LanceOtron: a deep learning peak caller for genome sequencing experiments.

MOTIVATION: Genome sequencing experiments have revolutionized molecular biology by allowing researchers to identify important DNA-encoded elements genome wide. Regions where these elements are found appear as peaks in the analog signal of an assay's coverage track, and despite the ease with which humans can visually categorize these patterns, the size of many genomes necessitates algorithmic implementations. Commonly used methods focus on statistical tests to classify peaks, discounting that the background signal does not completely follow any known probability distribution and reducing the information-dense peak shapes to simply maximum height. Deep learning has been shown to be highly accurate for many pattern recognition tasks, on par or even exceeding human capabilities, providing an opportunity to reimagine and improve peak calling. RESULTS: We present the peak calling framework LanceOtron, which combines deep learning for recognizing peak shape with multifaceted enrichment calculations for assessing significance. In benchmarking ATAC-seq, ChIP-seq and DNase-seq, LanceOtron outperforms long-standing, gold-standard peak callers through its improved selectivity and near-perfect sensitivity. AVAILABILITY AND IMPLEMENTATION: A fully featured web application is freely available from LanceOtron.molbiol.ox.ac.uk, command line interface via python is pip installable from PyPI at https://pypi.org/project/lanceotron/, and source code and benchmarking tests are available at https://github.com/LHentges/LanceOtron. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Thoracic Surgery and the Elderly; Is Lobectomy Safe in Octogenarians?

PURPOSE: Non-small cell lung cancer is the most common malignancy of the elderly, with 5-year survival estimates of 16.8%. The prognostic benefit of surgical resection for early lung cancer is irrefutable and maintained irrespective of age, even in patients over 75 years. Concerningly, despite the prognostic benefit of surgery there are deviations from standard treatment protocols with increasing age due to concerns of increased morbidity and mortality with surgery, without evidence to support this. METHOD: A state-wide retrospective registry study of Queensland's Cardiac Outcomes Registry's (QCOR) Thoracic Database examining the influence of age on the safety of Lung Resection (1 January 2016-20 April 2022). RESULTS: This included 1,232 patients, mean age at surgery was 66 years (range 14-91 years), with 918 thoracotomies performed. Three deaths occurred within 30-days (0.24%). Octogenarians (n=60) had lower rates of smoking (26% vs 6%), respiratory, cardiovascular, and cerebrovascular disease suggesting this subset of patients is carefully selected. Octogenarian status was not associated with an increased all-cause morbidity (p=0.09) or 30-day mortality (p=0.06). Further to this it was not associated with re-operation (4.4% vs 8.3%, p=0.1), increased postoperative stay (6.66 vs 6.65 days, p=0.99) or myocardial infarction. An independent predictor of morbidity was male sex (OR 1.58, CI 1.2-2.1 p=0.001). CONCLUSION: Age ≥80 years did not increase surgical morbidity or mortality in the appropriately selected patient and should not be a barrier to referral for consideration of surgical resection.

30-Day Outcomes With the Portico Transcatheter Heart Valve: Insights From a Multi-Centre Australian Observational Study.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is an established therapy for the treatment of aortic valve disease in appropriately selected patients. Previous studies using the self-expanding Portico transcatheter heart valve (THV), (Abbott Structural Heart, St Paul, MN, USA) have demonstrated the technical feasibility of this system albeit in the hands of relatively inexperienced Portico users. The objective of this study was to assess the real-world safety and efficacy of the Portico THV (with and without the FlexNav delivery system, Abbott Structural Heart) at the 30-day timepoint in an Australian cohort. METHODS AND RESULTS: This study was a retrospective real-world cohort analysis of 269 consecutive patients with severe aortic valve disease who underwent TAVI at multiple centres within Australia between February 2015 and April 2021. Of the 269 patients, 51.7% were female, mean Society of Thoracic Surgeons (STS) score was 5.2 (±6.8) and 98.5% had successful implantations. Thirty (30)-day post-implantation all-cause mortality was observed in one (0.4%) patient, major vascular complications in two (0.7%) patients, more-than-mild paravalvular leak in six (2.2%) patients and requirement for new permanent pacemaker implantation in 27 (10.2%) patients. Haemodynamic parameters at 30 days included mean effective orifice area (EOA) of 2.3 (±0.9) cm2 and mean aortic valve gradient (AVG) of 9.6 (±6.2) mmHg. CONCLUSION: This analysis of the Portico THV in a real-world setting suggested that the system is associated with satisfactory safety and efficacy parameters. Previously published datasets may not have found similar findings owing to lower operator experience with the Portico THV system.

