Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

Development and Implementation of a Digital Quality Measure of Emergency Cancer Diagnosis.

PURPOSE: Missed and delayed cancer diagnoses are common, harmful, and often preventable. Automated measures of quality of cancer diagnosis are lacking but could identify gaps and guide interventions. We developed and implemented a digital quality measure (dQM) of cancer emergency presentation (EP) using electronic health record databases of two health systems and characterized the measure's association with missed opportunities for diagnosis (MODs) and mortality. METHODS: On the basis of literature and expert input, we defined EP as a new cancer diagnosis within 30 days after emergency department or inpatient visit. We identified EPs for lung cancer and colorectal cancer (CRC) in the Department of Veterans Affairs (VA) and Geisinger from 2016 to 2020. We validated measure accuracy and identified preceding MODs through standardized chart review of 100 records per cancer per health system. Using VA's longitudinal encounter and mortality data, we applied logistic regression to assess EP's association with 1-year mortality, adjusting for cancer stage and demographics. RESULTS: Among 38,565 and 2,914 patients with lung cancer and 14,674 and 1,649 patients with CRCs at VA and Geisinger, respectively, our dQM identified EPs in 20.9% and 9.4% of lung cancers, and 22.4% and 7.5% of CRCs. Chart reviews revealed high positive predictive values for EPs across sites and cancer types (72%-90%), and a substantial percent represented MODs (48.8%-84.9%). EP was associated with significantly higher odds of 1-year mortality for lung cancer and CRC (adjusted odds ratio, 1.78 and 1.83, respectively, 95% CI, 1.63 to 1.86 and 1.61 to 2.07). CONCLUSION: A dQM for cancer EP was strongly associated with both mortality and MODs. The findings suggest a promising automated approach to measuring quality of cancer diagnosis in US health systems.

Medical Home Implementation and Follow-Up of Cancer-Related Abnormal Test Results in the Veterans Health Administration.

Importance: Lack of timely follow-up of cancer-related abnormal test results can lead to delayed or missed diagnoses, adverse cancer outcomes, and substantial cost burden for patients. Care delivery models, such as the Veterans Affairs' (VA) Patient-Aligned Care Team (PACT), which aim to improve patient-centered care coordination, could potentially also improve timely follow-up of abnormal test results. PACT was implemented nationally in the VA between 2010 and 2012. Objective: To evaluate the long-term association between PACT implementation and timely follow-up of abnormal test results related to the diagnosis of 5 different cancers. Design, Setting, and Participants: This multiyear retrospective cohort study used 14 years of VA data (2006-2019), which were analyzed using panel data-based random-effects linear regressions. The setting included all VA clinics and facilities. The participants were adult patients who underwent diagnostic testing related to 5 different cancers and had abnormal test results. Data extraction and statistical analyses were performed from September 2021 to December 2023. Exposure: Calendar years denoting preperiods and postperiods of PACT implementation, and the PACT Implementation Progress Index Score denoting the extent of implementation in each VA clinic and facility. Main Outcome and Measure: Percentage of potentially missed timely follow-ups of abnormal test results. Results: This study analyzed 6 data sets representing 5 different types of cancers. During the initial years of PACT implementation (2010 to 2013), percentage of potentially missed timely follow-ups decreased between 3 to 7 percentage points for urinalysis suggestive of bladder cancer, 12 to 14 percentage points for mammograms suggestive of breast cancer, 19 to 22 percentage points for fecal tests suggestive of colorectal cancer, and 6 to 13 percentage points for iron deficiency anemia laboratory tests suggestive of colorectal cancer, with no statistically significant changes for α-fetoprotien tests and lung cancer imaging. However, these beneficial reductions were not sustained over time. Better PACT implementation scores were associated with a decrease in potentially missed timely follow-up percentages for urinalysis (0.3-percentage point reduction [95% CI, -0.6 to -0.1] with 1-point increase in the score), and laboratory tests suggestive of iron deficiency anemia (0.5-percentage point reduction [95% CI,-0.8 to -0.2] with 1-point increase in the score). Conclusions and Relevance: This cohort study found that implementation of PACT in the VA was associated with a potential short-term improvement in the quality of follow-up for certain test results. Additional multifaceted sustained interventions to reduce missed test results are required to prevent care delays.

