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Background Single‐arm trials are common in precision oncology. Owing to the lack of randomized counterfactual, resultant data are not amenable to comparative outcomes analyses. Difference‐in‐difference (DID) methods present an opportunity to generate causal estimates of time‐varying treatment outcomes. Using DID, our study estimates within‐cohort effects of genomics‐informed treatment versus standard care on clinical and cost outcomes. Methods We focus on adults with advanced cancers enrolled in the single‐arm BC Cancer Personalized OncoGenomics program between 2012 and 2017. All individuals had a minimum of 1‐year follow up. Logistic regression explored baseline differences across patients who received a genomics‐informed treatment versus a standard care treatment after genomic sequencing. DID estimated the incremental effects of genomics‐informed treatment on time to treatment discontinuation (TTD), time to next treatment (TTNT), and costs. TTD and TTNT correlate with improved response and survival. Results Our study cohort included 346 patients, of whom 140 (40%) received genomics‐informed treatment after sequencing and 206 (60%) received standard care treatment. No significant differences in baseline characteristics were detected across treatment groups. DID estimated that the incremental effect of genomics‐informed versus standard care treatment was 102 days (95% CI: 35, 167) on TTD, 91 days (95% CI: −9, 175) on TTNT, and CAD$91,098 (95% CI: $46,848, $176,598) on costs. Effects were most pronounced in gastrointestinal cancer patients. Conclusions Genomics‐informed treatment had a statistically significant effect on TTD compared to standard care treatment, but at increased treatment costs. Within‐cohort evidence generated through this single‐arm study informs the early‐stage comparative effectiveness of precision oncology., Difference‐in‐difference analysis is used to address confounding when analyzing real‐world data from a single‐arm precision oncology trial. Enrolled patients receiving genomics‐informed treatment are treated longer, suggesting improved efficacy, but at an increased cost compared to those receiving standard care.

The presence of an anterior mediastinal mass should prompt rapid triage, workup and treatment to effectively manage and prevent emergent complications. Implementation of an AMM protocol can ensure the response is standardized and coordinated. Importantly, such a protocol can encourage prompt multi-disciplinary communication to mitigate risks associated with procedures required for timely diagnosis. The aim of this review is to evaluate the BC Children’s Hospital’s Pediatric New/Suspected Anterior Mediastinal Mass (AMM) Protocol. Retrospective chart review was conducted for 18 patients admitted from February 2016 to May 2020 with AMM for whom the protocol was enacted. Primary parameters assessed presence of high-risk feature at time of presentation, time from admission and/or protocol activation to specific time points, including imaging, first diagnostic procedure, and diagnosis. Data regarding perioperative management, including anesthetic considerations and peri-operative complications, was also collected. Mean time from protocol activation to first diagnostic procedure and diagnosis were 1.88 days (range 0–7) and 2.24 days (range 0–7), respectively. The majority of procedures were conducted under sedation (n = 77, 64%), followed by general anesthetic (GA; n = 34, 28%) and local anesthetic (n = 10, 8%). Despite 15 cases having more than one high risk feature, pre-operative steroids were only administered for four of the total 158 procedures (3%) and extracorporeal life support (ECLS) and otolaryngology (ENT) were only required for immediate availability for seven procedures (4%). Furthermore, only 10 procedures (8%) had associated complications and none of these complications resulted in patient death. Our data demonstrate that implementation of a streamlined multi-disciplinary protocol can expedite time to diagnosis without impacting patient safety.

There has been increased focus on atrocity prevention and the preventative elements associated with Pillar ii of the Responsibility to Protect. Policymakers and academics have offered a range of short-term preventative measures available so that the international community can better fulfil its Pillar ii responsibilities. This article challenges this current R2P thinking by arguing that its short-termism insufficiently focuses on de-escalation of risk within already present cycles of violence while dealing superficially with long-term causes and the ways in which the international community is a contributing factor in underwriting systemic and structural determinants of violence which erode state resilience against mass atrocity. As an alternative, this article examines a number of ways in which key actors of the international community contribute to determinants of mass violence and further offer recommendations for how they could better discharge their long-term preventative responsibilities by first reforming their own practices.

We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation. Expression of the altered p.(Met1141Lys) variant in a PLCγ2-knockout DT40 cell line showed clearly enhanced BCR-triggered influx of external calcium when compared to control-transfected cells. Our results further expand the molecular basis of pediatric CVID and phenotypic spectrum of PLCγ2-related defects.