Plaster pipes and crystalized graphite: Open transventricular transcatheter aortic valve replacement for failed mechanical aortic valve prostheses in the porcelain aorta.

Patients with a true porcelain aorta and a failed mechanical aortic valve prosthesis have limited treatment options. Using a hybrid of an open trans-ventricular approach with peripheral cardiopulmonary bypass and integration of transcatheter techniques this challenge can be overcome. Trans-ventricular mechanical valve extraction (with transcatheter endovascular occlusion and cardioplegia) followed by direct ante-grade transcatheter heart valve implantation offers a potential solution to this conundrum. The procedure described is a novel technique that allows for the effective treatment of patients with failed mechanical surgical aortic valve prostheses in the setting of an inoperable porcelain aorta. In addition, a collaborative integrated multi-disciplinary heart team environment is required for the management of these complex patients.

Growing up aspen: ontogeny and trade-offs shape growth, defence and reproduction in a foundation species.

BACKGROUND AND AIMS: Intraspecific variation in foundation species of forest ecosystems can shape community and ecosystem properties, particularly when that variation has a genetic basis. Traits mediating interactions with other species are predicted by simple allocation models to follow ontogenetic patterns that are rarely studied in trees. The aim of this research was to identify the roles of genotype, ontogeny and genotypic trade-offs shaping growth, defence and reproduction in aspen. METHODS: We established a common garden replicating >500 aspen genets in Wisconsin, USA. Trees were measured through the juvenile period into the onset of reproduction, for growth, defence chemistry (phenolic glycosides and condensed tannins), nitrogen, extrafloral nectaries, leaf morphology (specific leaf area), flower production and foliar herbivory and disease. We also assayed the TOZ19 sex marker and heterozygosity at ten microsatellite loci. KEY RESULTS: We found high levels of genotypic variation for all traits, and high heritabilities for both the traits and their ontogenetic trajectories. Ontogeny strongly shaped intraspecific variation, and trade-offs among growth, defence and reproduction supported some predictions while contradicting others. Both direct resistance (chemical defence) and indirect defence (extrafloral nectaries) declined during the juvenile stage, prior to the onset of reproduction. Reproduction was higher in trees that were larger, male and had higher individual heterozygosity. Growth was diminished by genotypic allocation to both direct and indirect defence as well as to reproduction, but we found no evidence of trade-offs between defence and reproduction. CONCLUSIONS: Key traits affecting the ecological communities of aspen have high levels of genotypic variation and heritability, strong patterns of ontogeny and clear trade-offs among growth, defence and reproduction. The architecture of aspen's community genetics - its ontogeny, trade-offs and especially its great variability - is shaped by both its broad range and the diverse community of associates, and in turn further fosters that diversity.

Postoperative Pain in Thoracic Surgical Patients: An Analysis of Factors Associated With Acute and Chronic Pain.

