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Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future. [ABSTRACT FROM AUTHOR]

This article presents a topology optimization (TO) method developed for maximizing the acoustic attenuation of a perforated dissipative muffler in the targeted frequency range by optimally distributing the absorbent material within the chamber. The finite element method (FEM) is applied to the wave equation formulated in terms of acoustic pressure (chamber) and velocity potential (central duct, due to the existence of thermal gradients and mean flow) in order to evaluate the acoustic performance of the noise control device in terms of transmission loss (TL). Sound propagation through the chamber fibrous material is modeled considering complex equivalent acoustic properties, which vary spatially not only as a function of temperature but also as a function of the filling density, since non-homogeneous density distributions are considered. The acoustic coupling at the perforated duct is performed by introducing a coordinate-dependent equivalent impedance. The objective function to maximize is expressed as the mean TL in the targeted frequency range. The sensitivities of this function with respect to the filling density of each element in the chamber are evaluated following the standard adjoint method. The method of moving asymptotes (MMA) is used to update the design variables at each iteration of the TO process, keeping the weight of absorbent material equal or lower than a given value, while maximizing attenuation. Additionally, several particular designs inferred from the topology optimization results are analyzed. For example, the sizing optimization of a number of rings is carried out simultaneously with the aforementioned TO process (density layout). A reactive chamber is added in order to evaluate the TL of a hybrid muffler and its shape optimization is also carried out simultaneously with the aforementioned TO. Results show an increase in the muffler's mean TL at target frequencies, for all cases under study, while the amount of absorbent material used is maintained or even reduced. [ABSTRACT FROM AUTHOR]

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In this paper, a method to in vivo estimate the relative stiffness between a hepatic lesion and the liver parenchyma is presented. This method is based on the finite element simulation of the deformation that the liver undergoes during the breathing process. Boundary conditions are obtained through a registration algorithm known as Coherent Point Drift (CPD), which compares the liver form in two phases of the breathing process. Finally, the relative stiffness of the tumour with respect to the liver parenchyma is calculated by means of a Genetic Algorithm, which does a blind search of this parameter. The relative stiffness together with the clinical information of the patient can be used to establish the type of hepatic lesion. The developed methodology was first applied to a test case, i.e., to a control case where the parameters were known, in order to verify its validity. After that, the method was applied to two real cases and low errors were obtained. [ABSTRACT FROM AUTHOR]

Purpose: Aberrant activation of MET as a result of exon 14-skipping (METex14) mutations or gene amplification is an oncogenic mechanism in non-small cell lung carcinoma (NSCLC) and a potential therapeutic target. The purpose of this study was to characterize MET alterations in a cohort of NSCLC patients treated with surgery.Methods and patients: 157 NSCLCs of various histopathologies, including pulmonary sarcomatoid carcinomas (PSC), were tested for MET alterations. METex14 mutations, MET copy number alterations and the levels of MET protein were determined by Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry, respectively. Concurrent alterations of other important cancer genes and immunostaining of the downstream effector, phopho-S6, were also determined.Results: METex14 mutations and MET amplification were detected in seven tumors. MET genetic alterations were found predominantly in the lung adenocarcinoma (ADC) and PSC histopathologies. High levels of MET protein were found in most MET-amplified tumors, but not in all METex14-mutated tumors. Strong phopho-S6 staining was observed in about half of the MET-activated tumors. One tumor with METex14 exhibited concurrent ERBB2 amplification.Conclusions: MET activation, by either METex14 mutations or amplification, is characteristic of a subset of early stage NSCLCs and may coexist with ERBB2 amplification. This may have potential therapeutic implications. The presence of METex14 mutations was associated with low levels of MET protein, which may limit the use of total MET immunostaining as a marker for preselecting patients for MET-targeted therapies. [ABSTRACT FROM AUTHOR]