BackgroundImagining ways to prevent or treat glioblastoma (GBM) have been hindered by a lack of understanding of its pathogenesis. Although PDGF-AA overexpression may be an early event, critical details of the core biology are lacking. Existing PDGF-driven models replicate its microscopic appearance but not the genomic architecture characteristic of the human disease. Here we report a new model of GBM that overcomes this barrier to authenticity.MethodsUsing a method developed to study neural stem cells, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, the putative cell of origin of GBM. We micro-dissected SVZ tissue from p53-null and wild-type adult mice, established primary cultures in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumour forming potential.ResultsCounterintuitive to its canonical role as a growth factor, we observed immediate and massive death of SVZ cells in PDGF-AA. Wild-type cells did not survive in PDGF-AA. However, a small fraction of null cells evaded apoptosis, displayed attenuated proliferation, gradually accumulated whole chromosome gains and losses, and, signalled by sudden rapid proliferation and growth factor independence, became tumorigenic in immune-competent syngeneic mice. Transformed cells had an OPC-like profile, were resistant to PDGFR-α inhibition, and harboured highly abnormal karyotypes similar to those seen in human GBMs.ConclusionThis model associates genome instability in SVZ cells with chronic exposure to PDGF-AA; it is the first model to replicate the genomic landscape of GBM and first in which the earliest phases of GBM can be directly observed.IMPORTANCE OF STUDYWe have developed a mouse model in which the initiation, evolution and genomic landscape of GBM can be thoroughly studied thus paving the way for ideas about how this deadly brain cancer might be prevented, interrupted at an occult stage, or treated with very different therapies.

IDH-wildtype GBM is the most common variant of this cancer and occurs in older adults. Unfortunately patients’ tumors are either inherently resistant to standard treatment, which includes radio- and chemo-therapy, or acquire resistance during the therapeutic process. Additionally, although effective in other cancers, targeted therapies have yielded disappointing results in GBM, perhaps because the fully developed disease has significant cellular and molecular heterogeneity, allowing the tumour to adapt to treatments. Better insight into managing GBM might result from a detailed knowledge of its initiating events, which have not yet been elucidated. With this in mind, we developed a mouse model of GBM in which the earliest stages can be studied. This ex vivo model recreates GBM by culturing subventricular zone (SVZ) cells, the putative ‘cell of origin’ of GBM in platelet-derived growth factor A (PDGFA). Under this condition SVZ cells from p53 null mice transform, becoming exogenous growth factor independent and tumorigenic in immune-competent mice. In contrast, wildtype SVZ cells do not proliferate in PDGFA and null cells in EGF/FGF do not transform. To discover why p53 null SVZ cells uniquely transform in PDGFA, we performed array comparative genomic hybridization (aCGH) on cells before and after transformation in PDGFA and whole genome sequencing (WGS) on transformed cells and tumours generated from PDGFA-transformed cells. aCGH and WGS revealed that the genomic landscape of transformed cells displayed a striking similarity to that observed in primary human GBM. Specifically, these studies showed that chromosomal alterations are a hallmark of culturing SVZ cells in PDGFA, an intriguing finding considering GBM is also characterized by a specific landscape of copy number alterations. This model may resemble the pathogenesis of human GBM and be leveraged to investigate the early stages of tumorigenesis, further leading to the development of preventative strategies and novel therapeutics.

Sequencing technology is increasingly essential in clinical cancer management. The majority of clinical cancer sequencing has focused on panel approaches, but recent trials have begun to report the use of transcriptome expression profiling to match patients to therapy. The Personalized OncoGenomics (POG) program at BC Cancer has sequenced over 500 patient tumors, integrating both whole genome and transcriptome data to inform treatment options for patients with advanced or metastatic disease. Here we present 570 patients who were sequenced from 2012 to 2017 and reviewed at the POG multidisciplinary molecular tumor board. Genome and transcriptome information identified clinically actionable targets in 83% (475/570) of sequenced cases, with 37% (209/570) receiving POG-informed therapy. Overall, 248 whole genome and transcriptome sequencing analysis (WGTA)-informed treatments were administered, with some patients receiving multiple treatment courses. Of the treated cases, 46% (114/248) were reported to have physician-assessed clinical benefit. Clinical benefit was assessed as per standard of care rather than strict timing as per RECIST criteria. Mutation, copy number, structural variant, expression, and genome signature data were all used individually or in combination to inform treatments. Treatments based in whole or in part from RNA expression data were the largest subgroup (66.9%, 166/248), and patients in this group had similar proportion of clinical benefit compared to those receiving treatments informed by DNA-based data. Importantly, the use of RNA data resulted in 14.5% (36/248) additional patients receiving WGTA-informed treatments with clinical benefit. Patients were directed to clinical trials, treated with therapeutics in off-label indications, or positioned to genomically-informed standard of care options. For a subset of 42 cases where the planned next line of therapy was documented prior to WGTA analysis, 76.2% (32/42) of genomically-informed standard therapies were different from those which would otherwise have been considered the next line of therapy by the treating clinician, or aided in a decision between multiple different therapy options under consideration. These results emphasize the importance of multiple data types, including expression information, to personalize treatment. We also observe that, in addition to positioning for trials or identifying cases for off-label treatment, choice of standard of care therapies is an important use of genomic data. Overall, our data supports the integration of whole genome and RNA sequencing data in the clinic, with implications both for cancer research and treatment, and ultimately the potential to improve cancer outcomes. Citation Format: Alexandra K. Bohm, Erin Pleasance, Emma Tittmus, Kathleen Wee, Gregory Taylor, Melika Bonakdar, Yaoqing Shen, Laura Williamson, Veronika Csizmok, Martin Jones, Jessica Nelson, Balvir Deol, Caralyn Reisle, Karen Mungall, Eric Chuah, Andrew Mungall, Richard Moore, Sophie Sun, Howard Lim, Daniel Renouf, Steven Jones, Marco Marra, Janessa Laskin. Personalized therapy choice integrating genome and expression data in advanced cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 98.

