NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need(6,7). Here we report the progressive accumulation of exhausted, unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8(+)PD1(+) T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8(+)PD1(+)CXCR6(+), TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8(+) T cells or TNF neutralization, suggesting that CD8(+) T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8(+)PD1(+) T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Science Networks

The notion of global governance is widely studied in academia and increasingly relevant to politics and policy making. Yet many of its fundamental elements remain unclear in both theory and practice. This book offers a fresh perspective by analyzing global governance in terms of three major trends, as exemplified by developments in global sustainability governance: the emergence of nonstate actors; new mechanisms of transnational cooperation; and increasingly segmented and overlapping layers of authority. The book, which is the synthesis of a ten-year “Global Governance Project” carried out by thirteen leading European research institutions, first examines new nonstate actors, focusing on international bureaucracies, global corporations, and transnational networks of scientists; then investigates novel mechanisms of global governance, particularly transnational environmental regimes, public-private partnerships, and market-based arrangements; and, finally, looks at fragmentation of authority, both vertically among supranational, international, national, and subnational layers, and horizontally among different parallel rule-making systems. The implications, potential, and realities of global environmental governance are defining questions for our generation. This book distills key insights from the past and outlines the most important research challenges for the future

OECD peer reviews and policy convergence: diffusing policies or discourses?

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Applying a synergistic learning approach to entrepreneurship learning

This article develops our understanding of how entrepreneurship may be enhanced in existing entrepreneurs and developed in nascent entrepreneurs. It describes the authors’ exploration in the design, development and evaluation of a new programme to create opportunities for learning entrepreneurship capacities. A tripartite approach was taken, bringing together nascent entrepreneurs (undergraduate students), existing entrepreneurs and entrepreneurship facilitators. The programme was delivered using a synergistic learning approach and participatory methods in which all participants were co-learners in a collaborative, peer-learning environment. This article describes the action research approach to the exploration of entrepreneurship education androgogy and contributes to the growing body of literature in entrepreneurship education. It provides insights into how entrepreneurship education can be delivered in innovative and effective ways that mirror the ‘real world’ experience of existing and nascent entrepreneurs. It also provides insights into the nature and use of a synergistic learning approach within an entrepreneurship education context. <br/

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

Evaluating participatory modeling: developing a framework for cross-case analysis

International audienceParticipatory modeling is increasingly recognized as an effective way to assist collective decision-making processes in the domain of natural resource management. This article introduces a framework for evaluating projects that have adopted a participatory modeling approach. This evaluation framework-known as the "Protocol of Canberra"aEuro"was developed through a collaboration between French and Australian researchers engaged in participatory modeling and evaluation research. The framework seeks to assess the extent to which different participatory modeling initiatives not only modify perceptions among and interactions between participants, but also contribute to collective decision-making. The article discusses the development of the framework and it's application to three case-studies, two from Australia and one from the Pacific Island of the Republic of Kiribati. The article concludes with some comments for future use of the framework in a range of participatory modeling contexts

Conceptualizing stakeholder engagement in the context of sustainability and its assessment

Stakeholder engagement in construction projects can be conceptualized in different ways. It can be seen from a strategic management perspective aimed at capturing knowledge, increasing ownership of the project by users, reducing conflict, encouraging innovation and facilitating spin-off partnerships. From an ethical perspective, meaningful stakeholder engagement can be seen to enhance inclusive decision making, promote equity, enhance local decision making and build social capital. The benefits from both of these perspectives are vital for sustainability; however, stakeholder engagement can also be seen from the perspective of an opportunity for social learning—a social process where diverse stakeholders share a common forum, learn about each other's values, reflect upon their own values and create a shared vision and shared objectives. Dialogue is also useful in increasing awareness, changing attitudes and affecting behaviours. Existing practices view stakeholder engagement: mostly from a management perspective; sometimes from an ethical perspective; less often as a combination of the two; and rarely have any element of the social learning perspective. There is a need for an approach that combines all the three perspectives if sustainability is to be pursued. A dialogue-oriented approach to integrated sustainability assessment could provide an ideal means to do so.Stakeholder, sustainability, strategic management, ethics, social learning, dialogue, sustainability assessment,

Quality assurance for composite structures An integrated process

It is described, that quality assurance proceedings in the aeronautics industry differ from the QA measures applied in regular industry. The high quality standards on aircraft passenger demands, are requiring measures which are confirmed due to the low number of accidents. The fast increasing application of Fibre Reinforced Plastics requested a concentrated and integrated cooperation of all involved disciplines. Design, M and P engineers, manufacturing and quality assurance personnel have found efficient ways for a successful concurrent engineering. A complete understanding of the peculiarities composites contain is a must which is managed in the aeronautic industry by a quality assurance control system. Methods to handle that complex designs and processes have been developed and verified. The QA measures ensure a tractability of materials and processes. The inspection methods such as monitoring of production, measurements, destructive and non destructive inspection are providing reliability. (orig./RHM)SIGLEAvailable from TIB Hannover: RR 2088(31-93 PUB)ME / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman