Lower Patient Survival Research Articles

Abstract 1653: Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. KRAS mutations and LKB1 inactivation commonly occur in NSCLC and are associated with poor prognosis. Several studies enunciate the role of the immune system in lung cancer progression through cancer cells' ability to escape immune surveillance. Therefore, understanding NSCLC progression requires the examination of the molecular mechanisms behind this process. The importance of oxidative phosphorylation (OXPHOS) and mitochondrial metabolism in lung cancer has been continuously emphasized; OXPHOS and mitochondrial biogenesis markers predict low survival in NSCLC patients. Additionally, heme is an essential molecule in the OXPHOS pathway, and previous studies have shown that heme sequestration using heme sequestering protein 2 (HeSP2) arrests tumor progression. HeSP2 can potentially normalize the tumor immune microenvironment (TIME) via multiple mechanisms including the normalization of vessels which may promote immune cell infiltration, the reduction of hypoxia which may promote antitumor immune function, and the reduction of heme levels which potentially decreases the production of immunosuppressive enzymes requiring heme as a cofactor. In this study, control and HeSP2-treated tumors generated from a genetically engineered mouse model LSL-KrasG12D LKB1-/- (LSL-KRASG12D; LKBloxP/loxP; LSL-Luciferase (KLLuc) infected with AdenoCre virus and sacrificed at 10 months were used for immunohistochemical analysis. We examined immune markers under HeSP2 treatment to determine the immune system response to heme targeting and its effects on tumor progression. Results demonstrated that HeSP2 can modulate the tumor immune microenvironment increasing the levels of immune markers, which suggests that heme targeting can potentiate immunotherapy efficacy in lung cancer treatment. Citation Format: Maria del Carmen Chacon Castro, Eranda Berisha, Narges Salamat, Li Zhang. Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1653.

Abstract 1238: Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells

Abstract Abstract Background Unlike Breast cancer (BRCA) luminal subtypes, Triple negative breast cancer (TNBC) subtype lacks expression of estrogen receptor-α (ERα/ESR1), progesterone receptor (PGR) and/or epidermal growth factor (EGF) family receptor HER2/ERBB2 where patients do not benefit from endocrine and HER2 based therapies in addition to its poor differentiation that results in greater aggressiveness and poorer prognosis. The 60 KD Heat shock protein (HSP60) is a Mitochondrial protein that plays a role in stabilizing and refolding proteins and is regulated by HSPD1 gene. In normal cells, HSPD1 gene expression is controlled, however in TNBC, HSPD1 overexpression is common and is associated with poor cancer-specific survival. This study aims to understand downstream signaling pathways dependent on the function of HSPD1 in TNBC. Method To understand downstream signaling pathways dependent on the function of HSPD1, we analyzed the transcriptomic profiles of metastatic MDA-MB-231-WT and HSPD1-KD cells. Results Bioinformatics data analysis shows that HSPD1 is overexpressed in TNBC, particularly in basal subtype. High expression of HSPD1 related to low survival in breast cancer patients. HSPD1 KD in MDA-MB-231 cells identified several differentially regulated genes (DEG) as compared to WT MDA-MB-231 cells by RNA-seq analysis. Pathway analysis of DEG showed downregulation of mitochondrial respiration, thermogenesis, citric acid cycle, PD-1 signaling while upregulation of estrogen dependent gene expression, estrogen mediated signaling, nuclear receptor transcription pathway. These suggests that HSP60 overexpression in TNBC promotes basal type phenotype. Downregulation of HSP60 expression upregulated hormone receptors, particularly estrogen receptor (ESR1) and androgen receptor (AR) expression, thus inducing basal to luminal switch in MDA-MB-231 cells. These findings suggest that loss of HSPD1 significantly Induces plasticity in TNBC. Conclusion Our results suggest that loss of HSPDI in the context TNBC cells may promotes oncogenic transformation to an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the upregulation of Estrogen-receptors signaling pathways. Ongoing analyses will be performed to identify the possible links between loss of HSPD1 and key transcription factors that define mammary epithelial cell differentiation. Citation Format: Muhammad G. Khodary, Alehegne W. Yirsaw, Temesgen Samuel, Clayton Yates, Deepa Bedi. Loss of HSPD1 induces cellular plasticity in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1238.