Kinase signalling adaptation supports dysfunctional mitochondria in disease.

Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.

Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response.

Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown to be inherently pro-inflammatory with emerging cellular roles, including its ability to elicit anti-tumour immunity. Nonetheless, how MOMP triggers inflammation and how the cell regulates this remains poorly defined. We find that upon MOMP, many proteins localised either to inner or outer mitochondrial membranes are ubiquitylated in a promiscuous manner. This extensive ubiquitylation serves to recruit the essential adaptor molecule NEMO, leading to the activation of pro-inflammatory NF-κB signalling. We show that disruption of mitochondrial outer membrane integrity through different means leads to the engagement of a similar pro-inflammatory signalling platform. Therefore, mitochondrial integrity directly controls inflammation, such that permeabilised mitochondria initiate NF-κB signalling.

Pharmacogenomic Considerations for Anticoagulant Prescription in Patients with Hereditary Haemorrhagic Telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia that commonly results in bleeding but with frequent indications for therapeutic anticoagulation. Our aims were to advance the understanding of drug-specific intolerance and evaluate if there was an indication for pharmacogenomic testing. Genes encoding proteins involved in the absorption, distribution, metabolism, and excretion of warfarin, heparin, and direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, and dabigatran were identified and examined. Linkage disequilibrium with HHT genes was excluded, before variants within these genes were examined following whole genome sequencing of general and HHT populations. The 44 genes identified included 5/17 actionable pharmacogenes with guidelines. The 76,156 participants in the Genome Aggregation Database v3.1.2 had 28,446 variants, including 9668 missense substitutions and 1076 predicted loss-of-function (frameshift, nonsense, and consensus splice site) variants, i.e., approximately 1 in 7.9 individuals had a missense substitution, and 1 in 71 had a loss-of-function variant. Focusing on the 17 genes relevant to usually preferred DOACs, similar variant profiles were identified in HHT patients. With HHT patients at particular risk of haemorrhage when undergoing anticoagulant treatment, we explore how pre-emptive pharmacogenomic testing, alongside HHT gene testing, may prove beneficial in reducing the risk of bleeding and conclude that HHT patients are well placed to be at the vanguard of personalised prescribing.

Study protocol: maintaining preventive care during public health emergencies through effective coordination.

BACKGROUND: Screening lies at the heart of preventive care. However, COVID-19 dramatically disrupted routine screening efforts, resulting in excess mortality not directly attributable to COVID-19. Screening rates during COVID varied markedly by facility and clinical condition, suggesting susceptibilities in screening and referral process workflow. To better understand these susceptibilities and identify new practices to mitigate interrupted care, we propose a qualitative study comparing facilities that exhibited high, low, and highly variable performance (respectively) in screening rates before and during the pandemic. We will be guided by Weaver et al.'s multi-team systems (MTS) model of coordination, using cancer and mental health screening rates as exemplars. METHOD: Qualitative analysis of interviews and focus groups with primary care personnel, leadership, and patients at 10 VA medical centers. We will select sites based on rurality, COVID-19 caseload at the beginning of the pandemic, and performance on five outpatient clinical performance indicators of cancer and mental health screening. Sites will be categorized into one of five screening performance groups: high performers, low performers, improvers, plummeters, and highly variable. We will create process maps for each performance measure to create a workflow baseline and then interview primary care leadership to update the map at each site. We will clinician conduct focus groups to elicit themes regarding clinician coordination patterns (e.g., handoffs), strategies, and barriers/facilitators to screening during COVID. We will also conduct patient interviews to examine their screening experience during this period, for context. All interviews and focus groups will be audio-recorded, transcribed, and enhanced by field notes. We will analyze clinician transcripts and field notes using iterative, rapid analysis. Patient interviews will be analyzed using inductive/deductive content analysis. DISCUSSION: Our study represents a unique opportunity to inform the multi-team systems literature by identifying specific forms of information exchange, collective problem solving, and decision-making associated with higher and improved clinical performance. Specifically, our study aims to detect the specific points in the screening and referral process most susceptible to disruption and coordination processes that, if changed, will yield the highest value. Findings apply to future pandemics or any event with the potential to disrupt care.