We propose a new method for light-induced in situ synthesis of gold nanoparticle gratings in polymer thin films. The polymer films are doped with gold precursors and then irradiated with an interference pattern leading to the spatially controlled photo-reduction of metallic ions. An annealing procedure is then used to induce nanoparticle growth while maintaining the spatial organization within the film. The originality of the method resides in the fact that we use continuous low-power laser excitation in the visible range, which opens the way to large-area manufacturing processes. In terms of optical properties, such fabricated gold nanoparticle gratings exhibit both plasmonic and diffractive properties with plasmon enhanced diffraction efficiency. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cancer worldwide as well as the leading cause of cancer related deaths as reported by Torre et al (CA Cancer J Clin 65:87-108, ]. Non-small cell lung cancer (NSCLC) accounts for up to 85 % of all lung cancers. Multiple advances in the staging, diagnostic procedures, therapeutic options, as well as molecular knowledge have been achieved during the past years, although the overall outlook has not greatly changed for the majority of patients with the overall 5-year survival having marginally increased over the last decade from 15.7 to 17.4 % as reported by Howlader et al. (SEER Cancer Statistics Review ). [ABSTRACT FROM AUTHOR]

In situconsolidation of pre-impregnated thermoplastic composite requires as much as possible intimate contact as well as an appropriate molecular diffusion across the interface, where the intimate contact takes place. The last depends on the temperature that influences the molecular mobility. Thus, in order to evaluate the consolidation, first, we must describe accurately the composite surfaces and then, when placed in contact for manufacturing the laminate, a high-resolution simulation of the resulting thermal model must be accomplished to have access to the thermal history at the rough contact surface. In this paper, we proceed in three steps: (i) first the pre-preg surface is assimilated to a random process, a fractional Brownian motion, that can be characterized by two main descriptors, the topothesy and the fractal dimension; then, (ii) assuming the rough surface is represented by a Cantor set, the different parameters describing the fractal are determined from the statistical surface description; and finally, (iii) the resulting Cantor set representation will be considered as the geometrical support of a high-resolution thermal analysis accomplished within the proper generalized decomposition framework that allows exploring scales never until now attained. [ABSTRACT FROM AUTHOR]

Today industries do not only require fast simulation techniques but also verification techniques for the simulations. The proper generalized decomposition (PGD) has been situated as a suitable tool for fast simulation for many physical phenomena. However, so far, verification tools for the PGD are under development. The PGD approximation error mainly comes from two different sources. The first one is related with the truncation of the PGD approximation and the second one is related with the discretization error of the underlying numerical technique. In this work we propose a fast error indicator technique based on recovery techniques, for the discretization error of the numerical technique used by the PGD technique, for refinement purposes. [ABSTRACT FROM AUTHOR]

SUMMARY The use of Cartesian meshes independent of the geometry has some advantages over the traditional meshes used in the finite element method. The main advantage is that their use together with an appropriate hierarchical data structure reduces the computational cost of the finite element analysis. This improvement is based on the substitution of the traditional mesh generation process by an optimized procedure for intersecting the Cartesian mesh with the boundary of the domain and the use efficient solvers based on the hierarchical data structure. One major difficulty associated to the use of Cartesian grids is the fact that the mesh nodes do not, in general, lie over the boundary of the domain, increasing the difficulty to impose Dirichlet boundary conditions. In this paper, Dirichlet boundary conditions are imposed by means of the Lagrange multipliers technique. A new functional has been added to the initial formulation of the problem that has the effect of stabilizing the problem. The technique here presented allows for a simple definition of the Lagrange multipliers field that even allow us to directly condense the degrees of freedom of the Lagrange multipliers at element level. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Goal-oriented error estimates (GOEE) have become popular tools to quantify and control the local error in quantities of interest (QoI), which are often more pertinent than local errors in energy for design purposes (e.g. the mean stress or mean displacement in a particular area, the stress intensity factor for fracture problems). These GOEE are one of the key unsolved problems of advanced engineering applications in, for example, the aerospace industry. This work presents a simple recovery-based error estimation technique for QoIs whose main characteristic is the use of an enhanced version of the Superconvergent Patch Recovery (SPR) technique previously used for error estimation in the energy norm. This enhanced SPR technique is used to recover both the primal and dual solutions. It provides a nearly statically admissible stress field that results in accurate estimations of the local contributions to the discretisation error in the QoI and, therefore, in an accurate estimation of this magnitude. This approach leads to a technique with a reasonable computational cost that could easily be implemented into already available finite element codes, or as an independent postprocessing tool. [ABSTRACT FROM AUTHOR]