220 Sex Differences in Cardiac Damage in Aortic Stenosis

OBJECTIVES/GOALS: Sex differences in aortic stenosis (AS) are vastly underestimated, contribute to disparities in treatment and worse outcomes for women including disproportionately higher mortality rates. This study aims to investigate sex differences in extent of cardiac damage (CD) from pressure overload in AS that may help account for the observed disparities. METHODS/STUDY POPULATION: CD in AS refers to a series of pathologic changes in the myocardium that occur due to chronic pressure overload imposed on the left ventricle by a progressively stenotic aortic valve (AV). These changes are associated with poor outcomes and lower survival in patients with AS. To acquire a deeper understanding of the factors and mechanisms affecting differences in the long-term survival and management of patients with AS, we are proposing to assess baseline stage of CD on echocardiography, and changes in transvalvular hemodynamics and CD stage (Δ CD) over time, in patients with moderate and severe AS at one of 2 large tertiary-care hospitals in MA. We also plan to assess time to and performance of aortic valve replacement (AVR), stratified by hemodynamic severity of stenosis and CD stage, and their interaction with sex. RESULTS/ANTICIPATED RESULTS: We hypothesize that women will have a higher stage of CD on their initial echocardiogram (TTE), demonstrating moderate or greater severity of AS, than men with the same hemodynamic severity of valvular stenosis. We additionally hypothesize that those with more advanced cardiac damage stage will likely have masking of transvalvular progression on echocardiogram. Finally, we anticipate that women will have AVR performed less frequently than men and will have minimal improvement in their Kansas City Cardiomyopathy Questionnaire (KCCQ) scores post-AVR indicative of more heart failure symptoms and a lower quality of life. DISCUSSION/SIGNIFICANCE: This study will seek to better understand sex-based differences in extent of cardiac damage to pressure overload in aortic stenosis (AS) to minimize treatment and outcome disparities for women and allow for more individualized and patient-centered care.

Clinical Impact of Spontaneous Portosystemic Shunts in Liver Transplantation: A Comprehensive Assessment Through Total Shunt Area Measurement.

The impact of spontaneous portosystemic shunts (SPSSs) on natural history of cirrhotic patients was recently evaluated through the measurement of total shunt area (TSA), a novel tool that allows a comprehensive assessment of SPSSs extension, identifying a direct correlation of higher TSA with lower patient survival. The role of SPSSs in liver transplant (LT) is still debated: we sought to investigate the clinical impact of TSA on the development of early allograft dysfunction (EAD), acute kidney injury (AKI), postoperative complications, and graft and patient survival following LT. Preoperative imaging of 346 cirrhotic patients undergoing primary LT between 2015 and 2020 were retrospectively revised, recording the size and anatomy of each SPSS to calculate TSA. The impact of TSA and selected patient and donor characteristics on the development of EAD, AKI, and clinically relevant complications was evaluated through univariate and multivariate logistic regression, whereas their effect on graft and patient survival was investigated through Cox regression analysis. A TSA exceeding 78.54 mm 2 resulted as an independent risk factor for the development of EAD (odds ratio [OR]: 2.327; P = 0.003), grade 3 AKI (OR: 2.093; P = 0.041), and clinically relevant complications (OR: 1.962; P = 0.015). Moreover, higher TSA was significantly related to early graft and patient survivals, emerging as an independent risk factor for 12-mo graft loss (hazard ratio: 3.877; P = 0.007) and patient death (hazard ratio: 2.682; P = 0.018). Higher TSA emerged as a significant risk factor for worse postoperative outcomes following LT, supporting the need for careful hemodynamic assessment and management of patients presenting multiple/larger shunts.

Subclinical cardiac abnormalities in children with biliary atresia correlate with outcomes after liver transplantation.

There are subclinical cardiac abnormalities (SCA) in children with biliary atresia (BA). However, data on the consequences of these cardiac changes after liver transplantation (LT) remain controversial in the pediatric field. We aimed to determine the relationship between outcomes and the subclinical cardiac abnormalities in pediatric patients with BA based on two-dimensional echocardiography (2DE) parameters. A total of 205 children with BA were enrolled in this study. The relationship between 2DE parameters and outcomes, including death and serious adverse events (SAE) after LT, was analyzed by regression analysis. Using receiver operator characteristic (ROC) curves to determine the optimal cut-off values of 2DE parameters for outcomes. Differences in the AUCs were compared using DeLong's test. The Kaplan -Meier method with log-rank testing was used to evaluate survival outcomes between groups. Left ventricular mass index (LVMI) and relative wall thickness (RWT) were found to be independently associated with SAE (OR: 1.112, 95% CI: 1.061 - 1.165, P < 0.001 and OR: 1.193, 95% CI: 1.078 - 1.320, P = 0.001, respectively). The cutoff value of LVMI for predicting the SAE was 68 g/m2.7 (AUC = 0.833, 95% CI 0.727-0.940, P < 0.001), and the cutoff value of RWT for predicting the SAE was 0.41 (AUC = 0.732, 95% CI 0.641-0.823, P < 0.001). The presence of subclinical cardiac abnormalities (LVMI > 68 g/m2.7, and/or RWT > 0.41) was associated with lower patient survival (1-year, 90.5% vs 100.0%; 3-year, 89.7% vs 100.0, log-rank P = 0.001). and higher incidence of SAE events. Subclinical cardiac abnormalities were correlated with post-LT mortality and morbidity in children with BA. LVMI can predict the occurrence of death and serious adverse events after liver transplantation.

