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.

No abstract

No abstract

The advent of open data in health care has increased healthcare innovation, with the publication of complete datasets aggregated by private and public entities that lead to efficiency through crowdsourcing working code, facilitating research into personalized medicine, and publishing reproducible data pipelines for experimental validation. However, there lacks an internationally recognized definition for health data governance at the scope of individual health data and open source big data, which bring about a discussion about the implications of open data on data privacy. First, healthcare data sourced directly from public healthcare systems: by whom and for what purpose is these data used for within the context of healthcare research. Second, health data from private research: the regulations needed for mutual disclosure. Third, personal user-generated health data: safeguards in a digital era needed to prevent misappropriation and abuse. This paper addresses the opportunities of open data in healthcare research in a digital age without transparent regulation. The consequence of open data on privacy leads to a framework of four safeguards for stakeholders: public education, operational transparency, regulation for accountability, and validation of research ethics. It also pioneers public policy direction for a balanced agenda between privacy and healthcare research.

Analyzing the information-rich content of RNA can help uncover genetic events associated with social insect castes or other social polymorphisms. Here, we exploit a series of cDNA libraries previously derived from whole-body tissue of different castes as well as from three behaviourally distinct populations of the Eastern subterranean termite Reticulitermes flavipes. We found that the number (~0.5 M) of single nucleotide variants (SNVs) was roughly equal between nymph, worker and soldier caste libraries, but dN/dS (ratio of nonsynonymous to synonymous substitutions) analysis suggested that some of these variants confer a caste-specific advantage. Specifically, the dN/dS ratio was high (~4.3) for genes expressed in the defensively specialized soldier caste, relative to genes expressed by other castes (~1.7–1.8) and regardless of the North American population (Toronto, Raleigh, Boston) from which the castes were sampled. The populations, meanwhile, did show a large difference in SNV count but not in the manner expected from known demographic and behavioural differences; the highly invasive unicolonial population from Toronto was not the least diverse and did not show any other unique substitution patterns, suggesting any past bottleneck associated with invasion or with current unicoloniality has become obscured at the RNA level. Our study raises two important hypotheses relevant to termite sociobiology. First, the positive selection (dN/dS > 1) inferred for soldier-biased genes is presumably indirect and of the type mediated through kin selection, and second, the behavioural changes that accompany some social insect urban invasions (i.e., ‘unicoloniality’) may be detached from the loss-of-diversity expected from invasion bottlenecks.