sectors are separated by an extra dimension and communicate only via gravitational interactions. By locality, soft breaking terms are forbidden at the classical level and reliably computable within an effective field theory approach at the quantum level. We present a self-contained discussion of these radiative gravitational effects and the resulting pattern of soft masses, and give an overview of realistic model building based on this set-up. We consider both flat and warped extra dimensions, as well as the possibility that there be localized kinetic terms for the gravitational fields.Comment: LaTex, 15 pages; brief review prepared for MPLA. v2: minor correction

Cryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation

The structure-specific endonuclease XPF-ERCC1 participates in multiple DNA damage repair pathways including nucleotide excision repair (NER) and inter-strand crosslink repair (ICLR). How XPF-ERCC1 is catalytically activated by DNA junction substrates is not currently understood. Here we report cryo-electron microscopy structures of both DNA-free and DNA-bound human XPF-ERCC1. DNA-free XPF-ERCC1 adopts an auto-inhibited conformation in which the XPF helical domain masks the ERCC1 (HhH)2 domain and restricts access to the XPF catalytic site. DNA junction engagement releases the ERCC1 (HhH)2 domain to couple with the XPF-ERCC1 nuclease/nuclease-like domains. Structure-function data indicate xeroderma pigmentosum patient mutations frequently compromise the structural integrity of XPF-ERCC1. Fanconi anaemia patient mutations in XPF often display substantial in-vitro activity but are resistant to activation by ICLR recruitment factor SLX4. Our data provide insights into XPF-ERCC1 architecture and catalytic activation

Hybrid Formalism, Supersymmetry Reduction, and Ramond-Ramond Fluxes

The supersymmetric hybrid formalism for Type II strings is used to study partial supersymmetry breaking in four and three dimensions. We use worldsheet techniques to derive effects of internal Ramond-Ramond fluxes such as torsions, superpotentials and warping.Comment: Harvmac. No figure

On Five-dimensional Superspaces

Recent one-loop calculations of certain supergravity-mediated quantum corrections in supersymmetric brane-world models employ either the component formulation (hep-th/0305184) or the superfield formalism with only half of the bulk supersymmetry manifestly realized (hep-th/0305169 and hep-th/0411216). There are reasons to expect, however, that 5D supergraphs provide a more efficient setup to deal with these and more involved (in particular, higher-loop) calculations. As a first step toward elaborating such supergraph techniques, we develop in this letter a manifestly supersymmetric formulation for 5D globally supersymmetric theories with eight supercharges. Simple rules are given to reduce 5D superspace actions to a hybrid form which keeps manifest only the 4D, N=1 Poincare supersymmetry. (Previously, such hybrid actions were carefully worked out by rewriting the component actions in terms of simple superfields). To demonstrate the power of this formalism for model building applications, two families of off-shell supersymmetric nonlinear sigma-models in five dimensions are presented (including those with cotangent bundles of Kahler manifolds as target spaces). We elaborate, trying to make our presentation maximally clear and self-contained, on the techniques of 5D harmonic and projective superspaces used at some stages in this letter.Comment: 46 pages, 3 figures. V5: version published in JHE