Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Clinical characteristics of women captured by extending the definition of severe postpartum haemorrhage with 'refractoriness to treatment': a cohort study

Background: The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods: In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results: One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion: The definition persistent postpartum haemo

A higher-order phase-field model for brittle fracture : formulation and analysis within the isogeometric analysis framework

Phase-field models based on the variational formulation for brittle fracture have recently been gaining popularity. These models have proven capable of accurately and robustly predicting complex crack behavior in both two and three dimensions. In this work we propose a fourth-order model for the phase-field approximation of the variational formulation for brittle fracture. We derive the thermodynamically consistent governing equations for the fourth-order phase-field model by way of a variational principle based on energy balance assumptions. The resulting model leads to higher regularity in the exact phase-field solution, which can be exploited by the smooth spline function spaces utilized in isogeometric analysis. This increased regularity improves the convergence rate of the numerical solution and opens the door to higher-order convergence rates for fracture problems. We present an analysis of our proposed theory and numerical examples that support this claim. We also demonstrate the robustness of the model in capturing complex three-dimensional crack behavior

A higher-order phase-field model for brittle fracture : formulation and analysis within the isogeometric analysis framework

Phase-field models based on the variational formulation for brittle fracture have recently been gaining popularity. These models have proven capable of accurately and robustly predicting complex crack behavior in both two and three dimensions. In this work we propose a fourth-order model for the phase-field approximation of the variational formulation for brittle fracture. We derive the thermodynamically consistent governing equations for the fourth-order phase-field model by way of a variational principle based on energy balance assumptions. The resulting model leads to higher regularity in the exact phase-field solution, which can be exploited by the smooth spline function spaces utilized in isogeometric analysis. This increased regularity improves the convergence rate of the numerical solution and opens the door to higher-order convergence rates for fracture problems. We present an analysis of our proposed theory and numerical examples that support this claim. We also demonstrate the robustness of the model in capturing complex three-dimensional crack behavior

von Willebrand Factor is elevated in HIV patients with a history of thrombosis

Background: Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chron