Crosstalk with lung fibroblasts shapes the growth and therapeutic response of mesothelioma cells.

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients.

Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA.

Despite whole-genome sequencing (WGS), many cases of single-gene disorders remain unsolved, impeding diagnosis and preventative care for people whose disease-causing variants escape detection. Since early WGS data analytic steps prioritize protein-coding sequences, to simultaneously prioritize variants in non-coding regions rich in transcribed and critical regulatory sequences, we developed GROFFFY, an analytic tool that integrates coordinates for regions with experimental evidence of functionality. Applied to WGS data from solved and unsolved hereditary hemorrhagic telangiectasia (HHT) recruits to the 100,000 Genomes Project, GROFFFY-based filtration reduced the mean number of variants/DNA from 4,867,167 to 21,486, without deleting disease-causal variants. In three unsolved cases (two related), GROFFFY identified ultra-rare deletions within the 3' untranslated region (UTR) of the tumor suppressor SMAD4, where germline loss-of-function alleles cause combined HHT and colonic polyposis (MIM: 175050). Sited >5.4 kb distal to coding DNA, the deletions did not modify or generate microRNA binding sites, but instead disrupted the sequence context of the final cleavage and polyadenylation site necessary for protein production: By iFoldRNA, an AAUAAA-adjacent 16-nucleotide deletion brought the cleavage site into inaccessible neighboring secondary structures, while a 4-nucleotide deletion unfolded the downstream RNA polymerase II roadblock. SMAD4 RNA expression differed to control-derived RNA from resting and cycloheximide-stressed peripheral blood mononuclear cells. Patterns predicted the mutational site for an unrelated HHT/polyposis-affected individual, where a complex insertion was subsequently identified. In conclusion, we describe a functional rare variant type that impacts regulatory systems based on RNA polyadenylation. Extension of coding sequence-focused gene panels is required to capture these variants.

Cardiac Troponin, Kidney Function, Heart Failure and Mortality After Myocardial Infarction in Patients With and Without Kidney Impairment.

Cardiac troponins (cTn) are routinely measured for the diagnosis and prognosis of myocardial infarction (MI). The relation between troponin levels, estimated glomerular filtration rate (eGFR), postinfarction heart failure (HF), and mortality is unclear in patients with kidney impairment. This is a retrospective, cross-sectional study of patients presenting to the Emergency Department at a single tertiary center. Participants presenting with confirmed type I MI from January 1, 2019, to December 31, 2021, were analyzed from the Myocardial Ischemia National Audit Project database. Main outcomes were acute HF, measured using Killip class, and inpatient mortality. Peak cardiac troponin T (cTnT) level was a secondary outcome. Data on 2,815 patients (67±14 years, 28% female) were analyzed. Ordinal logistic regression analysis was used to test for predictors of increasing Killip class. Binary logistic regression was used to test for predictors of inpatient mortality. Analysis of a sub-sample matched for age and diabetes mellitus status showed increased mortality in patients with eGFR <60 ml/min/1.73 m2 (12.2% vs 4.4%, p <0.001). Multivariate predictors of acute HF included log-transformed peak cTnT, eGFR, body mass index (BMI), and diabetes mellitus status. Multivariate predictors of inpatient mortality included log-transformed peak cTnT, eGFR, age, BMI, and Killip class 3/4. On multivariate analysis, eGFR, ST-elevation MI diagnosis, BMI, male gender, diabetes mellitus status, and hypertension were all predictive of peak cTnT after MI. In conclusion, peak cTnT level and eGFR at presentation after MI are independent predictors of acute HF severity and death in patients with and without kidney impairment.

