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Summary: This retrospective database study assessed 2-year persistence with bisphosphonates or denosumab in a large German cohort of women with a first-time prescription for osteoporosis treatment. Compared with intravenous or oral bisphosphonates, 2-year persistence was 1.5–2 times higher and risk of discontinuation was significantly lower (P < 0.0001) with denosumab.
Introduction: Persistence with osteoporosis therapies is critical for fracture risk reduction. Detailed data on long-term persistence (≥2 years) with bisphosphonates and denosumab are sparse.
Methods: From the German IMS® database, we included women aged 40 years or older with a first-time prescription for bisphosphonates or denosumab between July 2010 and August 2014; patients were followed up until December 2014. The main outcome was treatment discontinuation, with a 60-day permissible gap between filled prescriptions. Two-year persistence was estimated using Kaplan–Meier survival curves, with treatment discontinuation as the failure event. Denosumab was compared with intravenous (i.v.) and oral bisphosphonates separately. Cox proportional hazard ratios (HRs) for the 2-year risk of discontinuation were calculated, with adjustment for age, physician specialty, health insurance status, and previous medication use.
Results: Two-year persistence with denosumab was significantly higher than with i.v. or oral bisphosphonates (39.8 % [n = 21,154] vs 20.9 % [i.v. ibandronate; n = 20,472] and 24.8 % [i.v. zoledronic acid; n = 3966] and 16.7–17.5 % [oral bisphosphonates; n = 114,401]; all P < 0.001). Patients receiving i.v. ibandronate, i.v. zoledronic acid, or oral bisphosphonates had a significantly increased risk of treatment discontinuation than did those receiving denosumab (HR = 1.65, 1.28, and 1.96–2.02, respectively; all P < 0.0001).
Conclusions: Two-year persistence with denosumab was 1.5–2 times higher than with i.v. or oral bisphosphonates, and risk of discontinuation was significantly lower with denosumab than with bisphosphonates. A more detailed understanding of factors affecting medication-taking behavior may improve persistence and thereby reduce rates of fracture.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
This paper reports on Monte Carlo simulation results for future measurements of the moduli of time-like proton electromagnetic form factors, |GE | and |GM|, using the ¯pp → μ+μ− reaction at PANDA (FAIR). The electromagnetic form factors are fundamental quantities parameterizing the electric and magnetic structure of hadrons. This work estimates the statistical and total accuracy with which the form factors can be measured at PANDA, using an analysis of simulated data within the PandaRoot software framework. The most crucial background channel is ¯pp → π+π−,due to the very similar behavior of muons and pions in the detector. The suppression factors are evaluated for this and all other relevant background channels at different values of antiproton beam momentum. The signal/background separation is based on a multivariate analysis, using the Boosted Decision Trees method. An expected background subtraction is included in this study, based on realistic angular distribuations of the background contribution. Systematic uncertainties are considered and the relative total uncertainties of the form factor measurements are presented.
Aim: The cytokine receptor tumor necrosis factor receptor superfamily member 9 (TNFRSF9) is mainly considered to be a co-stimulatory activation marker in hematopoietic cells. Several preclinical models have shown a dramatic beneficial effect of treatment approaches targeting TNFRSF9 with agonistic antibodies. However, preliminary clinical phase I/II studies were stopped after the occurrence of several severe deleterious side effects. In a previous study, it was demonstrated that TNFRSF9 was strongly expressed by reactive astrocytes in primary central nervous system (CNS) tumors, but was largely absent from tumor or inflammatory cells. The aim of the present study was to address the cellular source of TNFRSF9 expression in the setting of human melanoma brain metastasis, a highly immunogenic tumor with a prominent tropism to the CNS.
Methods: Melanoma brain metastasis was analyzed in a cohort of 78 patients by immunohistochemistry for TNFRSF9 and its expression was correlated with clinicopathological parameters including sex, age, survival, tumor size, number of tumor spots, and BRAF V600E expression status.
Results: Tumor necrosis factor receptor superfamily member 9 was frequently expressed independently on both melanoma and endothelial cells. In addition, TNFRSF9 was also present on smooth muscle cells of larger vessels and on a subset of lymphomonocytic tumor infiltrates. No association between TNFRSF9 expression and patient survival or other clinicopathological parameters was seen. Of note, several cases showed a gradual increase in TNFRSF9 expression on tumor cells with increasing distance from blood vessels, an observation that might be linked to hypoxia-driven TNFRSF9 expression in tumor cells.
Conclusion: The findings indicate that the cellular source of TNFRSF9 in melanoma brain metastasis largely exceeds the lymphomonocytic pool, and therefore further careful (re-) assessment of potential TNFRSF9 functions in cell types other than hematopoietic cells is needed. Furthermore, the hypothesis of hypoxia-driven TNFRSF9 expression in brain metastasis melanoma cells requires further functional testing.