Abstract Background Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults ...and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly ‘GCTB-schedule’ (120 mg per 12/year, 1440 mg total dose/year) are lacking. Methods Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. Results Ninety-seven were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6–45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years range: 13–76 years, 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9–115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7–15 months). Adverse events Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84–100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). Conclusions Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.
Electronic packaging is a critical part of products such as computers, cellular phones, automotive components and other electronic devices. The package must be tailored to incorporate as many ...input/output interconnects as possible, in a limited amount of space. Until recently, most solder balls were made of a eutectic Pb-Sn alloy, because of its low melting point, excellent wetting characteristics and adequate creep and thermal fatigue strength. The potential health hazards associated with the toxicity of lead are significant. Given the widespread use of Pb-Sn solder in the manufacture and assembly of circuit boards, the development and reliability of new Pb-free solders is crucial for the successful substitution of these materials in the electronics industry. Pb-free solder alloys are complex materials with various important microstructural attributes. These include the nanoscale precipitates of Ag
3
Sn in Sn-Ag-Cu or Sn-Ag alloys, as well as Cu
6
Sn
5
intermetallic formed at the interface between the solder and Cu metallisation. The mechanical behaviour of solder alloys is extremely important because solder joints must retain their mechanical integrity under a myriad of conditions such as creep, thermal fatigue, and mechanical shock and drop resistance. A significant amount of work has been carried out on the monotonic shear, creep and thermal fatigue resistance of these materials. An important new area of research is the mechanical shock and vibration fatigue behaviour of Pb-free solders. The developments in all these areas are critically examined in this paper.
Nanoindentation is an important technique for probing the mechanical behavior of materials at small length scales. In this study, nanoindentation was used to extract the elastic and plastic ...properties of Cu, Sn–3.5Ag solder, Ag
3Sn, and intermetallics in Cu/Sn–Ag solder joints including Cu
6Sn
5, and Cu
3Sn. The elastic and plastic properties of Cu, Sn–3.5Ag solder, Ag
3Sn, Cu
6Sn
5, and Cu
3Sn were measured and where possible, compared to limited data available in the literature. Finite element analysis was used to simulate the indentation behavior from elastic–plastic properties of the intermetallics. The predicted values matched very well with experimental results. Finite element analysis also showed that pile-up took place in indentation of Cu and solder, while indentation sink-in was observed in Ag
3Sn, Cu
6Sn
5, and Cu
3Sn. The relative degree of pile-up/sink-in was shown to be a function of the work hardening exponent of the phase and the ratio of yield stress to Young's modulus.
The micromechanical behavior of single-crystal Cu6Sn5 was studied by microcompression testing of pillars. The pillars were fabricated by focused ion beam milling and tested using a nanoindenter with ...a flat tip. The stress-strain behavior and fractographic analysis show that Cu6Sn5 deforms elastically and undergoes cleavage, resulting in fracture. The strain bursts on stress-strain curves correspond to cleavage on various planes. The fracture stress calculated using the area at the top of pillars was independent of taper angle.
The microstructure and mechanical properties of sintered Fe–0.85Mo–Ni steels were investigated as a function of sintered density. A quantitative analysis of microstructure was correlated with tensile ...and fatigue behavior to understand the influence of pore size, shape, and distribution on mechanical behavior. Tensile strength, Young's modulus, strain-to-failure, and fatigue strength all increased with a decrease in porosity. The decrease in Young's modulus with increasing porosity was predicted by analytical modeling. Two-dimensional microstructure-based finite element modeling showed that the enhanced tensile and fatigue behavior of the denser steels could be attributed to smaller, more homogeneous, and more spherical porosity which resulted in more homogeneous deformation and decreased strain localization in the material. The implications of pore size, morphology, and distribution on the mechanical behavior and fracture of P/M steels are discussed.
Metal-ceramic nanolaminate composites show promise as high strength and toughness materials. Micropillar compression was used to characterize the mechanical behavior of Al-SiC multilayers in ...different orientations including loading at 0 degree , 45 degree and 90 degree with respect to the direction of the layers. The 0 degree orientation showed the highest strength while the 45 degree orientation showed the lowest strength. Each orientation showed unique deformation behavior. Effects of pillar size and aspect ratio were also studied. Higher compressive strengths were observed in smaller pillars for all orientations. This effect was shown to be due to a lower probability of flaws using Weibull statistics. Additionally, changes in the aspect ratio was shown to have no significant effect on the behavior except an increase in the strain to failure in the 0 degree orientation. Finite element analysis (FEA) was used to simulate and understand the effect of these parameters on the deformation behavior.
