•This ESMO Clinical Practice Guideline provides key recommendations for managing immunotherapy-related toxicity.•The guideline covers assessment, diagnosis and treatment of the most common and severe ...immunotherapy-related toxicities.•Recommended assessment and treatment algorithms according to the grade of toxicity are provided.•The authors comprise a multidisciplinary group of experts from different institutions in Europe, Australia and the USA.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
Adolescence is associated with enhanced striatal activity in response to rewards. This has been linked to increased risk-taking behavior and negative health outcomes. However, striatal activity is ...also important for learning, yet it is unknown whether heightened striatal responses in adolescence also benefit cognitive learning performance. In this longitudinal fMRI study (736 scans spanning 5 years in participants ages 8-29), we investigate whether adolescents show enhanced striatal activity during feedback learning, and whether this enhanced activity is associated with better learning performance. Here we report that neural activity indicating sensitivity to informative value of feedback peaks in late adolescence and occurs in dorsal caudate, ventral caudate, and nucleus accumbens. Increased activity in dorsal and ventral caudate predicts better current and future learning performance. This suggests that enhanced striatal activity in adolescents is adaptive for learning and may point to adolescence as a unique life phase for increased feedback-learning performance.
Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated ...protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required.
In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity.
High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established.
TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.
Forest edges influence more than half of the world's forests and contribute to worldwide declines in biodiversity and ecosystem functions. However, predicting these declines is challenging in ...heterogeneous fragmented landscapes. Here we assembled a global dataset on species responses to fragmentation and developed a statistical approach for quantifying edge impacts in heterogeneous landscapes to quantify edge-determined changes in abundance of 1,673 vertebrate species. We show that the abundances of 85% of species are affected, either positively or negatively, by forest edges. Species that live in the centre of the forest (forest core), that were more likely to be listed as threatened by the International Union for Conservation of Nature (IUCN), reached peak abundances only at sites farther than 200-400 m from sharp high-contrast forest edges. Smaller-bodied amphibians, larger reptiles and medium-sized non-volant mammals experienced a larger reduction in suitable habitat than other forest-core species. Our results highlight the pervasive ability of forest edges to restructure ecological communities on a global scale.
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