BACKGROUND: Thoracic surgery is associated with high levels of acute and chronic pain, which is associated with significant morbidity, reduced quality of life, and increased health care expenditure. This study aims to identify patient-care factors associated with higher levels of acute and chronic pain after thoracic surgery. METHODS: The acute pain component of this study retrospectively analysed 53 patients, surgical, anaesthetic, and postoperative factors against an average measure of acute pain during a patient's hospital admission, for 134 individual acute admission episodes. The chronic pain component analysed 58 care factors against a binary chronic pain outcome based on the Neuropathic Pain Scale and the Brief Pain Inventory, for 72 patients, at an average of 7 months postoperatively. RESULTS: Younger age, chronic opioid use, use of talc, and multi-port video-assisted thoracoscopic surgery (VATS) compared to uniport VATS, were all associated with higher levels of acute postoperative pain. Seven (7) months postoperatively, the rate of chronic sensation change or numbness was 31%. The rate of troublesome chronic pain was 8%. History of a mental health condition, chronic opioid use, urgent operation, and the use of tramadol postoperatively were independently associated with a higher risk of chronic pain. CONCLUSIONS: This study identifies several factors associated with higher rates of acute and chronic postoperative pain, and defines the rate of chronic pain in a large tertiary thoracic surgery centre. Consideration should be given to modifying those surgical practices which were identified as being associated with higher levels of pain, including multi-port VATS, and the use of talc. It is important that non-modifiable risk factors for pain, including history of mental health condition, opioid use, age, and urgency of operation, are taken into consideration when informing a patient of the risk of pain postoperatively.

Pathway position constrains the evolution of an ecologically important pathway in aspens (Populus tremula L.).

Many ecological interactions of aspens and their relatives (Populus spp.) are affected by products of the phenylpropanoid pathway synthesizing condensed tannins (CTs), whose production involves trade-offs with other ecologically important compounds and with growth. Genes of this pathway are candidates for investigating the role of selection on ecologically important, polygenic traits. We analysed sequences from 25 genes representing 10 steps of the CT synthesis pathway, which produces CTs used in defence and lignins used for growth, in 12 individuals of European aspen (Populus tremula). We compared these to homologs from P. trichocarpa, to a control set of 77 P. tremula genes, to genome-wide resequencing data and to RNA-seq expression levels, in order to identify signatures of selection distinct from those of demography. In Populus, pathway position exerts a strong influence on the evolution of these genes. Nonsynonymous diversity, divergence and allele frequency shifts (Tajima's D) were much lower than for synonymous measures. Expression levels were higher, and the direction of selection more negative, for upstream genes than for those downstream. Selective constraints act with increasing intensity on upstream genes, despite the presence of multiple paralogs in most gene families. Pleiotropy, expression level, flux control and codon bias appear to interact in determining levels and patterns of variation in genes of this pathway, whose products mediate a wide array of ecological interactions for this widely distributed species.

Heterozygosity, gender, and the growth-defense trade-off in quaking aspen.

Although plant growth is generally recognized to be influenced by allocation to defense, genetic background (e.g., inbreeding), and gender, rarely have those factors been addressed collectively. In quaking aspen (Populus tremuloides Michx.), phenolic glycosides (PGs) and condensed tannins (CTs) constitute up to 30 % of leaf dry weight. To quantify the allocation cost of this chemical defense, we measured growth, defense chemistry, and individual heterozygosity (H obs at 16 microsatellite loci) for male and female trees in both controlled and natural environments. The controlled environment consisted of 12 juvenile genets grown for 3 years in a common garden, with replication. The natural environment consisted of 51 mature genets in wild populations, from which we sampled multiple ramets (trees) per genet. Concentrations of PGs and CTs were negatively correlated. PGs were uncorrelated with growth, but CT production represented a major cost. Across the range of CT levels found in wild-grown trees, growth rates varied by 2.6-fold, such that a 10 % increase in CT concentration occurred with a 38.5 % decrease in growth. H obs had a marked effect on aspen growth: for wild trees, a 10 % increase in H obs corresponded to a 12.5 % increase in growth. In wild trees, this CT effect was significant only in females, in which reproduction seems to exacerbate the cost of defense, while the H obs effect was significant only in males. Despite the lower growth rate of low-H obs trees, their higher CT levels may improve survival, which could account for the deficit of heterozygotes repeatedly found in natural aspen populations.

Veno-Arterial ECMO in the Setting of Post-Infarct Ventricular Septal Defect: A Bridge to Surgical Repair.

