Citations

AbstractBackgroundPost‐operative pain management is a critical component of perioperative care. Patients at risk of poorly controlled post‐operative pain may benefit from early measures to optimize pain management. We sought to identify risk factors for post‐operative pain and opioid consumption in patients undergoing liver resection.MethodsThis is a multi‐institutional prospective nested cohort study of patients undergoing open liver resection. Opioid consumption and pain scores were collected following surgery. To estimate the effects of patient factors on opioid consumption (oral morphine equivalents—OME) and on pain scores (NRS‐11), we used generalized linear models and multivariable linear regression model, respectively.ResultsOne hundred and fifty‐three patients who underwent open liver resection between 2013 and 2016 were included in the study. The mean patient age was 62.2 years, and 43.3% were female. Younger patients were significantly more likely to use more opioids in the early post‐operative period (16.7 OME/10 years, p < 0.001). Patient factors that were significantly associated with increased NRS‐11 pain scores also included younger patient age (difference in pain score of 0.3/10 years with cough and 0.2/10 years at rest, p < 0.01 for both) as well as a history of analgesic use (difference in pain score of 0.9 with cough and 0.6 at rest, p < 0.01 and p = 0.07, respectively).ConclusionYounger patients and those with a history of analgesic use are more likely to report higher post‐operative pain and require higher doses of opioids. Early identification of these patients, and measures to better manage their pain, may contribute to optimal perioperative care.

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background This repeated cross-sectional survey study was conducted to determine the prevalence of, and factors associated with, burnout, distress, and depression among anesthesiology residents and first-year graduates. We hypothesized that heavy workload and student debt burden were associated with a higher risk of physician burnout, distress, and depression, and that perception of having adequate workplace resources, work–life balance, and social support were associated with a lower risk. Methods Physicians beginning U.S. anesthesiology residency between 2013 and 2016 were invited to take online surveys annually from their clinical anesthesia year 1 to 1 yr after residency graduation. The Maslach Burnout Inventory, the Physician Well-Being Index, and the Harvard Department of Psychiatry/National Depression Screening Day Scale were used to measure burnout, distress, and depression, respectively. Logistic regression analyses were conducted to examine whether self-reported demographics, personal, and professional factors were associated with the risk of burnout, distress, and depression. Results The response rate was 36% (5,295 of 14,529). The prevalence of burnout, distress, and depression was 51% (2,531 of 4,966), 32% (1,575 of 4,941), and 12% (565 of 4,840), respectively. Factors associated with a lower risk of all three outcomes included respondents’ perceived workplace resource availability, (odds ratio = 0.51 [95% CI, 0.45 to 0.57] for burnout; 0.51 [95% CI, 0.45 to 0.56] for distress; 0.52 [95% CI, 0.45 to 0.60] for depression) and perceived ability to maintain work–life balance (0.61 [95% CI, 0.56 to 0.67] for burnout; 0.50 [95% CI, 0.46 to 0.55] for distress; 0.58 [95% CI, 0.51 to 0.65] for depression). A greater number of hours worked per week and a higher amount of student debt were associated with a higher risk of distress and depression, but not burnout. Conclusions Burnout, distress, and depression are notable among anesthesiology residents. Perceived institutional support, work–life balance, strength of social support, workload, and student debt impact physician well-being.

This study compared anesthesiology residency graduates’ written certification examination performance before and after the American Board of Anesthesiology (ABA) introduced the staged examination system. After equating test scores using common test items, the first 2 cohorts (2013, 2014) in the staged system scored 7.1 points and 8.3 points higher than the 2011 baseline cohort in the former examination system. The 2013 and 2014 cohorts’ pass rates (94.2% and 95.9%) were also higher than the 2011 and 2012 cohorts (91.9% and 92.6%) if a common standard had been applied. The staged examination system may be associated with improved knowledge of anesthesiology graduates.