Lighting can play an important role in encouraging cycling after-dark and making it safer. This paper describes ongoing research to establish a basis for design guidance when lighting for cyclists. Comparison of cyclist counts and estimated illuminance levels suggest a small increase in illuminance after-dark can significantly reduce the negative impact darkness has on cycling rates. Experimental work investigating obstacle detection by cyclists reveals that cycle lighting may not provide any benefit for detecting obstacles on lit roads and may even make detection worse, with the vertical position of the front cycle lamp being important. Cycle lamps also serve the purpose of making cyclists more visible but drivers often fail to detect cyclists even when they are highly visible. Lighting should therefore be considered alongside other approaches to cyclist safety, one of which is introducing presumed liability as a legal consideration to increase driver’s attention for cyclists.

Background Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced. However, even in responsive cases, its beneficial effect is undermined by the emergence of drug resistance. Here, we tested whether inhibition of poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced the effectiveness of TMZ. Methods Using patient derived brain tumor initiating cells (BTICs) and orthotopic xenografts as models of newly diagnosed and recurrent high-grade glioma, we assessed the effects of TMZ, ABT-888, and the combination of TMZ and ABT-888 on the viability of BTICs and survival of tumor-bearing mice. We also studied DNA damage repair, checkpoint protein phosphorylation, and DNA replication in mismatch repair (MMR) deficient cells treated with TMZ and TMZ plus ABT-888. Results Cells and xenografts derived from newly diagnosed MGMT methylated high-grade gliomas were sensitive to TMZ while those derived from unmethylated and recurrent gliomas were typically resistant. ABT-888 had no effect on the viability of BTICs or tumor bearing mice, but co-treatment with TMZ restored sensitivity in resistant cells and xenografts from newly diagnosed unmethylated gliomas and recurrent gliomas with MSH6 mutations. In contrast, the addition of ABT-888 to TMZ had little sensitizing effect on cells and xenografts derived from newly diagnosed methylated gliomas. In a model of acquired TMZ resistance mediated by loss of MMR gene MSH6, re-sensitization to TMZ by ABT-888 was accompanied by persistent DNA strand breaks, re-engagement of checkpoint kinase signaling, and interruption of DNA synthesis. Conclusion In laboratory models, the addition of ABT-888 to TMZ overcame resistance to TMZ.

Cosmopolitans often argue that the international community has a humanitarian responsibility to intervene militarily in order to protect vulnerable individuals from violent threats and to pursue the establishment of a condition of cosmopolitan justice based on the notion of a ‘global rule of law’. The purpose of this article is to argue that many of these cosmopolitan claims are incomplete and untenable on cosmopolitan grounds because they ignore the systemic and chronic structural factors that underwrite the root causes of these humanitarian threats. By way of examining cosmopolitan arguments for humanitarian military intervention and how systemic problems are further ignored in iterations of the Responsibility to Protect, this article suggests that many contemporary cosmopolitan arguments are guilty of focusing too narrowly on justifying a responsibility to respond to the symptoms of crisis versus demanding a similarly robust justification for a responsibility to alleviate persistent structural causes. Although this article recognizes that immediate principles of humanitarian intervention will, at times, be necessary, the article seeks to draw attention to what we are calling principles of Jus ante Bellum (right before war) and to stress that current cosmopolitan arguments about humanitarian intervention will remain insufficient without the incorporation of robust principles of distributive global justice that can provide secure foundations for a more thoroughgoing cosmopolitan condition of public right.

The Responsibility to Protect (RtP) report has been hailed by academics and policy makers alike as an important policy development in the international community's potential to protect vulnerable and insecure populations from violence. This article critically assesses the RtP, examining the problems with its particular conception of justice and security based on the nature and source of threats to individuals. It criticises the RtP's focus on crises, arguing that this downplays the importance of systemic, ‘chronic’ problems of injustice and disorder across the globe – and thus the importance of responding to these chronic problems. This emphasis, together with the RtP's focus on civil and political rights over socioeconomic rights, results in the causes of crises being perceived as local, thereby obviating the need to admit the role of the international community in contributing to current crises and systemic injustices. Based on these criticisms, this article concludes that the RtP's narrow conception of the relationship between justice and security will not further the international community's ability to discharge its responsibility towards individuals across the globe.