Distinct phenotypes of kidney transplant recipients aged 80 years or older in the USA by machine learning consensus clustering

ObjectivesThis study aimed to identify distinct clusters of very elderly kidney transplant recipients aged ≥80 and assess clinical outcomes among these unique clusters.DesignCohort study with machine learning (ML) consensus clustering...

Bmi-1: A master regulator of head and neck cancer stemness.

Head and neck cancers are composed of a diverse group of malignancies, many of which exhibit an unacceptably low patient survival, high morbidity and poor treatment outcomes. The cancer stem cell (CSC) hypothesis provides an explanation for the substantial patient morbidity associated with treatment resistance and the high frequency of tumor recurrence/metastasis. Stem cells are a unique population of cells capable of recapitulating a heterogenous organ from a single cell, due to their capacity to self-renew and differentiate into progenitor cells. CSCs share these attributes, in addition to playing a pivotal role in cancer initiation and progression by means of their high tumorigenic potential. CSCs constitute only a small fraction of tumor cells but play a major role in tumor initiation and therapeutic evasion. The shift towards stem-like phenotype fuels many malignant features of a cancer cell and mediates resistance to conventional chemotherapy. Bmi-1 is a master regulator of stem cell self-renewal as part of the polycomb repressive complex 1 (PRC1) and has emerged as a prominent player in cancer stem cell biology. Bmi-1 expression is upregulated in CSCs, which is augmented by tumor-promoting factors and various conventional chemotherapies. Bmi-1+ CSCs mediate chemoresistance and metastasis. On the other hand, inhibiting Bmi-1 rescinds CSC function and re-sensitizes cancer cells to chemotherapy. Therefore, elucidating the functional role of Bmi-1 in CSC-mediated cancer progression may unveil an attractive target for mechanism-based, developmental therapeutics. In this review, we discuss the parallels in the role of Bmi-1 in stem cell biology of health and disease and explore how this can be leveraged to advance clinical treatment strategies for head and neck cancer.

Predicting chemoresponsiveness in epithelial ovarian cancer patients using circulating small extracellular vesicle-derived plasma gelsolin

BackgroundResistance to chemotherapy continues to be a challenge when treating epithelial ovarian cancer (EOC), contributing to low patient survival rates. While CA125, the conventional EOC biomarker, has been useful in monitoring patients’ response to therapy, there are no biomarkers used to predict treatment response prior to chemotherapy. Previous work in vitro showed that plasma gelsolin (pGSN) is highly expressed in chemoresistant EOC cell lines, where it is secreted in small extracellular vesicles (sEVs). Whether sEVs from tumour cells are secreted into the circulation of EOC patients and could be used to predict patient chemoresponsiveness is yet to be determined. This study aims to identify if sEV-pGSN in the circulation could be a predictive biomarker for chemoresistance in EOC.MethodsSandwich ELISA was used to measure pGSN concentrations from plasma samples of 96 EOC patients (primarily high grade serous EOC). sEVs were isolated using ExoQuick ULTRA and characterized using western blot, nanoparticle tracking analysis, and electron microscopy after which pGSN was measured from the sEVs. Patients were stratified as platinum sensitive or resistant groups based on first progression free interval (PFI) of 6 or 12 months.ResultsTotal circulating pGSN was significantly decreased and sEV-pGSN increased in patients with a PFI ≤ 12 months (chemoresistant) compared to those with a PFI > 12 months (chemosensitive). The ratio of total pGSN to sEV-pGSN further differentiated these groups and was a strong predictive marker for chemoresistance (sensitivity: 73.91%, specificity: 72.46%). Predetermined CA125 was not different between chemosensitive and chemoresistant groups and was not predictive of chemoresponsiveness prior to treatment. When CA125 was combined with the ratio of total pGSN/sEV-pGSN, it was a significant predictor of chemoresponsiveness, but the test performance was not as robust as the total pGSN/sEV-pGSN alone.ConclusionsTotal pGSN/sEV-pGSN was the best predictor of chemoresponsiveness prior to treatment, outperforming the individual biomarkers (CA125, total pGSN, and sEV-pGSN). This multianalyte predictor of chemoresponsiveness could help to inform physicians’ treatment and follow up plan at the time of EOC diagnosis, thus improving patients’ outcomes.

