No abstract

The outcome of ex vivo TIL expansion is highly influenced by spatial heterogeneity of the tumor Tcell repertoire and differences in intrinsic in vitro growth capacity between T-cell clones AUTHORS -

Background: Treatment with tumor-Infiltrating Lymphocytes (TIL) is an innovative therapy for advanced melanoma with promising clinical phase I/II study results and likely beneficial cost-effectiveness. As a randomized controlled trial on the effectiveness of TIL therapy in advanced melanoma compared to ipilimumab is still ongoing, adoption of TIL therapy by the field is confronted with uncertainty. To deal with this, scenario drafting can be used to identify potential barriers and enables the subsequent anticipation on these barriers. This study aims to inform adoption decisions of TIL by evaluating various scenarios and evaluate their effect on the cost-effectiveness. Methods: First, 14 adoption scenarios for TIL-therapy were drafted using a Delphi approach with a group of involved experts. Second, the likelihood of the scenarios taking place within 5 years was surveyed among international experts using a web-based questionnaire. Third, based on the questionnaire results and recent literature, scenarios were labeled as being either "likely" or "-unlikely". Finally, the cost-effectiveness of TIL treatment involving the "likely" scored scenarios was calculated. Results: Twenty-nine experts from 12 countries completed the questionnaire. The scenarios showed an average likelihood ranging from 29 to 58%, indicating that future developments of TIL-therapy were surrounded with quite some uncertainty. Eight of the 14 scenarios were labeled as "likely". The net monetary benefit per patient is presented as a measure of cost-effectiveness, where a positive value means that a scenario is cost-effective. For six of these scenarios the cost-effectiveness was calculated: "Commercialization of TIL production" (the price was assumed to be 3 times the manufacturing costs in the academic setting) (−€51,550), "Pharmaceutical companies lowering the prices of ipilimumab" (€11,420), "Using TIL-therapy combined with ipilimumab" (−€10,840), "Automatic TIL production" (€22,670), "TIL more effective" (€23,270), "Less Interleukin-2" (€20,370).

To improve immunotherapy efficacy, a better understanding of the factors that regulate Tcell migration into tumors is essential. Here we uncover a role for autotaxin (ATX) in this process. ATX (encoded by ENPP2) produces lysophosphatidic acid (LPA) that activates G protein-coupled receptors (LPAR1-6) to regulate multiple (patho)physiological processes, including tumor progression via LPAR1 and lymphocyte homing via LPAR2.Unexpectedly, we find that melanoma cell-secreted ATX is a major chemorepellent for tumor-infiltrating lymphocytes ex vivo through Gα12/13-coupled LPAR6, with ATX functioning as an LPA-producing chaperone. Using an anti-cancer vaccination model, we provide proof-of-concept that secreted ATX opposes tumor infiltration of CD8+ T cells.Additionally, ENPP2 expression in melanoma tumors correlates with reduced CD8+ T-cell infiltration as inferred from single-cell transcriptomics. Hence, by counteracting T-cell infiltration while activating tumor cells via different LPA receptors, the ATX/LPA complex exerts dual actions in the tumor immune microenvironment, which may provide new therapeutic approaches.

Abstract-Existing sampling-based robot motion planning methods are often inefficient at finding trajectories for kinodynamic systems, especially in the presence of narrow passages between obstacles and uncertainty in control and sensing. To address this, we propose EG-RRT, an Environment-Guided variant of RRT designed for kinodynamic robot systems that combines elements from several prior approaches and may incorporate a cost model based on the LQG-MP framework to estimate the probability of collision under uncertainty in control and sensing. We compare the performance of EG-RRT with several prior approaches on challenging sample problems. Results suggest that EG-RRT offers significant improvements in performance.

No abstract

ObjectivesTo investigate associations of job demands and resources with patient-related burnout among physicians.DesignMulticentre observational study.SettingFifty medical departments at 14 (academic and non-academic) hospitals in the Netherlands.ParticipantsFour hundred sixty-five physicians (71.6% response rate), comprising 385 (82.8%) medical specialists and 80 (17.2%) residents.Main outcome measuresJob demands (workload and bureaucratic demands), job resources (participation in decision making, development opportunities, leader’s inspiration, relationships with colleagues and patients)—measured with the validated Questionnaire of Experience and Evaluation of Work and Physician Worklife Survey—and patient-related burnout, measured using the validated Copenhagen Burnout Inventory.ResultsPatient-related burnout was positively associated with workload (b=0.36; 95% CI, 0.25 to 0.48; p<0.001) and negatively associated with development opportunities (b=–0.18; 95% CI, –0.27 to –0.08; p<0.001) and relationships with patients (b=–0.12; 95% CI, –0.22 to –0.03; p=0.01). Relationships with patients moderated the association between bureaucratic demands and patient-related burnout (b=–0.15; 95% CI, –0.27 to –0.04; p=0.01).ConclusionsPhysicians with high workloads and few development opportunities reported higher levels of patient-related burnout. Those with positive patient relationships were less likely to experience patient-related burnout, even in the presence of excessive bureaucracy. Therefore, positive physician–patient relationships may be supported to reduce the likelihood of physicians’ patient-related burnout. However, the specific support needed to effectively reduce patient-related burnout may vary per healthcare context and thus requires intensified research across healthcare systems and settings.

No abstract