Extracorporeal membrane oxygenation (ECMO) is a complex rescue therapy utilised to provide circulatory and/or respiratory support to critically ill patients who have failed maximal conventional therapy. The use of ECMO in adult cardiac surgery is not routine, occurring in a minority of critically ill patients, typically postoperatively. Presented here are three cases of post-infarct ventricular septal defect with cardiogenic shock managed preoperatively with ECMO support as a bridge to definitive surgical closure. We present a review of ECMO in the adult cardiac surgical population and highlight the potential role of preoperative ECMO for cardiogenic shock in the setting of post-infarct ventricular septal defect (PI VSD) as a bridge to definitive closure.

Gene-environment interaction in dyslipidemia.

PURPOSE OF REVIEW: Recent genome-wide association studies have identified numerous common genetic variants associated with plasma lipid traits and have provided new insights into the regulation of lipoprotein metabolism including the identification of novel biological processes. These findings add to a body of existing data on dietary and environmental factors affecting plasma lipids. Here we explore how interactions between genetic risk factors and other phenotypes may explain some of the missing heritability of plasma lipid traits. RECENT FINDINGS: Recent studies have identified true statistical interaction between several environmental and genetic risk factors and their effects on plasma lipid fractions. These include interactions between behaviors such as smoking or exercise as well as specific dietary nutrients and the effect size of specific genetic variants on plasma lipid traits risk and modifying effects of measures of adiposity on the cumulative impact of a number of common genetic variants on each of plasma triglycerides and HDL cholesterol. SUMMARY: Interactions between genetic risk factors and clinical phenotypes may account for some of the unexplained heritability of plasma lipid traits. Recent studies provide biological insight into specific genetic associations and may aid in the identification of dyslipidemic patients for whom specific lifestyle interventions are likely to be most effective.

Adiposity significantly modifies genetic risk for dyslipidemia.

Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain <12% of variation in lipid traits. Adiposity is also an important determinant of plasma lipoproteins, particularly plasma TGs and HDL cholesterol (HDLc) concentrations. Thus, interactions between genes and clinical phenotypes may contribute to this unexplained heritability. We have applied a weighted genetic risk score (GRS) for both plasma TGs and HDLc in two large cohorts at the extremes of BMI. Both BMI and GRS were strongly associated with these lipid traits. A significant interaction between obese/lean status and GRS was noted for each of TG (P(Interaction) = 2.87 × 10(-4)) and HDLc (P(Interaction) = 1.05 × 10(-3)). These interactions were largely driven by SNPs tagging APOA5, glucokinase receptor (GCKR), and LPL for TG, and cholesteryl ester transfer protein (CETP), GalNAc-transferase (GALNT2), endothelial lipase (LIPG), and phospholipid transfer protein (PLTP) for HDLc. In contrast, the GRSLDL cholesterol × adiposity interaction was not significant. Sexual dimorphism was evident for the GRSHDL on HDLc in obese (P(Interaction) = 0.016) but not lean subjects. SNP by BMI interactions may provide biological insight into specific genetic associations and missing heritability.

Opportunities for improving partner notification for HIV: results from a community-based participatory research study.

To identify actionable opportunities for improving Partner Notification (PN) for HIV among men who have sex with men (MSM), we characterized the perspectives and experiences of PN among Medical Case Managers (case managers), Disease Intervention Specialists (DIS), and MSM. In partnership with an AIDS service organization and the Connecticut State Health Department, we conducted a focus group of case managers (n = 14) and in-depth interviews with DIS (n = 7) and MSM (n = 24). We found differences between MSM's and providers' (case managers and DIS) perspectives regarding (1) determinants of sexual risk behaviors; (2) considerations impacting HIV disclosure; and (3) barriers to trusting relationships between MSM and providers. Factors impacting MSM perspectives on PN were incompletely appreciated by both case managers and DIS. PN may be improved through improving provider understanding of the complexities for MSM regarding sexual risk behaviors and disclosure and transcending barriers to trusting relationships between MSM and providers.

Novel, intermediate-fidelity simulator for aortic arch surgery for the cardiothoracic surgical trainee.