Aim: Compare the effect of Latarjet and Trillat procedures on glenohumeral stability and range of motion. Background: Little is known about the impact of the location of the sling effect on joint stability and range of motion. Methods: 12 cadaveric shoulders were cleaned of soft tissue except for the subscapularis, conjoined tendon, and anterior capsule. A custom-made apparatus generating anterior humeral translation and joint compression was used. The machine applied compression load in the medial direction. The subscapularis and conjoint tendon were loaded. Internal/external range of motion and joint stability were assessed at 0°, 30° and 60° glenohumeral abduction. Range of motion was assessed by rotating the humeral shaft. Joint stability was assessed at maximum external rotation, translating the humerus. Specimen were tested in five conditions: 1) intact shoulder, 2) 6-mm bony glenoid defect (20% defect) 3) Trillat procedure, 4) Latarjet procedure with subscapularis split at the junction between its superior 2/3rds and inferior 1/3 rd, 5) Latarjet procedure with subscapularis split at the superior 1/3rds and inferior 2/3rds. Means were compared with a full factorial-repeated measures ANOVA with pairwise post hoc comparisons. Results: Peak translation force and stability ratio were significantly lower with the glenoid defect when compared to the intact and all the repaired conditions at all levels of glenohumeral abduction. The level of the subscapularis split had no significant influence on these values and no significant difference could be found between Trillat and Latarjet procedures. Range of motion in internal and external rotation were not significantly different between the different conditions. Conclusions: Joint stability and range of motion after a Latarjet are not impacted by the location of the subscapularis muscle split. Trillat and Latarjet techniques provide comparable stabilization of the joint, even in the presence of a critical bony defect of the glenoid.

e20639 Background: Multiple randomized controlled trials (RCTs) have shown a robust benefit of immunotherapy with immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). We did a meta-analysis to examine the benefit of ICI in various subgroups. Methods: PubMed was searched up to Jan 15, 2019 for RCTs comparing overall survival (OS) between ICI and control (without ICI) arms. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated for each subgroup. Interaction tests were done to compare relative benefit between opposed subgroups of interest (eg. men vs women; reported as Pheterogeneity). All analyses were performed with a random effects model in Comprehensive Meta Analysis (v2). Results: Twelve phase 2/3 RCTs involving 7244 patients were included. A significant OS benefit of ICI was found in both squamous and non-squamous histology. Current/former smokers, EGFR wild-type, and KRAS mutant patients had a significant OS benefit from ICI, but never smokers, EGFR mutant, and KRAS wild-type patients did not. An OS benefit of ICI was found in patients with or without baseline brain metastasis, PD-L1 < 1% or ≥1%, men or women, age < 65 or ≥65, and ECOG PS 0 or ≥1. No significant difference of relative benefit from ICI over control was found in patients with different PD-L1 expression, sex, age, or ECOG PS (Table). Conclusions: OS benefit of ICI in NSCLC was associated with a smoking history, wild-type EGFR or KRAS mutation. However, the OS benefit of ICI was seen regardless of histology, PD-L1 expression, sex, age, and ECOG PS. [Table: see text]

3101 Background: PDO is a promising translational tool that recapitulates the biology and drug response of donor cancer patient. However, an unmet need is to have PDO drug-screening data available for treatment decision making in clinic. We conducted a pilot study to determine whether PDO testing results will be available at critical treatment decision points in metastatic GI cancer patients. Methods: Metastatic GI cancer patients undergoing core-needle biopsy were eligible. Tumor cells isolated from ≤4 fresh biopsy tissues were grown in a Matrigel-based culture. PDO response to anti-cancer drugs were evaluated; and when available, correlated with donors’ clinical response to the same agent(s). PDO response was defined as IC50 < 0.1 × published Cmax of the drug clinically; stable as IC50 between 0.1 to 10 × Cmax. Radiographic response was per RECIST criteria. Results: We enrolled 27 refractory metastatic GI cancer patients (9 colorectal [CRC], 9 pancreas, and 9 biliary tract). Median lines of therapy were 4, 2, and 2; the success rate of organoid establishment was 89%, 44%, and 55%, respectively. The median time from biopsy to availability of drug-testing data was 64 days (range: 24 to 93 days). The median time from biopsy to next CT re-staging in donors was 64 days. The established PDOs shared histological and genomic features with donor clinical tissue. PDO and clinical responses to the same agent(s) were correlated in 2 CRC donors including (1) BRAFV600E-mutated PDO responded to vemurafenib + panitumumab, as did the donor who had partial response (PDO drug-testing data were available 55 days post-biopsy, 23 days prior to restaging scan); (2) KRAS/FGF-dual amplified PDO had stable disease status to regorafenib, as did the biopsied lesion from the donor (73 days post-biopsy, 5 days post-scan). Conclusions: We showed the feasibility of completing PDO drug sensitivity testing in metastatic GI cancer patients within a short time that could impact clinical decision making, particularly in CRC. PDO drug response showed correlation with clinical response. With further refinement, PDO can be a powerful tool for personalizing cancer therapy in metastatic GI cancer patients.