Asbestos accelerates disease onset in a genetic model of malignant pleural mesothelioma.

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit.

Developing electronic clinical quality measures to assess the cancer diagnostic process.

OBJECTIVE: Measures of diagnostic performance in cancer are underdeveloped. Electronic clinical quality measures (eCQMs) to assess quality of cancer diagnosis could help quantify and improve diagnostic performance. MATERIALS AND METHODS: We developed 2 eCQMs to assess diagnostic evaluation of red-flag clinical findings for colorectal (CRC; based on abnormal stool-based cancer screening tests or labs suggestive of iron deficiency anemia) and lung (abnormal chest imaging) cancer. The 2 eCQMs quantified rates of red-flag follow-up in CRC and lung cancer using electronic health record data repositories at 2 large healthcare systems. Each measure used clinical data to identify abnormal results, evidence of appropriate follow-up, and exclusions that signified follow-up was unnecessary. Clinicians reviewed 100 positive and 20 negative randomly selected records for each eCQM at each site to validate accuracy and categorized missed opportunities related to system, provider, or patient factors. RESULTS: We implemented the CRC eCQM at both sites, while the lung cancer eCQM was only implemented at the VA due to lack of structured data indicating level of cancer suspicion on most chest imaging results at Geisinger. For the CRC eCQM, the rate of appropriate follow-up was 36.0% (26 746/74 314 patients) in the VA after removing clinical exclusions and 41.1% at Geisinger (1009/2461 patients; P < .001). Similarly, the rate of appropriate evaluation for lung cancer in the VA was 61.5% (25 166/40 924 patients). Reviewers most frequently attributed missed opportunities at both sites to provider factors (84 of 157). CONCLUSIONS: We implemented 2 eCQMs to evaluate the diagnostic process in cancer at 2 large health systems. Health care organizations can use these eCQMs to monitor diagnostic performance related to cancer.

CKD Progression Risk and Subsequent Cause of Death: A Population-Based Cohort Study.

Rationale & Objective: Chronic kidney disease (CKD) is a prevalent condition with high mortality rates. Cardiovascular disease (CVD) is accepted as the leading cause of death in CKD, but data are limited, and no study has evaluated the cause of death in those with progressive CKD versus stable kidney function. Study Design: Retrospective cohort. Setting & Participants: Adults receiving primary care at M Health Fairview (MHFV) after December 31, 2012, with linked Minnesota Death Index data before December 31, 2019, were included. A second cohort was created from adult participants in the 1996-2006 National Health and Nutrition Examination Survey (NHANES) linked with the National Death Index through 2015. Individuals with kidney replacement therapy at baseline were excluded. Exposures: Estimated glomerular filtration rate (eGFR) and proteinuria assessed at baseline defined the exposure categories for MHFV and NHANES. CKD progression in MHFV was also defined as an eGFR decrease ≥30% from baseline or incident kidney replacement therapy. Outcome: CVD-, malignancy-, and dementia-attributed death. Analytical Approach: Multinomial logistic regression. Results: For both cohorts, CVD death was more common than malignancy death for those with eGFR <60 mL/min/1.73 m2, whereas the converse was true for those with higher eGFR without proteinuria. In NHANES, CVD deaths were higher in those with proteinuria and eGFR ≥60 mL/min/1.73 m2. CKD progression in MHFV had a limited impact on the association with the cause of death except on dementia deaths, which were less common with progression at several stages of CKD. Proteinuria had limited impact on the association with the cause of death across a range of eGFR levels. Limitations: Limited follow-up and, for MHFV, nonprotocolized measures of kidney function were limitations, as were the intrinsic accuracy limitations for death certificates. Conclusions: CVD death is the most significant cause of death observed for those with a reduced eGFR irrespective of CKD progression.