BACKGROUND: Training cardiothoracic surgeons in open aortic surgery is challenging due to limited operator experience, low patient volume and technically demanding skills to be performed within a deep thoracic cavity. Surgical simulation has become a cornerstone of cardiothoracic surgical training and has been shown to improve skill acquisition and performance in the operating theatre. Due to the complexity of aortic surgery, there is a paucity of simulators that are concomitantly accessible and of sufficient fidelity. The purpose of this study was to develop a reproducible, intermediate-fidelity simulator for aortic surgery. METHOD: This novel simulator was constructed from plastic storage containers to simulate the depth of a thoracic cavity. Head vessels and distal arch were reconstructed within the stimulator with synthetic Dacron polyester grafts to maximize model fidelity. A porcine or bovine heart was used for the simulation of aortic root replacement and anastomosis to the distal arch graft. RESULTS: The simulator was reproduced in a wet-lab skills session at an annual Australian cardiothoracic trainee meeting. Qualitative feedback was obtained from the current cardiothoracic trainees. It is a feasible model for the practice of aortic surgery. CONCLUSION: As the surgical education paradigm shifts towards simulation, this easily reproducible, intermediate-fidelity model provides an effective avenue to equip the trainee for the operating room and is a method of surgical training that can be considered by colleges.

Perspectives on unhealthy alcohol use among men who have sex with men prescribed HIV pre-exposure prophylaxis: A qualitative study.

Unhealthy alcohol use is a common, often unaddressed behavior associated with increased risk for acquisition of HIV and may also be associated with decreased adherence to oral pre-exposure prophylaxis (PrEP) among gay, bisexual, and other men who have sex with men (MSM) living in the United States. To inform future alcohol-reduction interventions among individuals engaging in PrEP care, we sought to explore perspectives on alcohol use, PrEP adherence, and the acceptability of alcohol use treatment options for MSM prescribed oral formulations of PrEP in the Northeastern United States. Between February 2019 and July 2020, we conducted semi-structured interviews with 15 MSM without HIV who were prescribed PrEP and screened positive for unhealthy alcohol use with AUDIT-C ≥ 4 and were receiving care in Providence, Rhode Island or New Haven, Connecticut. Interviews were coded and analyzed using thematic analysis. Three themes emerged: 1) Consequences of fluctuations in drinking 2) Alcohol use negatively impacts health and relationships; and 3) Desire for a multimodal approach to treatment of unhealthy alcohol use. Our findings support the need to raise awareness of potential alcohol-related harms, address the spectrum of unhealthy alcohol use among MSM prescribed PrEP, and the acceptability and preferences for alcohol reduction interventions within PrEP programs.

RfaL is required for Yersinia pestis type III secretion and virulence.

Yersinia pestis, the causative agent of plague, uses a type III secretion system (T3SS) to inject cytotoxic Yop proteins directly into the cytosol of mammalian host cells. The T3SS can also be activated in vitro at 37°C in the absence of calcium. The chromosomal gene rfaL (waaL) was recently identified as a virulence factor required for proper function of the T3SS. RfaL functions as a ligase that adds the terminal N-acetylglucosamine to the lipooligosaccharide core of Y. pestis. We previously showed that deletion of rfaL prevents secretion of Yops in vitro. Here we show that the divalent cations calcium, strontium, and magnesium can partially or fully rescue Yop secretion in vitro, indicating that the secretion phenotype of the rfaL mutant may be due to structural changes in the outer membrane and the corresponding feedback inhibition on the T3SS. In support of this, we found that the defect can be overcome by deleting the regulatory gene lcrQ. Consistent with a defective T3SS, the rfaL mutant is less virulent than the wild type. We show here that the virulence defect of the mutant correlates with a decrease in both T3SS gene expression and ability to inject innate immune cells, combined with an increased sensitivity to cationic antimicrobial peptides.

Genomic and transcriptomic analyses reveal polygenic architecture for ecologically important traits in aspen (Populus tremuloides Michx.).