Overweight and Obesity are Associated with Poorer Survival Among Patients with Advanced Non-Small Cell Lung Cancer Receiving Platinum-Based Chemotherapy

Most patients with non-small cell lung cancer (NSCLC) are diagnosed in advanced-stage disease and therefore have poor overall survival. It remains unclear whether nutritional status affects response rate and overall survival in NSCLC patients. This study aimed to evaluate the association of nutritional status with treatment response and overall survival in patients with advanced stage of NSCLC. Patients aged ≥18 years with stage II-IV NSCLC (January-June 2018) in a national cancer center in Indonesia were enrolled in this study. The patients were followed up for 2 years since NSCLC diagnosis was established. Clinical data including age, sex, histology of cancer, disease stage, cachexia, and weight status before chemotherapy were reviewed and analyzed. Logistic regression and Cox regression analyses were performed. A total of 174 patients (71% males, mean age = 58±9.4 years) was included. Complete response was found in <1% patients, partial response 41%, stable disease 33%, and progressive disease 25%. Median survival was 12 months (95% CI: 11-13 months). Mortality rate was 5.7 per 100 person-months. Poor survival was associated with being males (HR: 1.77, 95% CI: 1.15-2.72, P = 0.009), and overweight or obesity (HR 1.67, 95% CI: 1.04-2.69, P = 0.034). These associations were independent of sex, age, staging, histopathology, performance status and D-dimer level at baseline. Cachexia and BMI at baseline were not associated with treatment response. Males and having overweight or obesity are independently associated with lower survival in patients with advanced stage of NSCLC undergoing platinum-based chemotherapy.

Extracorporeal Membrane Oxygenation Cannulation Timing in the Pediatric Myocarditis Population: An Exploratory Analysis From the Extracorporeal Life Support Organization Registry.

Retrospective review of a large international registry. Primary outcome was survival to hospital discharge, stratified by incident cardiac arrest (CA) prior to ECMO and time to cannulation after intubation. The Extracorporeal Life Support Organization registry was queried for patients less than or equal to 18 years old receiving ECMO support for myocarditis between 2007 and 2018. Exclusion criteria included being nonindex runs, non-venoarterial ECMO or missing data points for main variables studied. None. Population characteristics and survival were compared using t test, Wilcoxon rank-sum test, or Fisher exact test. Multivariable logistic regression was used for significant factors in the unadjusted logistic regression. Among 506 index ECMO runs in pediatric patients with myocarditis, survival for the cohort was 72%, with no difference between early and late eras (2007-2012 vs 2013-2018; p = 0.69). Survivors demonstrated higher pre-ECMO pH levels as well as shorter intubation-to-cannulation (ITC) times (3 hr [interquartile range (IQR)], 1-14 hr vs 6 hr [IQR, 2-20 hr]; p = 0.021). CA occurred within 24 hours prior to ECMO cannulation, including extracorporeal cardiopulmonary resuscitation, in 54% of ECMO runs (n = 273). Accounting for the interaction between pre-ECMO CA occurrence and ITC time, longer ITC time remained associated with lower survival for patients who did not experience a CA prior to ECMO, with adjusted odds ratio of 0.09 (IQR, 0.02-0.40; p = 0.002) for ITC time greater than or equal to 18 hours. The results of this multicenter analysis of ECMO utilization and outcomes for pediatric myocarditis suggest that patients approaching ECMO cannulation who have not experienced CA may have better survival outcomes if cannulated onto ECMO early after intubation.