NUAK1 governs centrosome replication in pancreatic cancer via MYPT1/PP1ß and GSK3ß-dependent regulation of PLK4.

The AMP-activated protein kinase (AMPK)-related kinase NUAK1 (NUAK family SNF1-like kinase 1) has emerged as a potential vulnerability in MYC-dependent cancer but the biological roles of NUAK1 in different settings are poorly characterised, and the spectrum of cancer types that exhibit a requirement for NUAK1 is unknown. Unlike canonical oncogenes, NUAK1 is rarely mutated in cancer and appears to function as an obligate facilitator rather than a cancer driver per se. Although numerous groups have developed small-molecule NUAK inhibitors, the circumstances that would trigger their use and the unwanted toxicities that may arise as a consequence of on-target activity are thus undetermined. Reasoning that MYC is a key effector of RAS pathway signalling and the GTPase KRAS is almost uniformly mutated in pancreatic ductal adenocarcinoma (PDAC), we investigated whether this cancer type exhibits a functional requirement for NUAK1. Here, we show that high NUAK1 expression is associated with reduced overall survival in PDAC and that inhibition or depletion of NUAK1 suppresses growth of PDAC cells in culture. We identify a previously unknown role for NUAK1 in regulating accurate centrosome duplication and show that loss of NUAK1 triggers genomic instability. The latter activity is conserved in primary fibroblasts, raising the possibility of undesirable genotoxic effects of NUAK1 inhibition.

Hepatic glutamine synthetase controls N5-methylglutamine in homeostasis and cancer.

Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine from glutamate and ammonia is essential for neurotransmission and ammonia detoxification. Here, we show that mammalian GS uses glutamate and methylamine to produce a methylated glutamine analog, N5-methylglutamine. Untargeted metabolomics revealed that liver-specific GS deletion and its pharmacological inhibition in mice suppress hepatic and circulating levels of N5-methylglutamine. This alternative activity of GS was confirmed in human recombinant enzyme and cells, where a pathogenic mutation in the active site (R324C) promoted the synthesis of N5-methylglutamine over glutamine. N5-methylglutamine is detected in the circulation, and its levels are sustained by the microbiome, as demonstrated by using germ-free mice. Finally, we show that urine levels of N5-methylglutamine correlate with tumor burden and GS expression in a ß-catenin-driven model of liver cancer, highlighting the translational potential of this uncharacterized metabolite.

Can 10 000 Healthy Steps a Day Slow Aortic Root Dilation in Pediatric Patients With Marfan Syndrome?

Background Stiffer aortas are associated with a faster rate of aortic root (AoR) dilation and higher risk of aortic dissection in patients with Marfan syndrome. We have previously shown that mild aerobic exercise reduces aortic stiffness and rate of AoR dilation in a Marfan mouse model. In this study, we investigated if these results could be translated to pediatric patients with Marfan syndrome. Methods and Results We enrolled 24 patients with Marfan syndrome aged 8 to 19 years to participate in a 6-month physical activity intervention, excluding those with ventricular dysfunction or prior history of aortic surgery. We instructed patients to take 10 000 steps per day, tracked by an activity tracker. At baseline and 6 months, we measured AoR dimension, arterial stiffness, endothelial function, physical activity indices, inflammatory biomarkers, and coping scores. Controls consisted of 15 age-matched patients with Marfan syndrome. Twenty-four patients with Marfan syndrome (median age, 14.4 years [interquartile range {IQR}, 12.2-16.8], 14 male patients) were enrolled. Baseline assessment demonstrated that the majority of these patients were sedentary and had abnormal arterial health. Twenty-two patients completed the intervention and took an average of 7709±2177 steps per day (median, 7627 [IQR, 6344-9671]). Patients wore their Garmin trackers at a median of 92.8% (IQR, 84%-97%) of their intervention days. AoR Z score in the intervention group had a significantly lower rate of change per year compared with the controls (rate of change, -0.24 versus +0.008; P=0.01). Conclusions In this clinical intervention in pediatric patients with Marfan syndrome, we demonstrated that a simple physical activity intervention was feasible in this population and has the potential to decrease the AoR dilation rate. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03567460.