Intraspecific genetic variation in foundation species such as aspen (Populus tremuloides Michx.) shapes their impact on forest structure and function. Identifying genes underlying ecologically important traits is key to understanding that impact. Previous studies, using single-locus genome-wide association (GWA) analyses to identify candidate genes, have identified fewer genes than anticipated for highly heritable quantitative traits. Mounting evidence suggests that polygenic control of quantitative traits is largely responsible for this "missing heritability" phenomenon. Our research characterized the genetic architecture of 30 ecologically important traits using a common garden of aspen through genomic and transcriptomic analyses. A multilocus association model revealed that most traits displayed a highly polygenic architecture, with most variation explained by loci with small effects (likely below the detection levels of single-locus GWA methods). Consistent with a polygenic architecture, our single-locus GWA analyses found only 38 significant SNPs in 22 genes across 15 traits. Next, we used differential expression analysis on a subset of aspen genets with divergent concentrations of salicinoid phenolic glycosides (key defense traits). This complementary method to traditional GWA discovered 1243 differentially expressed genes for a polygenic trait. Soft clustering analysis revealed three gene clusters (241 candidate genes) involved in secondary metabolite biosynthesis and regulation. Our work reveals that ecologically important traits governing higher-order community- and ecosystem-level attributes of a foundation forest tree species have complex underlying genetic structures and will require methods beyond traditional GWA analyses to unravel.

SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

The influence of the COVID-19 pandemic on lung cancer surgery in Queensland.

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic poses unprecedented challenges to global healthcare. The contemporary influence of COVID-19 on the delivery of lung cancer surgery has not been examined in Queensland. METHODS: We performed a retrospective registry analysis of the Queensland Cardiac Outcomes Registry (QCOR), thoracic database examining all adult lung cancer resections across Queensland from 1/1/2016 to 30/4/2022. We compared the data prior to, and after, the introduction of COVID-restrictions. RESULTS: There were 1207 patients. Mean age at surgery was 66 years and 1115 (92%) lobectomies were performed. We demonstrated a significant delay from time of diagnosis to surgery from 80 to 96 days (P < 0.0005), after introducing COVID-restrictions. The number of surgeries performed per month decreased after the pandemic and has not recovered (P = 0.012). 2022 saw a sharp reduction in cases with 49 surgeries, compared to 71 in 2019 for the same period. CONCLUSION: Restrictions were associated with a significant increase in pathological upstaging, greatest immediately after the introduction of COVID-restrictions (IRR 1.71, CI 0.93-2.94, P = 0.05). COVID-19 delayed the access to surgery, reduced surgical capacity and consequently resulted in pathological upstaging throughout Queensland.

Comparison of Lung Cancer Surgery Outcomes in Queensland for Indigenous and Nonindigenous Australians.

Introduction: Indigenous Australians (Aboriginal and Torres Strait Islander) have lower overall survival from lung cancer compared with nonindigenous Australians. Indigenous Australians receive higher rates of chemotherapy and/or radiotherapy. The equity of peri-operative care and thoracic surgical outcomes in Australian indigenous populations have not been contemporarily evaluated. Methods: We performed a retrospective registry analysis of the Queensland Cardiac Outcomes Registry Thoracic Database evaluating all adult lung cancer resections across Queensland from January 1, 2016 to April 20, 2022. Evaluating the time from diagnosis to surgery, operative data, and postoperative morbidity and mortality comparing Aboriginal and/or Torres Strait Islander people with nonindigenous Australians. Results: There were 31 patients (2.56%) of 1208 who identified as indigenous. The mean age at surgery was 68.2 years versus 66 years in the indigenous and nonindigenous, respectively (p = 0.23). There was female predominance among indigenous patients (n = 28, 90.32%, p < 0.01) and the average body mass index was lower (22.52 versus 27.09, p < 0.01). There was no variation in the surgical parameters or histopathologic distribution of cancer type between groups. Multivariable logistic regression analysis suggested that indigenous patients were at elevated risk of blood transfusion (relative risk 3.9, p = 0.014, OR = 9.01, 95% confidence interval [CI]: 2.25-36.33, p < 0.01) and had greater transfusion requirements (risk ratio 4.08, p = 0.0116 and OR = 12.67, 95% CI: 2.25-71.49, p < 0.01); however, the influence of low absolute number of transfusions must be acknowledged here. Indigenous status was not associated with increased intensive care unit admission (OR = 1.79, 95% CI: 0.17-18.80, p = 0.62), return to operating theater (OR = 2.1, 95% CI: 0.24-18.15, p = 0.50), new atrial fibrillation (OR = 0.52, 95% CI: 0.07-4.01, p = 0.55), prolonged air leak (OR = 0.29, 95% CI: 0.04- 2.16, p = 0.228), or pneumonia postoperatively (OR = 4.77, 95% CI: 0.55-41.71, p = 0.16). With only three deaths, no meaningful trends were observed. Time from diagnosis to surgery was comparable in the indigenous and nonindigenous groups (88.6 d, 95% CI: 54.26-123.24 versus 86.2 d, 81.40-91.02, p = 0.87). Postoperative length of stay was not numerically or statistically different between groups. (indigenous 7.54 d versus nonindigenous 7.13 d, p = 0.90). Conclusions: Indigenous patients are more likely to receive a blood transfusion than nonindigenous patients during lung resection. Reassuringly, the perioperative care provided to indigenous Australians undergoing lung resection in Queensland seems to be comparable to that of the nonindigenous population.