This work presents an analysismethodology based on the use of the Finite ElementMethod (FEM) nowadays considered one of the main numerical tools for solving Boundary Value Problems (BVPs).The proposedmethodology, so-called cg-FEM (Cartesian grid FEM), has been implemented for fast and accurate numerical analysis of 2D linear elasticity problems. The traditional FEM uses geometry-conforming meshes; however, in cg-FEM the analysis mesh is not conformal to the geometry. This allows for defining very efficient mesh generation techniques and using a robust integration procedure, to accurately integrate the domain's geometry. The hierarchical data structure used in cg-FEM together with the Cartesian meshes allow for trivial data sharing between similar entities. The cg-FEMmethodology uses advanced recovery techniques to obtain an improved solution of the displacement and stress fields (for which a discretization error estimator in energy norm is available) that will be the output of the analysis. All this results in a substantial increase in accuracy and computational efficiency with respect to the standard FEM. cg-FEM has been applied in structural shape optimization showing robustness and computational efficiency in comparison with FEM solutions obtained with a commercial code, despite the fact that cg-FEM has been fully implemented in MATLAB. [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3+ cell dose 107/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.Leukemia (2007) 21, 943–948. doi:10.1038/sj.leu.2404641; published online 15 March 2007 [ABSTRACT FROM AUTHOR]

Relationships between discharge and suspended sediment are very complex in most Mediterranean catchments. In the case of the Arnás catchment (Central Spanish Pyrenees), with a long history of human activity, the main factors that explain the variability of suspended sediment concentration (SCC) during floods are the peak flow and the intensity of precipitation. A cluster analysis distinguishes four types of floods according to different characteristics of precipitation, discharge, suspended sediment transport and antecedent moisture conditions. G1 and G2 floods occur under dry conditions (which prevail most of the year), with moderate rainfall and low precipitation intensity; the discharge and suspended sediment response are very fast but limited in intensity. This suggests that the origin of water and sediment is restricted to areas located very close to the channel. G3 floods also occur under dry conditions, although during intense rainfall events; then the response in both discharge and suspended sediment is very high, showing an enlargement of the contributing areas. Under very wet conditions (G4 floods) relatively moderate precipitation produces a very high response in discharge, but suspended sediment concentration records moderate values due to the effect of dilution when the entire catchment is contributing. [ABSTRACT FROM AUTHOR]

We investigated the risk factors for graft- versus-host disease (GVHD) in 82 patients treated with donor lymphocyte infusions (DLI) using an escalating dose regimen for chronic myeloid leukaemia in relapse following conventional allografting. Two factors emerged as predictors of both acute and chronic GVHD: the infusion of male recipients with lymphocytes from a female donor and the interval between transplant and last DLI, but only the first remained significant at multivariate analysis. Surprisingly, lymphocyte dose did not influence the incidence of GVHD. Our results suggest that DLI can be given in large cell doses without increasing the risk of GVHD. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of allogeneic hemopoietic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) largely relies on the graft-versus-leukemia (GvL) effect exerted by donor T cells. CD4+CD25high regulatory T cells (Tregs) have been shown to downregulate antitumor responses but their role on GvL has not been evaluated. We performed a cross-sectional study in which we enumerated and characterized CD4+CD25high Tregs in the peripheral blood of CML patients undergoing allogeneic SCT. We documented higher frequencies of Tregs in patients after transplant as compared to normal controls and newly diagnosed patients. The increment was particularly evident in patients who had received their SCT 18 months before. In vitro functional studies demonstrated that the Tregs purified from SCT patients exhibited a more potent suppressive activity than Tregs isolated from healthy volunteers. Patients in whom Tregs numbers were higher than controls more than 18 months after SCT showed evidence of disease relapse. Although the increment in Tregs might have an advantageous effect on graft rejection in the early phase post-transplant, our data suggest that Tregs exert an inhibitory effect on GvL.Leukemia (2007) 21, 472–479. doi:10.1038/sj.leu.2404522; published online 18 January 2007 [ABSTRACT FROM AUTHOR]