Effect of omega-3 supplementation on the nutritional status of patients with pancreatic cancer: A protocol for systematic review of clinical trials

Globally, pancreatic cancer is the seventh most common cause of cancer-related death in both sexes, accounting for 466,003 deaths and 495,773 new cases in 2020. The purpose of this study was to synthesize and evaluate evidence on the effects of omega-3 supplementation on the nutritional status of patients with pancreatic cancer. This systematic review protocol will be guided by Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. Five databases will be searched: MEDLINE/PubMed, CENTRAL Cochrane, EMBASE, Web of Science, and SCOPUS, with no restrictions on the publication date nor language. The internal validity and risk of bias of randomized controlled trials will be assessed using the revised Cochrane Risk-Of-Bias tool for randomized trials (RoB 2), whereas the risk of bias in non-randomized studies of interventions will be evaluated using the ROBINS-I. The heterogeneity among the studies will be assessed using the I2 statistic. Based on the results of this test, we will verify whether the meta-analysis would be feasible. If feasibility would be confirmed, a random-effect model analysis will be performed. For data analysis, the calculation of the pooled effect estimates will have a 95% confidence interval, while the alpha will be set to 0.05 using the R statistical software version 4.0.4. All methodological steps of this review will be performed independently by two reviewers and will be conducted and managed in the EPPI-Reviewer Software™. This review may be of particular interest to researchers and clinicians, given the low survival and overall burden of patients with pancreatic cancer. Furthermore, the results of this systematic review may contribute to the development of new nutritional interventions in these patients. To the best of our knowledge, this will be the first study to critically assess the scientific evidence and estimate the effect of omega-3 supplementation on the nutritional status of patients with pancreatic cancer. The review will perform a rigorous approach, adhering to the PRISMA Statement 2020 using a comprehensive and systematic search strategy in five databases and additional sources with no time period nor language restrictions.

A novel autophagy-related long non-coding RNAs prognostic risk score for clear cell renal cell carcinoma.

As the main histological subtype of renal cell carcinoma, clear cell renal cell carcinoma (ccRCC) places a heavy burden on health worldwide. Autophagy-related long non-coding RNAs (ARlncRs) have shown tremendous potential as prognostic signatures in several studies, but the relationship between them and ccRCC still has to be demonstrated. The RNA-sequencing and clinical characteristics of 483 ccRCC patients were downloaded download from the Cancer Genome Atlas and International Cancer Genome Consortium. ARlncRs were determined by Pearson correlation analysis. Univariate and multivariate Cox regression analyses were applied to establish a risk score model. A nomogram was constructed considering independent prognostic factors. The Harrell concordance index calibration curve and the receiver operating characteristic analysis were utilized to evaluate the nomogram. Furthermore, functional enrichment analysis was used for differentially expressed genes between the two groups of high- and low-risk scores. A total of 9 SARlncRs were established as a risk score model. The Kaplan-Meier survival curve, principal component analysis, and subgroup analysis showed that low overall survival of patients was associated with high-risk scores. Age, M stage, and risk score were identified as independent prognostic factors to establish a nomogram, whose concordance index in the training cohort, internal validation, and external ICGC cohort was 0.793, 0.671, and 0.668 respectively. The area under the curve for 5-year OS prediction in the training cohort, internal validation, and external ICGC cohort was 0.840, 0.706, and 0.708, respectively. GO analysis and KEGG analysis of DEGs demonstrated that immune- and inflammatory-related pathways are likely to be critically involved in the progress of ccRCC. We established and validated a novel ARlncRs prognostic risk model which is valuable as a potential therapeutic target and prognosis indicator for ccRCC. A nomogram including the risk model is a promising clinical tool for outcomes prediction of ccRCC patients and further formulation of individualized strategy.

Anesthetic propofol suppresses growth and metastasis of lung adenocarcinoma in vitro through downregulating circ-MEMO1-miR-485-3p-NEK4 ceRNA axis.