3049 Background: For multi-cancer detection using cfDNA, TOO determination is critical to enable safe and efficient diagnostic follow-up. Previous array-based studies captured < 2% of genomic CpGs. Here, we report genome-wide fragment-level methylation patterns across 811 cancer cell methylomes representing 21 tumor types (97% of SEER cancer incidence), and define effects of this methylation database on TOO prediction within a machine learning framework. Methods: Genomic DNA from 655 formalin-fixed paraffin-embedded (FFPE) tumor tissues and 156 isolated cells from tumors was subjected to a prototype 30x whole-genome bisulfite sequencing (WGBS) assay, as previously reported in the Circulating Cell-free Genome Atlas (CCGA) study (NCT02889978). Two independent TOO models, one with and one without the methylation database, were fitted on training samples; each was used to predict on the test set. A WGBS classifier was used to detect cancer at 98% specificity; reported TOO results reflect percent agreement between predicted and true TOO among those detected cancers (166 cases: 81 stage I-III, 69 stage IV, 16 non-informative). Results: Genome-wide methylation data generated from this database allowed fragment-level analysis and coverage of ~30 million CpGs across the genome (~60-fold greater than array-based approaches). Incorrect TOO assignments decreased by 35% (20% to 13%) after incorporating methylation database information into TOO classification. Improvement was observed across all cancer types and was consistent in early-stage cancers (stage I-III). Respective performances in breast cancer (n = 23) were 87% vs 96%; in lung cancer (n = 32) were 85% vs 88%; in hepatobiliary (n = 10) were 70% vs 90%; and in pancreatic cancer (n = 17) were 94% vs 100%. Results using an optimized approach informed by these results in a large cohort of CCGA participants will be reported. Conclusions: Incorporating data from a large methylation database improved TOO performance in multiple cancer types. This supports feasibility of this methylation-based approach as an early cancer detection test across cancer types. Clinical trial information: NCT02889978.

2621 Background: TMB is an emerging predictor of survival with immunotherapy. TMB is determined by taking the difference between somatic and germline datasets when tumor-normal pairs are available. In the case of commonly utilized tumor-only sequencing, additional steps are needed to estimate the somatic alterations. Computational tools have been developed that determine germline contribution based on sample copy state, purity estimates and occurrence of the variant in population databases. Given the potential bias of population datasets, we hypothesized that tumor-only filtering approaches may overestimate the actual TMB. Methods: We assessed the TMB from 50 tumors in 10 diseases including all missense, indels, and frameshift variants with an allelic fraction (AF) ≥5% and Coverage ≥100X within the tumor. Tumor-only TMB was evaluated against the gold standard of matched germline subtracted TMB at three levels. Level 1 removed all the tumor-only variants with AF in the non-TCGA ExAC database ≥1%. Level 2 removed all variants observed in population databases simulating a naive approach of removing germline variation. Level 3 used an internal tumor-only pipeline for calculating TMB. Results: There were significantly higher estimates of TMB with Level 1, Level 2 and Level 3 tumor-only filtering approaches than that determined by germline subtraction, resulting in significant bias. Whereas there was no correlation between TMB estimates and tumor-germline TMB for Level 1 filtering, there were improvements in correlations for Level 2 and Level 3. Conclusions: The tumor-only approaches that filter variants in population databases overestimate TMB compared to that determined by germline subtraction. Despite improved correlations with more stringent filtering approaches, these falsely elevated estimates may result in the inappropriate categorization of tumor specimens and negatively impact clinical trial results and patient outcomes. [Table: see text]

TPS2075 Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.