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- Das, A., et al.
(författare)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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| 2. |
- Lee, Eun-Young, et al.
(författare)
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Play, Learn, and Teach Outdoors—Network (PLaTO-Net) : terminology, taxonomy, and ontology
- 2022
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Ingår i: International Journal of Behavioral Nutrition and Physical Activity. - : BioMed Central (BMC). - 1479-5868. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A recent dialogue in the field of play, learn, and teach outdoors (referred to as “PLaTO” hereafter) demonstrated the need for developing harmonized and consensus-based terminology, taxonomy, and ontology for PLaTO. This is important as the field evolves and diversifies in its approaches, contents, and contexts over time and in different countries, cultures, and settings. Within this paper, we report the systematic and iterative processes undertaken to achieve this objective, which has built on the creation of the global PLaTO-Network (PLaTO-Net). Methods: This project comprised of four major methodological phases. First, a systematic scoping review was conducted to identify common terms and definitions used pertaining to PLaTO. Second, based on the results of the scoping review, a draft set of key terms, taxonomy, and ontology were developed, and shared with PLaTO members, who provided feedback via four rounds of consultation. Third, PLaTO terminology, taxonomy, and ontology were then finalized based on the feedback received from 50 international PLaTO member participants who responded to ≥ 3 rounds of the consultation survey and dialogue. Finally, efforts to share and disseminate project outcomes were made through different online platforms. Results: This paper presents the final definitions and taxonomy of 31 PLaTO terms along with the PLaTO-Net ontology model. The model incorporates other relevant concepts in recognition that all the aspects of the model are interrelated and interconnected. The final terminology, taxonomy, and ontology are intended to be applicable to, and relevant for, all people encompassing various identities (e.g., age, gender, culture, ethnicity, ability). Conclusions: This project contributes to advancing PLaTO-based research and facilitating intersectoral and interdisciplinary collaboration, with the long-term goal of fostering and strengthening PLaTO’s synergistic linkages with healthy living, environmental stewardship, climate action, and planetary health agendas. Notably, PLaTO terminology, taxonomy and ontology will continue to evolve, and PLaTO-Net is committed to advancing and periodically updating harmonized knowledge and understanding in the vast and interrelated areas of PLaTO.
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