Recently, circular RNAs (circRNAs) have been emerging as new regulators in the propofol-induced tumor-suppressive role. Here, we intended to investigate the involvement of circRNA-Mediator of cell motility 1 (circ-MEMO1; hsa_circ_0007385) in propofol role in cancer hallmarks of lung adenocarcinoma (LUAD). Real-time quantitative PCR and western blotting examined transcriptional and translational levels of circ-MEMO1, microRNA (miR)-485-3p, and NIMA-related kinase-4 (NEK4), and markers of growth and metastasis including E-cadherin, CyclinD1, and Vimentin. Cancer hallmarks were measured by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, 5-ethynyl-2-deoxyuridine assay, and transwell assay. The interaction among circ-MEMO1, miR-485-3p, NEK4 was determined by dual-luciferase reporter assay and Pearson's correlation analysis. Circ-MEMO1 and NEK4 were high-expressed, and miR-485-3p was low-expressed in LUAD patients and cells; moreover, circ-MEMO1 and NEK4 expression in LUAD cells could be suppressed, whereas miR-485-3p could be elevated with propofol anesthesia. Functionally, propofol restrained cell viability, cell cycle entrance, cell proliferation, migration, and invasion of LUAD cells, accompanied by promoted E-cadherin and depressed CyclinD1 and Vimentin. Coincidently, high circ-MEMO1 was associated with low overall survival of LUAD patients, and overexpressing circ-MEMO1 could overall attenuate propofol effects in LUAD cells. Of note, upregulating miR-485-3p and/or interfering NEK4 could partially countermand the adverse impacts of circ-MEMO1 on propofol's role in LUAD cells. Importantly, circ-MEMO1 acted as a sponge for miR-485-3p to modulate the expression of miR-485-3p-targeted oncogene NEK4. Promoting the circ-MEMO1-miR-485-3p-NEK4 axis might halt the tumor-inhibiting role of propofol in LUAD cells in vitro, suggesting a potential epigenetic pathway of propofol.

Network module function enrichment analysis of lung squamous cell carcinoma and lung adenocarcinoma.

Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) are the two major subtypes of non-small cell lung cancer that pose a serious threat to human health. However, both subtypes currently lack effective indicators for early diagnosis. To identify tumor-specific indicators and predict cancer-related signaling pathways, LUSC and LUAD gene weighted co-expression networks were constructed. Combined with clinical data, core genes in LUSC and LUAD modules were then screened using protein-protein interaction networks and their functions and pathways were analyzed. Finally, the effect of core genes on survival of LUSC and LUAD patients was evaluated. We identified 12 network modules in LUSC and LUAD, respectively. LUSC modules "purple" and "green" and LUAD modules "brown" and "pink" are significantly associated with overall survival and clinical traits of tumor node metastasis, respectively. Eleven genes from LUSC and eight genes from LUAD were identified as candidate core genes, respectively. Survival analysis showed that high expression of SLIT3, ABI3BP, MYOCD, PGM5, TNXB, and DNAH9 are associated with decreased survival in LUSC patients. Furthermore, high expression of BUB1, BUB1B, TTK, and UBE2C are associated with lower patient survival. We found biomarker genes and biological pathways for LUSC and LUAD. These network hub genes are associated with clinical characteristics and patient outcomes and they may play important roles in LUSC and LUAD.

LncRNA-EWSAT1 promotes hepatocellular carcinoma metastasis via activation of the Src-YAP signaling axis.

Regardless of the improvements in diagnostic and therapeutic methods, the clinical outcomes of hepatocellular carcinoma (HCC) patients remain poor. Although accumulating evidence indicates that lncRNAs (long noncoding RNAs) are essential within the control of tumorigenesis and the metastasis of cancer, the underlying mechanisms remain largely unknown. This work explored the pattern of expression and functional significance of a newly found lncRNA, Ewing sarcoma-associated transcript 1 (EWSAT1), in HCC metastasis. The results indicated that EWSAT1 was upregulated significantly in HCC relative to that in normal tissues and was correlated with an aggressive phenotype and low patient survival. Functional experiments demonstrated that EWSAT1 could promote proliferation and HCC cell metastasis both in vitro and in vivo. Mechanistically, EWSAT1 binds directly to Yes-associated protein (YAP), promotes Sarcoma gene (Src)-induced phosphorylation of YAP, facilitates nuclear translocation of YAP, and consequently, activates the transcription of Hippo-YAP signaling target genes involved in cancer evolution. This study found that EWSAT1 plays a crucial role in HCC metastasis and that it has the potential to be a prognosis biomarker and a target for therapeutics.

