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BACKGROUND A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO’s ability to predict clinical response to gastrointestinal (GI) cancers. METHODS We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments. RESULTS We report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures. CONCLUSION While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers. TRIAL REGISTRATION Not applicable. FUNDING The Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

Background: Venous thromboembolism (VTE) is a life-threatening vascular event with environmental and genetic determinants. Recent VTE genome-wide association studies (GWAS) meta-analyses involved nearly 30 000 VTE cases and identified up to 40 genetic loci associated with VTE risk, including loci not previously suspected to play a role in hemostasis. The aim of our research was to expand discovery of new genetic loci associated with VTE by using cross-ancestry genomic resources. Methods: We present new cross-ancestry meta-analyzed GWAS results involving up to 81 669 VTE cases from 30 studies, with replication of novel loci in independent populations and loci characterization through in silico genomic interrogations. Results: In our genetic discovery effort that included 55 330 participants with VTE (47 822 European, 6320 African, and 1188 Hispanic ancestry), we identified 48 novel associations, of which 34 were replicated after correction for multiple testing. In our combined discovery-replication analysis (81 669 VTE participants) and ancestry-stratified meta-analyses (European, African, and Hispanic), we identified another 44 novel associations, which are new candidate VTE-associated loci requiring replication. In total, across all GWAS meta-analyses, we identified 135 independent genomic loci significantly associated with VTE risk. A genetic risk score of the significantly associated loci in Europeans identified a 6-fold increase in risk for those in the top 1% of scores compared with those with average scores. We also identified 31 novel transcript associations in transcriptome-wide association studies and 8 novel candidate genes with protein quantitative-trait locus Mendelian randomization analyses. In silico interrogations of hemostasis and hematology traits and a large phenome-wide association analysis of the 135 GWAS loci provided insights to biological pathways contributing to VTE, with some loci contributing to VTE through well-characterized coagulation pathways and others providing new data on the role of hematology traits, particularly platelet function. Many of the replicated loci are outside of known or currently hypothesized pathways to thrombosis. Conclusions: Our cross-ancestry GWAS meta-analyses identified new loci associated with VTE. These findings highlight new pathways to thrombosis and provide novel molecules that may be useful in the development of improved antithrombosis treatments.

Abstract CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

BACKGROUND: The lingual process of the sphenoid bone (LP) and the petrolingual ligament (PLL) surround laterally the internal carotid artery within the middle cranial fossa (MCF). OBJECTIVE: To study the LP and the PLL and anatomical variations considering their relationships with different structures and landmarks within the MCF, especially oriented toward the endoscopic endonasal approaches. METHODS: Seventy-two sides of dry skulls and 20 sides of embalmed specimens were studied. The measurements of the LP and the PLL were obtained, considering important landmarks in the MCF. RESULTS: The LP had a mean length and height of 5 mm and 3 mm, respectively. Its distance from the foramen lacerum was 6 mm, from the foramen ovale 10 mm, foramen rotundum 15 mm, and petrous apex 9 mm. In 44 sides (61.11%), the LP partially closed the lateral aspect of the carotid sulcus; in 17 sides (23.61%), it was found as a near-ring; and in 11 sides (15.2%), it was considered rudimentary. Considering the PLL, its length and height were, respectively, 9 mm, and 4 mm. CONCLUSION: The LP and PLL separate the carotid artery at the inferior aspect of Meckel's cave and constitute important landmarks for endoscopic endonasal approaches to Meckel's cave and MCF, and their identification and removal is essential for internal carotid artery mobilization in this area.

Abstract Purpose: The purpose of this study was to evaluate the feasibility and specimen quality of lymph node biopsies prepared through a novel automated system for automated fixation, drying and staining compared to standard slide preparation method. Methods: We performed a prospective, single-center study of patients undergoing endobronchial ultrasound. Samples were split into conventional standard of care (SOC) slide preparation and preparation using the device (ASP). Pathologists compared the SOC slides to the slides prepared by the automated system and assessed the following metrics: nuclear and cytoplasmic quality, presence of debris/artifact, staining quality, creation of a monolayer, and ease of adequacy/diagnosis assessment. A score between 1 (lowest quality) and 3 (highest quality) was assigned to the above metrics. Results: 60 patients were recruited. One to three lymph nodes were sampled for each patient with a total of 73 samples collected. The mean scores of each assessment category showed no statistical difference between the two preparation techniques except for improved monolayer creation in the ASP samples. All samples showed diagnostic equivalency between the automated slides and conventional slides except for one which was reported to be suspicious on the ASP sample and atypical on the SOC. Conclusion: Study results suggest that slides prepared by the automated system are of adequate quality for adequacy assessment with diagnostic concordance when compared to SOC slides.

