Search

Background Nutritional stress is a mechanism that allows tumor cells to evade the immune system. Arginine (ARG), an amino acid involved in immunomodulation, aids in regulating T-lymphocyte cell activity and the antitumor response. ARG deficiency in the tumor microenvironment can impair T-cell response while ARG supplementation may promote antitumor immune activity. In this exploratory post hoc analysis of the randomized phase II CO.26 trial, we investigated the role of plasma ARG in predicting response to immune checkpoint inhibitors (ICI) in patients with microsatellite stable refractory metastatic colorectal cancer (mCRC).Methods CO.26 randomized patients with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from pretreatment blood samples using high-performance liquid chromatography-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying patients into ARG-high (≥10 700 ng/mL) versus ARG-low (

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Introduction Premature onset of type 2 diabetes and excess mortality are critical issues internationally, particularly in Indigenous populations. There is an urgent need for developmentally appropriate and culturally safe models of care. We describe the methods for the codesign, implementation and evaluation of enhanced models of care with Aboriginal and Torres Strait Islander youth living with type 2 diabetes across Northern Australia.Methods and analysis Our mixed-methods approach is informed by the principles of codesign. Across eight sites in four regions, the project brings together the lived experience of Aboriginal and Torres Strait Islander young people (aged 10–25) with type 2 diabetes, their families and communities, and health professionals providing diabetes care through a structured yet flexible codesign process. Participants will help identify and collaborate in the development of a range of multifaceted improvements to current models of care. These may include addressing needs identified in our formative work such as the development of screening and management guidelines, referral pathways, peer support networks, diabetes information resources and training for health professionals in youth type 2 diabetes management. The codesign process will adopt a range of methods including qualitative interviews, focus group discussions, art-based methods and healthcare systems assessments. A developmental evaluation approach will be used to create and refine the components and principles of enhanced models of care. We anticipate that this codesign study will produce new theoretical insights and practice frameworks, resources and approaches for age-appropriate, culturally safe models of care.Ethics and dissemination The study design was developed in collaboration with Aboriginal and Torres Strait Islander and non-Indigenous researchers, health professionals and health service managers and has received ethical approval across all sites. A range of outputs will be produced to disseminate findings to participants, other stakeholders and the scholarly community using creative and traditional formats.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.

KRAS wildtype metastatic pancreatic ductal adenocarcinoma (mPDAC) could represent a distinct molecular entity from other PDACs. Here, the authors analyse KRAS wildtype mPDAC tumours using genomics and transcriptomics and find molecular similarities with cholangiocarcinomas.

Abstract Background Tumor mutation burden (TMB) is a key characteristic used in a tumor-type agnostic context to inform the use of immune checkpoint inhibitors (ICI). Accurate and consistent measurement of TMB is crucial as it can significantly impact patient selection for therapy and clinical trials, with a threshold of 10 mutations/Mb commonly used as an inclusion criterion. Studies have shown that the most significant contributor to variability in mutation counts in whole genome sequence (WGS) data is differences in analysis methods, even more than differences in extraction or library construction methods. Therefore, tools for improving consistency in whole genome TMB estimation are of clinical importance. Methods We developed a distributable TMB analysis suite, TMBur, to address the need for genomic TMB estimate consistency in projects that span jurisdictions. TMBur is implemented in Nextflow and performs all analysis steps to generate TMB estimates directly from fastq files, incorporating somatic variant calling with Manta, Strelka2, and Mutect2, and microsatellite instability profiling with MSISensor. These tools are provided in a Singularity container downloaded by the workflow at runtime, allowing the entire workflow to be run identically on most computing platforms. To test the reproducibility of TMBur TMB estimates, we performed replicate runs on WGS data derived from the COLO829 and COLO829BL cell lines at multiple research centres. The clinical value of derived TMB estimates was then evaluated using a cohort of 90 patients with advanced, metastatic cancer that received ICIs following WGS analysis. Patients were split into groups based on a threshold of 10/Mb, and time to progression from initiation of ICIs was examined using Kaplan–Meier and cox-proportional hazards analyses. Results TMBur produced identical TMB estimates across replicates and at multiple analysis centres. The clinical utility of TMBur-derived TMB estimates were validated, with a genomic TMB ≥ 10/Mb demonstrating improved time to progression, even after correcting for differences in tumor type (HR = 0.39, p = 0.012). Conclusions TMBur, a shareable workflow, generates consistent whole genome derived TMB estimates predictive of response to ICIs across multiple analysis centres. Reproducible TMB estimates from this approach can improve collaboration and ensure equitable treatment and clinical trial access spanning jurisdictions.

The ability to recognize and associate objects with prior experiences has been demonstrated in several avian taxa. Corvids, for example, recognize visual stimuli associated with negative previous experiences and will modify their behavioral responses according to the level of perceived threat. However, the extent to which similar memory-based behaviors exist in seabirds is poorly understood. Our study investigated object recognition by Herring Gulls ( Larus argentatus smithsonianus ) on their breeding grounds, the site of a long-term monitoring project. When handling gulls and conducting field research, researchers wear standard bicycle helmets as a protective measure against physical aggression by nesting gulls. We tested whether previously banded gulls vary their behavioral responses based on the headgear worn by human researchers. Herring Gulls were significantly more aggressive when approached by helmeted observers compared to those wearing neutral headwear or even holding a helmet, thus indicating a potential association between wearing bike helmets and the negative experience with researchers. Our study demonstrates that Herring Gulls are capable of object memory and object recognition within context, and display different behaviors toward different objects according to their levels of perceived threat. This information is key when designing studies with nesting gulls to ensure that behavioral biases are not unintentionally created due to gull prior experiences or researcher safety gear.

Abstract Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide–MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers.

Abstract 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.