Abstract B052: Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDA) is predicted to become the second leading cause of cancer-related death in 2025 and has a 5-year survival rate of only 11%. Progression of the pancreatic disease is in part driven by the transdifferentiation of acinar cells into metaplastic ducts in the pancreas. Metaplastic tuft cells (MTCs) are a specialized subset of the metaplastic epithelium that has the potential to drive tumor progression through communication with the microenvironment and modulate PDA progression. Also known as solitary chemosensory cells, tuft cells were first discovered in rodent luminal surfaces, including the nose, stomach, intestine, and bladder, more than 60 years ago. They are characterized by the “tuft” of microvilli reaching into the lumen and, only recently, have studies started to determine the role of normal tuft cells in different organs. These studies determined that tuft cells have different roles depending on the organ in which they reside. Tuft cells are found in several different organs during normal development; however, studies have shown that tuft cells are not present in a normal pancreas. MTCs are only present in the pancreas in PanINs during PDA progression in both humans and mice. Furthermore, the population of MTCs in the pancreas disappears as PDA progresses into invasive carcinoma when using canonical markers of tuft cells. We know little about the role of MTCs in the pancreas, but prior studies have suggested their role as a progenitor cell during PDA. However, these studies do not exclusively mark MTCs during their genesis in a progressive model of PDA due to a lack of a mouse model as well as the complexity of culturing them ex vivo. We have generated a unique mouse model to drive lineage tracing of MTCs during PDA, and I have preliminary data to suggest that MTCs are not disappearing as PDA progresses but can transdifferentiate into another cell type that is correlated with lower survival in patients. Citation Format: Daniel Salas-Escabillas, Howard Crawford, Megan Hoffman. Uncovering the lineage of chemosensory cells in the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B052.

Progressive Disease With Low Survival in Adult Patients With Pulmonary Fibrosis Carrying Surfactant-Related Gene Mutations: An Observational Study

In some patients with progressive fibrosing interstitial lung disease (ILD), disease is caused by carriage of a mutation in a surfactant-related gene (SRG) such as SFTPC, SFTPA2, or ABCA3. However, no aggregated data on disease evolution and treatment outcome have been presented for these patients. In adult patients with ILD with an SRG mutation, what is the course of lung function after diagnosis and during treatment and the survival in comparison with patients with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)? We retrospectively examined the clinical course of a cohort of adults with an SRG mutation by screening 48 patients from 20 families with an SRG mutation for availability of clinical follow-up data. For comparison, 248 patients with FPF and 575 patients with sIPF were included. Twenty-three patients with ILD (median age: 45 years; 11 men) with an SRG mutation fulfilled criteria. At diagnosis, patients with an SRG mutation were younger and less often male, but had lower FVC (72%predicted) and diffusing capacity of the lungs for carbon monoxide (46%predicted) compared with patients with FPF or sIPF. In the SRG mutation group, median FVC decline 6months after diagnosis was -40mL and median transplant-free survival was 44months and not different from patients with FPF or sIPF. FVC course was not different among the three cohorts; however, a significantly larger decrease in FVC was found while patients received immunomodulatory or antifibrotic treatment compared with those receiving no treatment. Subsequent analysis in the SRG group showed that patients with a surfactant mutation (n= 7) treated for 6months with antifibrotic drugs showed stable lung function with a median change in FVC of+40mL (interquartile range, -40 to 90mL), whereas patients with an SRG mutation treated with immunomodulatory drugs showed a variable response dependent on the gene involved. This study showed that patients with ILD carrying an SRG mutation experience progressive loss of lung function with severely reduced survival despite possible beneficial effects of treatment.

Serum zinc values, ankle brachial index and mortality in hemodialysis patients

IntroductionThe atherosclerotic state of haemodialysis (HD) patients may be influenced by heavy metals. The purpose of our study was to assess the relationship between serum zinc (Zn) ankle brachial index (ABI) as a non-invasive diagnostic tool for atherosclerosis, and mortality in chronic haemodialysis (HD) patients.MethodsSixty one HD patients were included (mean age 61.2 ± 13.8 years). The ABI was measured with an automated measuring device (ABPI MD, MESI®, Slovenia). Two groups of patients were formed based on the median value of Zn (14.1 mcmol/l). The average observation time was 2.8 years. Comorbidities (arterial hypertension (AH), diabetes mellitus (DM), dyslipidaemia), smoking and oral nutritional supplements (ONS) consumption were noted. Survival rates were analysed by Kaplan–Meier and Cox regression was used to determine the influence of Zn, ABI, AH, DM, dyslipidaemia, smoking and ONS.ResultsZn values were between 9.2 and 23.5 mcmol/l (14.4 ± 2.34), ABI values ranged from 0.8 to 1.4 (1.14 ± 0.12). Patients with lower Zn values had lower ABI (p = 0.036). Mean survival time of patients with higher Zn values was 985 days ± 277 days and with lower Zn values 1055 ± 143 days. Six (19.4%) patients with lower Zn and five (16.7%) patients with higher Zn died. We found statistically insignificant lower survival in patients with higher Zn. We failed to find any predictor of all-cause mortality, except for ONS consumption (95% CI 1.6–33.3; p = 0.012).ConclusionsLower Zn is associated with lower ABI in HD patients, but we found no impact of Zn on patient survival.