A review is provided of the use of analytical models and two dimensional (2D) and three dimensional (3D) microstructure based FEM models to accurately predict the properties of particle reinforced ...composite materials. It is shown that analytical models do not account for the microstructural factors that influence the mechanical behavior of the material. 2D models do capture the anisotropy in deformation behavior induced by anisotropy in particle orientation. The experimentally-observed dependence of Young's modulus and tensile strength is confirmed by the 2D microstructure-based numerical model. However, because of the 2D stress state, a realistic comparison to actual experimental values is not possible. A serial sectioning process can be used to reproduce and visualize the 3D microstructure of particle reinforced metal matrix composites. The 3D microstructure-based FEM accurately represents the alignment, aspect ratio, and distribution of the particles. Comparison with single particle and multiparticle models of simple shape (spherical and ellipsoidal) shows that the 3D microstructure-based approach is more accurate in simulating and understanding material behavior.
The presence of reflow porosity in Sn-based solder alloys is one of the key factors affecting their reliability and mechanical performance. In this study we have used X-ray microtomography to ...visualize the reflow porosity in a Pb-free solder joint and to reconstruct a three-dimensional model based on the exact geometry of the pores. Interrupted shear tests and subsequent tomography were conducted to image the joint at several stages of deformation. The initial reconstructed microstructure was used as a basis for a finite element (FE) model to simulate damage and predict failure of the single lap shear joint. Sphericity analysis was conducted to verify the accuracy of the FE results. The deformation predicted by the FE simulation incorporating the ductile damage model showed very good agreement with experimental observations. The model was also able to accurately predict the crack nucleation sites and propagation path.
Nanolaminate composites show promise as high strength and toughness materials. However, due to the limited volume of these materials, micron scale mechanical testing methods must be used to determine ...the properties of these films. To this end, a novel approach combining a double notch shear testing geometry and compression with a flat punch in a nanoindenter was developed to determine the mechanical properties of these films under shear loading. To further elucidate the failure mechanisms under shear loading, in situ TEM experiments were performed using a double notch geometry cut into the TEM foil. Aluminum layer thicknesses of 50nm and 100nm were used to show the effect of constraint on the deformation. Higher shear strength was observed in the 50nm sample (690±54MPa) compared to the 100nm sample (423±28.7MPa). Additionally, failure occurred close to the Al–SiC interface in the 50nm sample as opposed to failure within the Al layer in the 100nm sample.
Standard therapy for an enhancing renal mass is surgical. However, operative treatment may not be plausible in all clinical circumstances. Data on the natural history of untreated enhancing renal ...lesions is limited but could serve as a decision making resource for patients and physicians. We examined available data on the natural history of observed solid renal masses.
A Medline review of the literature was performed from 1966 to the present regarding untreated, observed, localized solid renal masses. To these data we added our institutional experience with a total of 61 lesions observed in 49 patients for a minimum of 1 year. Variables examined were initial lesion size at presentation, growth rate, duration of followup, pathological findings and progression to metastatic disease. Overall weighted mean estimates were calculated for lesion size at presentation, growth rate and followup based upon combining single institutional series with complete information.
We identified 10 reports from 9 single institutional series in the world literature regarding the natural history of untreated solid localized renal lesions. The series included 6 to 40 patients (mean 25) with a mean followup of 30 months (range 25 to 39). When combined with our institutional data, a total of 286 lesions were analyzed, of which 234 could be included in the meta-analysis. Mean lesion size at presentation was 2.60 cm (median 2.48, range 1.73 to 4.08). Meta-analysis revealed a mean growth rate of 0.28 cm yearly (median 0.28, range 0.09 to 0.86) at a mean followup of 34 months (median 32, range 26 to 39) in all series combined. Pathological confirmation was available in 46% of the cases (131 of 286) and it confirmed 92% (120 of 131) as RCC variants. Evaluable data in this subset of confirmed RCC demonstrated a mean growth rate of 0.40 cm yearly (median 0.35, range 0.42 to 1.6). Lesion size at presentation did not predict the overall growth rate (p = 0.46). Progression to metastatic disease was identified in only 1% of lesions (3 of 286) during followup.
The majority of small enhancing renal masses grow at a slow rate when observed. Although metastatic and cancer specific death are low, serial radiographic data alone are insufficient to predict the true natural history of these lesions. Therefore, physicians and patients assume a calculated risk when following these tumors. Basic biological data are needed to assess the natural history of untreated renal masses.
PDF