A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation.

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (IDH)-mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1R132H-driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

Cancer Evaluations During the COVID-19 Pandemic: An Observational Study Using National Veterans Affairs Data.

INTRODUCTION: Fewer cancer diagnoses have been made during the COVID-19 pandemic. Pandemic-related delays in cancer diagnosis could occur from limited access to care or patient evaluation delays (e.g., delayed testing after abnormal results). Follow-up of abnormal test results warranting evaluation for cancer was examined before and during the pandemic. METHODS: Electronic trigger algorithms were applied to the Department of Veterans Affairs electronic health record data to assess follow-up of abnormal test results before (March 10, 2019-March 7, 2020) and during (March 8, 2020-March 6, 2021) the pandemic. RESULTS: Electronic triggers were applied to 8,021,406 veterans' electronic health records to identify follow-up delays for abnormal results warranting evaluation for 5 cancers: bladder (urinalysis with high-grade hematuria), breast (abnormal mammograms), colorectal (positive fecal occult blood tests/fecal immunochemical tests or results consistent with iron deficiency anemia), liver (elevated alpha-fetoprotein), and lung (chest imaging suggestive of malignancy) cancers. Between prepandemic and pandemic periods, test quantities decreased by 12.6%-27.8%, and proportions of abnormal results lacking follow-up decreased for urinalyses (-0.8%), increased for fecal occult blood tests/fecal immunochemical test (+2.3%) and chest imaging (+1.8%), and remained constant for others. Follow-up times decreased for most tests; however, control charts suggested increased delays at 2 stages: early (pandemic beginning) for urinalyses, mammograms, fecal occult blood tests/fecal immunochemical test, iron deficiency anemia, and chest imaging and late (30-45 weeks into pandemic) for mammograms, fecal occult blood tests/fecal immunochemical test, and iron deficiency anemia. CONCLUSIONS: Although early pandemic delays in follow-up may have led to reduced cancer rates, the significant decrease in tests performed is likely a large driver of these reductions. Future emergency preparedness efforts should bolster essential follow-up and testing procedures to facilitate timely cancer diagnosis.

Translating electronic health record-based patient safety algorithms from research to clinical practice at multiple sites.

INTRODUCTION: Researchers are increasingly developing algorithms that impact patient care, but algorithms must also be implemented in practice to improve quality and safety. OBJECTIVE: We worked with clinical operations personnel at two US health systems to implement algorithms to proactively identify patients without timely follow-up of abnormal test results that warrant diagnostic evaluation for colorectal or lung cancer. We summarise the steps involved and lessons learned. METHODS: Twelve sites were involved across two health systems. Implementation involved extensive software documentation, frequent communication with sites and local validation of results. Additionally, we used automated edits of existing code to adapt it to sites' local contexts. RESULTS: All sites successfully implemented the algorithms. Automated edits saved sites significant work in direct code modification. Documentation and communication of changes further aided sites in implementation. CONCLUSION: Patient safety algorithms developed in research projects were implemented at multiple sites to monitor for missed diagnostic opportunities. Automated algorithm translation procedures can produce more consistent results across sites.

THEM6-mediated reprogramming of lipid metabolism supports treatment resistance in prostate cancer.

Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, we show that the ER membrane-associated protein THEM6 regulates intracellular levels of ether lipids and is essential to trigger the induction of the ER stress response (UPR). Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated activation of ATF4. Finally, we demonstrate that high THEM6 expression is associated with poor survival and correlates with high levels of UPR activation in PCa patients. Altogether, our results highlight THEM6 as a novel driver of therapy resistance in PCa as well as a promising target for the treatment of CRPC.