Effect of patient frailty status on outcomes of fenestrated-branched endovascular aortic repair for complex abdominal and thoracoabdominal aortic aneurysms.

In the present study, we assessed the effects of patient frailty status on the early outcomes and late survival after fenestrated-branched endovascular aortic repair (FB-EVAR) for complex abdominal and thoracoabdominal aortic aneurysms. We retrospectively reviewed the clinical data and outcomes of consecutive patients who had undergone elective FB-EVAR from 2007 to 2019 in a single institution. A previously validated 11-item modified frailty index (mFI-11) was derived from the comorbidity and preoperative functional status data. An mFI-11<0.3 was defined as low risk, 0.3 to 0.5 as medium risk, and >0.5 as high risk. The studied outcomes were 90-day mortality, major adverse events (MAE), and long-term survival. Multivariate analyses were performed to identify the independent predictors of these outcomes. A total of 592 patients (155 women, mean age, 75± 8years) had undergone FB-EVAR. Using the mFI-11, 310 patients (52%) were included in the low-risk, 199 (34%) in the medium-risk, and 83 (14%) in the high-risk group. The 90-day mortality was significantly higher in the high-risk group than in the medium- and low-risk groups (13%, 4%, and 3%, respectively; P< .01). The corresponding MAE rates were 27%, 18%, and 19% (P= .23). As a subgroup, 44 patients in the high-risk group had had chronic kidney disease (CKD). The 90-day mortality for these patients was as high as 23%, and 32% had experienced MAE. On multivariable analysis, the independent risk factors for 90-day mortality were CKD, respiratory disease, and a high mFI-11. The independent risk factors for MAE were female sex, CKD, larger aneurysm diameter, and the high-risk subgroup with CKD. The independent risk factors for long-term mortality were age, a low body mass index, CKD, larger aneurysm diameter, extent I-III thoracoabdominal aortic aneurysm, respiratory disease, congestive heart failure, a history of cerebrovascular problems, and higher mFI-11. The estimated survival at 1year was 91%± 2% in the low-risk, 88%± 2% in the medium-risk, and 78%± 5% in the high-risk group (P< .001). The corresponding 5-year survival estimates were 60%± 4%, 52%± 5%, and 32%± 6%. The mean follow-up time was 2.9± 2.3years. The patients treated during the first quartile of the study period were significantly more frail than were those in the later quartiles. Also, the outcomes of FB-EVAR had improved over time. Greater frailty was significantly associated with early mortality. Together with CKD, frailty was also associated with MAE and lower patient survival after FB-EVAR. The mFI-11 represents the accumulation of comorbidities and can be used to assist in better patient selection for FB-EVAR.

Procalcitonin and High APACHE (Acute Physiological and Chronic Health Evaluation) Level Are Associated with the Course of Acute Kidney Injury in Patients with SARS-CoV-2.

Background Acute kidney injury (AKI) is associated with poor outcomes in patients infected with SARS-CoV-2. Sepsis, direct injury to kidney cells by the virus, and severe systemic inflammation are mechanisms implicated in its development. We investigated the association between inflammatory markers (C-reactive protein, procalcitonin, D-dimer, lactate dehydrogenase, and ferritin) in patients infected with SARS-CoV-2 and the development of AKI. Methods A prospective cohort study performed at the Civil Hospital (Dr. Juan I. Menchaca) Guadalajara, Mexico, included patients aged >18 years with a diagnosis of SARS-CoV-2 pneumonia confirmed by RT-PCR and who did or did not present with AKI (KDIGO) while hospitalized. Biomarkers of inflammation were recorded, and kidney function was estimated using the CKD-EPI formula. Results 291 patients were included (68% males; average age, 57 years). The incidence of AKI was 40.5% (118 patients); 21% developed stage 1 AKI, 6% developed stage 2 AKI, and 14% developed stage 3 AKI. The development of AKI was associated with higher phosphate (p = 0.002) (RR 1.39, CI 95% 1.13–1.72), high procalcitonin levels at hospital admission (p = 0.005) (RR 2.09, CI 95% 1.26–3.50), and high APACHE scores (p = 0.011) (RR 2.0, CI 95% 1.17–3.40). The survival analysis free of AKI according to procalcitonin levels and APACHE scores demonstrated a lower survival in patients with procalcitonin >0.5 ng/ml (p = 0.001) and APACHE >15 points (p = 0.004). Conclusions Phosphate, high procalcitonin levels, and APACHE levels >15 were predictors of AKI development in patients hospitalized with COVID-19.