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.Leukemia (2004) 18, 1420-1426. doi:10.1038/sj.leu.2403423 Published online 24 June 2004 [ABSTRACT FROM AUTHOR]

Imatinib mesylate (Gleevec®/Glivec®, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. Several clinical trials have demonstrated the efficacy of imatinib in different phases of this disease. On the other hand, imatinib is also active against other tyrosine kinases, such as ABL, the stem cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this regard, imatinib has already shown a remarkable activity in patients with hypereosinophilic syndrome and gastrointestinal stromal tumours. Imatinib is an example of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a molecular-targeted therapy. [ABSTRACT FROM AUTHOR]

Summary:High-dose therapy (HDT) followed by autologous stem cell support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. The aim of this study was to identify pretransplant predictors of CR in responding myeloma patients intensified with HDT. A total of 59 patients with chemosensitive disease received myeloablative therapy. The intensification regimen consisted of MEL-200 (23), MEL-140/TBI 12?Gy (21) or busulfan-based regimens (15). Serum and urine negative immunofixation were required for CR. After HDT, the CR rate increased from 8 to 37%. For the overall series, the median event-free survival (EFS) and overall survival (OS) from the initiation of therapy were 41 and 68 months, respectively. Patients who achieved CR had an EFS (median 47 vs 36 months; P=0.023) as well as an OS (median not reached vs 60 months; P=0.006) significantly longer than those attaining a lower degree of response. Finally, the pretransplant features significantly associated to CR were a low M-protein size (serum ?10?g/l and urine <0.5?g/24?h) (P=0.0003) and a proportion of bone marrow plasma cells of ?5% (P=0.02).Bone Marrow Transplantation (2004) 33, 61-64. doi:10.1038/sj.bmt.1704313 [ABSTRACT FROM AUTHOR]

Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M-protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM ( n = 22), characterized by a progressive increase in serum M-protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non-evolving SMM ( n = 26) with stable M-protein that abruptly increases when symptomatic MM develops. Thirty-four patients developed symptomatic MM. The median time to progression in the overall series was 3·2 years and the only feature associated with a shorter time to progression was the evolving versus non-evolving type (1·3 vs. 3·9 years respectively, P = 0·007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty-seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8·2 and 3·5 years respectively. [ABSTRACT FROM AUTHOR]

We used multiplex amplification of nine microsatellite sequences (PCR-STR) to analyse chimerism in pure populations of T cells and neutrophils from peripheral blood from 40 patients submitted to an allogeneic transplant, 22 having received a T-cell depleted (TCD) peripheral blood graft by means of CD34[sup +] selection (alIo-PBT/CD34[sup +]), and 18, an unmodified graft (allo-SCT; 13 allogeneic bone marrow transplants and five allo-PBT). T-cell mixed chimerism (TcMC) was observed in 16 of the 22 (72.3%) patients receiving an allo-PBT/ CD34', but in only one of the 18 (5.5%) patients receiving an allo-SCT (P=0.0001). TcMC was transient (n=6), stable (n=7), and associated with poor haematopoietic engraftment (n=4). All patients with TcMC who developed graft failure had more than 30% of host T cells. Myeloid MC (MyMC) was observed in four (19%) allo-PBT/CD34[sup +] patients and in three (17%) allo-SCT patients (P=NS). Five out of seven (71%) patients with MyMC relapsed, all of them diagnosed with myeloid malignancies, as compared with two of the 20 (10%) patients with complete donor chimerism (P<0.0001). In conclusion, TcMC appears in a significant number of allo-PBT/CD34[sup +] patients and may be associated with poor engraftment when the percentage of host T cells is > 30%; likewise, MyMC appears in a small percentage of recipients of both allo-PBT/CD34[sup +] and allo-SCT patients, and is associated with leukaemia relapse in myeloid malignancies. [ABSTRACT FROM AUTHOR]