Cost-effectiveness of alternative methods of surgical repair of inguinal hernia

Objectives: To assess the relative cost-effectiveness of laparoscopic methods of inguinal hernia repair compared with open flat mesh and open non-mesh repair. Methods: Data on the effectiveness of these alternatives came from three systematic reviews comparing: (i) laparoscopic methods with open flat mesh or non-mesh methods; (ii) open flat mesh with open non-mesh repair; and (iii) methods that used synthetic mesh to repair the hernia defect with those that did not. Data on costs were obtained from the authors of economic evaluations previously conducted alongside trials included in the reviews. A Markov model was used to model cost-effectiveness for a five-year period after the initial operation. The outcomes of the model were presented using a balance sheet approach and as cost per hernia recurrence avoided and cost per extra day at usual activities. Results: Open flat mesh was the most cost-effective method of preventing recurrences. Laparoscopic repair provided a shorter period of convalescence and less long-term pain compared with open flat mesh but was more costly. The mean incremental cost per additional day back at usual activities compared with open flat mesh was €38 and €80 for totally extraperitoneal and transabdominal preperitoneal repair, respectively. Conclusions: Laparoscopic repair is not cost-effective compared with open flat mesh repair in terms of cost per recurrence avoided. Decisions about the use of laparoscopic repair depend on whether the benefits (reduced pain and earlier return to usual activities) outweigh the extra costs and intraoperative risks. On the evidence presented here, these extra costs are unlikely to be offset by the short-term benefits of laparoscopic repair.Luke Vale, Adrian Grant, Kirsty McCormack, Neil W. Scott and the EU Hernia Trialists Collaboratio

Comments on Non-holomorphic Modular Forms and Non-compact Superconformal Field Theories

We extend our previous work arXiv:1012.5721 [hep-th] on the non-compact N=2 SCFT_2 defined as the supersymmetric SL(2,R)/U(1)-gauged WZW model. Starting from path-integral calculations of torus partition functions of both the axial-type (`cigar') and the vector-type (`trumpet') models, we study general models of the Z_M-orbifolds and M-fold covers with an arbitrary integer M. We then extract contributions of the degenerate representations (`discrete characters') in such a way that good modular properties are preserved. The `modular completion' of the extended discrete characters introduced in arXiv:1012.5721 [hep-th] are found to play a central role as suitable building blocks in every model of orbifolds or covering spaces. We further examine a large M-limit (the `continuum limit'), which `deconstructs' the spectral flow orbits while keeping a suitable modular behavior. The discrete part of partition function as well as the elliptic genus is then expanded by the modular completions of irreducible discrete characters, which are parameterized by both continuous and discrete quantum numbers modular transformed in a mixed way. This limit is naturally identified with the universal cover of trumpet model. We finally discuss a classification of general modular invariants based on the modular completions of irreducible characters constructed above.Comment: 1+40 pages, no figure; v2 some points are clarified with respect to the `continuum limit', typos corrected, to appear in JHEP; v3 footnotes added in pages 18, 23 for the relation with arXiv:1407.7721[hep-th

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein-protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein-protein interactions