•Bevacizumab (Avastin®), a VEGF-A targeting monoclonal antibody, was the first approved angiogenesis inhibitor.•Approved in a range of solid tumor indications, bevacizumab is an important part of the ...standard of care in oncology.•The recently identified immune modulatory roles of VEGF provide a powerful rationale for combination therapies.•First clinical studies of the combination of bevacizumab with immune checkpoint inhibitors have shown efficacy.
When the VEGF-A-targeting monoclonal antibody bevacizumab (Avastin®) entered clinical practice more than 15 years ago, it was one of the first targeted therapies and the first approved angiogenesis inhibitor. Marking the beginning for a new line of anti-cancer treatments, bevacizumab remains the most extensively characterized anti-angiogenetic treatment. Initially approved for treatment of metastatic colorectal cancer in combination with chemotherapy, its indications now include metastatic breast cancer, non-small-cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer and cervical cancer. This review provides an overview of the clinical experience and lessons learned since bevacizumab’s initial approval, and highlights how this knowledge has led to the investigation of novel combination therapies.
In the past 15 years, our understanding of VEGF’s role in the tumor microenvironment has evolved. We now know that VEGF not only plays a major role in controlling blood vessel formation, but also modulates tumor-induced immunosuppression. These immunomodulatory properties of bevacizumab have opened up new perspectives for combination therapy approaches, which are being investigated in clinical trials. Specifically, the combination of bevacizumab with cancer immunotherapy has recently been approved in non-small-cell lung cancer and clinical benefit was also demonstrated for treatment of hepatocellular carcinoma. However, despite intense investigation, reliable and validated biomarkers that would enable a more personalized use of bevacizumab remain elusive.
Overall, bevacizumab is expected to remain a key agent in cancer therapy, both due to its established efficacy in approved indications and its promise as a partner in novel targeted combination treatments.
Lorsqu’ils reconnaissent des droits fonciers ancestraux, les organes décisionnels de l’Organisation des États américains promeuvent le rapport à la terre qu’entretiennent les peuples autochtones avec ...le territoire où ils exercent leurs droits culturels. Ce rapport apparent entre des notions sociales, géographiques et juridiques peut s’expliquer au regard de la géographie du droit, une théorie estimant que l’interface du droit et de l’espace sert à modeler la vie sociale sise sur un territoire. Les théories critiques développées par la géographie du droit permettent cependant de soutenir que la suprématie réclamée par les États et les droits des tiers sur les territoires peuvent servir notamment de vecteurs au droit et à l’espace afin de nier les revendications foncières autochtones et, avec elles, de restreindre le rapport particulier qui les unit à leur territoire.
In patients with glioblastoma, the addition of bevacizumab to radiotherapy and temozolomide induction therapy and the use of bevacizumab maintenance therapy did not influence overall survival. ...Freedom from progression was slightly increased but at the cost of increased toxic effects.
Tumor progression in glioblastoma, the most common primary brain cancer,
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is associated with deterioration in neurocognitive function,
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decreased functional independence,
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and a progressive decrease in health-related quality of life.
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After surgical resection, the standard of care for patients with newly diagnosed glioblastoma and a good Karnofsky performance score (≥70, on a scale of 0 to 100, with higher numbers indicating better functioning) is concurrent radiotherapy and temozolomide, followed by adjuvant temozolomide.
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The prognosis remains poor; no further improvements in outcomes have been documented since the introduction of radiotherapy–temozolomide therapy in 2005.
Glioblastomas are characterized by overexpression . . .
Introduction La vergence oculaire active améliore la stabilité posturale ; la vergence fonctionne en synergie avec l’accommodation. Ici, nous étudions le développement chez l’enfant de la synergie ...vergence-accommodation et du contrôle postural. Matériel et méthode Cinquante-sept enfants sains (de 6 à 17 ans, âge moyen 10,53 ± 3,44 ans) ont effectué en position orthostatique une tâche de vergence active entre deux cibles placées à 20 cm (18° de vergence requise, 5 dioptries d’accommodation) et 70 cm (5° de vergence requise, 1,33 dioptries d’accommodation). La vergence et l’accommodation ont été enregistrées avec l’accommodomètre PowerRefractor II (PlusOptix). En même temps, la posture a été enregistrée avec la plateforme PosturoWin. Résultats La durée de la réponse vergence-accommodation diminue avec l’âge de façon quasi-linéaire (de 800 à 400 ms). De la même façon, la surface d’oscillation posturale diminue avec l’âge de 411 mm2 à 55 mm2 . Toutefois vergence et accommodation présentent des comportements différents en termes de précision et variabilité : la réponse accommodative de chaque œil reste très variable tout au long des âges étudiés (variation de 6 dioptries). En revanche, la vergence (stimulé principalement par la disparité) s’amplifie progressivement avec l’âge, devient plus précise et sa variabilité diminue. Ainsi la synergie vergence accommodation est instable au cours de développement. Discussion L’amélioration de la stabilité posturale accompagnant les mouvements actifs vergence-accommodation vient surtout de la vergence qui s’améliore avec l’âge alors que l’accommodation reste très variable. L’amélioration de la posture opère en dépit de l’instabilité développementale dans la synergie vergence-accommodation.