First-in-human phase 1 clinical trial of anti-core 1 O-glycans targeting monoclonal antibody NEO-201 in treatment-refractory solid tumors.

BACKGROUND: NEO201 is a humanized IgG1 monoclonal antibody (mAb) generated against tumor-associated antigens from patients with colorectal cancer. NEO-201 binds to core 1 or extended core 1 O-glycans expressed by its target cells. Here, we present outcomes from a phase I trial of NEO-201 in patients with advanced solid tumors that have not responded to standard treatments. METHODS: This was a single site, open label 3 + 3 dose escalation clinical trial. NEO-201 was administered intravenously every two weeks in a 28-day cycle at dose level (DL) 1 (1 mg/kg), DL 1.5 (1.5 mg/kg) and DL 2 (2 mg/kg) until dose limiting toxicity (DLT), disease progression, or patient withdrawal. Disease evaluations were conducted after every 2 cycles. The primary objective was to assess the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of NEO-201. The secondary objective was to assess the antitumor activity by RECIST v1.1. The exploratory objectives assessed pharmacokinetics and the effect of NEO-201 administration on immunologic parameters and their impact on clinical response. RESULTS: Seventeen patients (11 colorectal, 4 pancreatic and 2 breast cancers) were enrolled; 2 patients withdrew after the first dose and were not evaluable for DLT. Twelve of the 15 patients evaluable for safety discontinued due to disease progression and 3 patients discontinued due to DLT (grade 4 febrile neutropenia [1 patient] and prolonged neutropenia [1 patient] at DL 2, and grade 3 prolonged (> 72 h) febrile neutropenia [1 patient] at DL 1.5). A total of 69 doses of NEO-201 were administered (range 1-15, median 4). Common (> 10%) grade 3/4 toxicities occurred as follows: neutropenia (26/69 doses, 17/17 patients), white blood cell decrease (16/69 doses, 12/17 patients), lymphocyte decrease (8/69 doses, 6/17 patients). Thirteen patients were evaluable for disease response; the best response was stable disease (SD) in 4 patients with colorectal cancer. Analysis of soluble factors in serum revealed that a high level of soluble MICA at baseline was correlated with a downregulation of NK cell activation markers and progressive disease. Unexpectedly, flow cytometry showed that NEO-201 also binds to circulating regulatory T cells and reduction of the quantities of these cells was observed especially in patients with SD. CONCLUSIONS: NEO-201 was safe and well tolerated at the MTD of 1.5 mg/kg, with neutropenia being the most common adverse event. Furthermore, a reduction in the percentage of regulatory T cells following NEO-201 treatment supports our ongoing phase II clinical trial evaluating the efficiency of the combination of NEO-201 with the immune checkpoint inhibitor pembrolizumab in adults with treatment-resistant solid tumors. TRIAL REGISTRATION: NCT03476681 . Registered 03/26/2018.