Abstract Motivation Despite the increasing evidence of utility of genomic medicine in clinical practice, systematically integrating genomic medicine information and knowledge into clinical systems with a high-level of consistency, scalability and computability remains challenging. A comprehensive terminology is required for relevant concepts and the associated knowledge model for representing relationships. In this study, we leveraged PharmGKB, a comprehensive pharmacogenomics (PGx) knowledgebase, to formulate a terminology for drug response phenotypes that can represent relationships between genetic variants and treatments. We evaluated coverage of the terminology through manual review of a randomly selected subset of 200 sentences extracted from genetic reports that contained concepts for ‘Genes and Gene Products’ and ‘Treatments’. Results Results showed that our proposed drug response phenotype terminology could cover 96% of the drug response phenotypes in genetic reports. Among 18 653 sentences that contained both ‘Genes and Gene Products’ and ‘Treatments’, 3011 sentences were able to be mapped to a drug response phenotype in our proposed terminology, among which the most discussed drug response phenotypes were response (994), sensitivity (829) and survival (332). In addition, we were able to re-analyze genetic report context incorporating the proposed terminology and enrich our previously proposed PGx knowledge model to reveal relationships between genetic variants and treatments. In conclusion, we proposed a drug response phenotype terminology that enhanced structured knowledge representation of genomic medicine. Supplementary information Supplementary data are available at Bioinformatics online.

ImportanceThere is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C).ObjectiveTo determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence.Design, Setting, and ParticipantsThis cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry.ExposureAdministration of steroids within 2 days of admission.Main Outcomes and MeasuresLength of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching.ResultsA total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators.Conclusions and RelevanceSteroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

125 Background: The advent of immunotherapy (IO) has led to significant improvement in outcomes for patients (pts) with advanced non-small cell lung cancer (adv NSCLC). The rate of crossovers and receipt of post-protocol IO in pivotal trials leading to FDA approvals of IO in NSCLC has not been systematically evaluated. Here, we evaluate crossover rates and post protocol therapies for pts with adv NSCLC across multiple first-line (1L) IO monotherapy and chemotherapy/IO (chemo/IO) combination trials. Methods: We utilized the publicly available data from pivotal clinical trials leading to approvals of IO or chemo/IO regimens in 1L treatment of adv NSCLC. We extracted data on outcomes, rate of crossover from control arm to IO, proportion of pts in control arm receiving IO and the start dates of these clinical trials. The primary outcomes were the rates of crossover and the proportion of patients in control arms who received post-control IO. Results: The study included 4 trials with IO monotherapy and 12 trials with chemo/IO combinations in 1L adv NSCLC. The primary endpoints for these trials were PFS (25%), OS (19%), and both PFS and OS (56%). The crossover rate from control arm to experimental arm (with IO) ranged from 0-74% in IO monotherapy trials and 0-49% in chemo/IO trials. Two IO monotherapy trials and five chemo/IO trials did not allow crossover; among them, 3 trials had a PFS/OS co-primary endpoint, while others had OS as primary endpoint. Ten of 16 trials provided explicit information on use of subsequent post-protocol therapies in their publications. Among the two IO monotherapy trials which did not allow crossover, post-protocol IO was administered in only 20-30% of patients. Among the six chemo/IO trials with information on post-protocol therapies, 30%-59% patients on the control arm subsequently received some form of IO on progression. Nine of 12 trials started accrual after 10/2015, when nivolumab was approved in the United States as second-line (2L) therapy for adv NSCLC regardless of tumor PD-L1 expression. Conclusions: Despite the highly significant OS benefit from 2L IO, which was the standard of care (SOC) in the United States, the rates of crossover and post-protocol IO administration was distressingly low in 1L IO monotherapy and chemo/IO trials for 1L adv NSCLC. This low rate of 2L treatment with IO may have been due to limited global availability prior to widespread regulatory approval during the conduct of these trials. There is an increased need for consistency in reporting of crossover treatment and post-protocol treatments to allow adequate assessment of the true 1L benefit with IO. Control arms in pivotal trials require scrutiny to ensure confirmation with SOC to provide access to optimal treatments for patients and prevent magnification of observed benefits in experimental arms. The difficulty lies in the global conduct of large randomized clinical trials with differing regulatory approvals.

Prostate cancer (PCa) accounted for more than 34,000 deaths in US males [...]