ABSTRACT
Quantitative assessment of structural complexity is essential for characterization of engineered complex systems. In this paper, we describe a quantitative measure for structural complexity, ...conduct an empirical validation study of the structural complexity metric, and introduce a complexity management framework for engineering system development. We perform empirical validation of the proposed complexity metric using simple experiments using ball and stick models and show that the development effort increases superlinearly with increasing structural complexity. The standard deviation of the build time for ball and stick models is observed to vary superlinearly with structural complexity. We also describe a generic statistical procedure for building such cost estimation relationships with structural complexity as the independent variable. We distinguish the notion of perception of complexity as an observer‐dependent property and contrast that with complexity, which is a property of the system architecture. Finally, we introduce the notion of system value based on performance‐complexity trade space and introduce a complexity management framework for system development.
By contrast with previous trials of cilengitide in pancreatic, prostate, and head and neck cancers, the three phase 2 trials done in glioblastoma did not have a control group without cilengitide.7-9 ...In recurrent glioblastoma, the signal of activity came from a modest 6-month progression-free survival of 15% and a radiographic response rate of 13% (both reported with a cilengitide dose of 2000 mg).7 In patients with newly diagnosed glioblastoma, the signal of activity was interpreted in a small subgroup of patients (n=23) and subsequently compared with a historical non-contemporary control group.8 In another study, despite a substantially higher signal of activity in recurrent glioblastoma, bevacizumab increased progression-free survival but not overall survival in patients with newly diagnosed tumours, underlining the challenge of improving first-line treatment of patients with glioblastoma.10 This trial was restricted to patients with methylated MGMT promoter, based mainly on a slightly increased indication of cilengitide activity in this subgroup compared with patients with unmethylated MGMT promoter.8 However, to my knowledge, no biological data have documented an association between MGMT status and integrin biology. ...findings from in-vitro studies have suggested that MGMT does not change the response of glioma cells to cilengitide, subsequently confirmed in another phase 2 study in which the survival signal of cilengitide activity was noted irrespective of MGMT status.4,9 Tailoring of therapy to patients' individual profiles has generated many achievements (and reached some limits) in oncology in recent years.
Abstract
Erythrocyte aggregation kinetics is accelerated in diseases with a strong inflammation component. This study aimed to evaluate whether, in an emergency setting, a new point-of-care test ...measuring erythrocyte aggregation kinetics (EAK) can identify patients with underlying inflammation. Patients visiting an emergency department and needing a blood exam were successively included. EAK was measured at the point-of-care in 20 s directly on the blood samples collected in regular tubes without any manipulation. The primary measure was EAK’s half-life during the first 5 s (EAK5s). Each patient’s inflammation status was assessed blind to the EAK test results. Receiver Operating Characteristic (ROC) curves for inflammation status were built. 268 patients had their EAK5s measured, and a clear inflammation status was determined for 214 patients (65 had inflammation). Mean EAK5s were 2.18 s and 1.75 s for no inflammation and inflammation groups respectively (p < 0.001). EAK5s appears to be a better inflammation marker than C-Reactive protein (CRP), with an area under the ROC curve of 0.845 compared to 0.806 for CRP (p < 0.0001). The Youden threshold for prediction of inflammation was 1.86 s with 84.6% (78.5–89.9%) specificity and 70.8% (60–81.5%) sensitivity. Point-of-care EAK is an easily measured, immediately available marker of inflammation with a better predictive power than CRP’s.
The results of a test series on the punching behavior of slabs with varying flexural reinforcement ratios and without transverse reinforcement are presented. The aim of the tests was to investigate ...the behavior of slabs failing in punching shear with low reinforcement ratios. The size of the specimens and of the aggregate was also varied to investigate its effect on punching shear. Measurements at the concrete surface as well as through the thickness of the specimens allowed the observation of phenomena related to the development of the internal critical shear crack prior to punching. The results are compared with design codes and to the critical shear crack theory. From that comparison, it is shown that the formulation of ACI 318-08 can lead to less conservative estimates of the punching strength for thick slabs and for lower reinforcement ratios than in the test results. Satisfactory results are, on the other hand, obtained using Eurocode 2 and the critical shear crack theory.
With the recent progress of techniques in computer vision and processor design, vehicles are able to perform a greater number of functions, and are reaching higher levels of autonomy. As the list of ...autonomous tasks that the car is supposed to perform grows, two design questions arise: how to group these tasks into modules and which processors and data buses should instantiate these modules and their links in the physical architecture. Both questions are linked, as the processing capacity of the processors influences how centralized the architecture can be, and the modularization influences the overall system latency as well. Furthermore, our interest lies in designing architectures that perform the tasks rapidly, while minimizing cost. This multiobjective problem is intractable without architecture exploration and an analysis tool. This paper presents a linear optimization formulation to capture these tradeoffs, and to systematically find relevant architectures with optimal latency and cost. The results show that enforcing all safety constraints on the architecture leads to a worst case increase of 17% in latency and 18% component cost per vehicle. The increase in latency is significant at the scale of human driver reaction times.
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