Poor Clinical Outcome In Patients Research Articles

Sarcopenia as a Determinant of the Efficacy of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: A Meta-Analysis

ObjectiveThe impact of pre-immunotherapy sarcopenia in patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICIs) is elusive. We performed a meta-analysis to investigate the association between sarcopenia and clinical outcomes of ICIs.MethodsPubMed, EMBASE, and the Cochrane Library were searched.ResultsThirteen clinical trials were selected. The 1,2-year overall survival rate was lower in the sarcopenia group (odds ratio (OR) = 2.44, 95% confidence interval (CI), 1.78–3.35, P < 0.00001; OR = 1.60, 95% CI, 1.08–2.37, P = 0.02), with I2 = 34%, P = 0.15, and I2 = 41%, P = 0.12. The 1,2-year progression-free survival (PFS) was the same (OR = 3.43, 95% CI, 1.86–6.33, P < 0.0001; OR = 2.06, 95% CI, 1.19–3.58, P < 0.0001), with I2 = 31%, P = 0.17 and I2=31%, P = 0.17. Sarcopenia reduced the overall response rate (OR = 2.22, 95% CI, 1.01–4.84, P = 0.02), with I2= 56%, P = 0.02, and disease control rate (OR = 3.15, 95% CI, 2.10–4.72, P < 0.0001) with I2 = 33%, P = 0.18.ConclusionPre-immunotherapy sarcopenia was associated with poor clinical outcomes in patients with advanced NSCLC who received ICIs.

Targeting Vimentin (VIM) in Acute Myelogenous Leukemia (AML)

Background: Vimentin (VIM) is a type III intermediate filament (IF) that anchors organelles in the cell, maintains cell integrity, and facilitates mitosis. A 2018 study demonstrated that the up-regulation of VIM is associated with poor clinical outcome in patients with Acute Myeloid Leukemia (AML). This study also reported that VIM regulates signaling networks that promote leukemic cell survival while conferring resistance to various stressors. A separate study revealed that VIM over-expression was associated both with markedly shorter overall survival (OS) and leukemia-free survival (LFS) in adult AML patients. VIM has been shown to be targetable by the steroidal lactone Withaferin-A which directly binds VIM, hyper-phosphorylates VIM's Serine 38 residue, and leads to an anti-proliferative effect characterized by perturbation of intermediary filaments. We investigated VIM expression and prognostic impact in pediatric AML, and whether inhibiting VIM affected chemosensitivity in vitro. Methods: Reverse Phase Protein Array (RPPA) was performed to quantify relative expression of 233 total and 63 post-translational modified proteins in 500 pediatric AML patients from the COG AAML1031 trial. AML cell lines with low VIM expression (OCI-2) and high VIM expression (OCI-3) as well as fresh, primary AML samples were exposed to the VIM inhibitor Withaferin-A alone, or in combination with Doxorubicin and Cytarabine chemotherapy. Other known VIM inhibitors including FiVe1, Simvastatin, and Ganoderic Acid A were tested for efficacy in our context, but only Withaferin-A produced a promising anti-leukemia effect. Results: In pediatric AML, VIM was over-expressed relative to normal CD34+ cells in all subtypes: bulk, CD3/CD19 depleted, CD34+, CD34+/38+, CD34+/38-, CD34-, CD34-/38+, and CD34-/38-. Pearson correlation analysis revealed significant negative correlations between VIM and proteins known to decrease during metastasis such as PDGFR-beta, TP15.pS15, HIF1-alpha and VHL. Elevated VIM correlated positively with HNRNPK, WTAP, ASH2L, and KDM1A, and H3K4Me2; alterations in histone methylation that are associated with metastatic potency. VIM expression was highest in FAB subtypes M4 and M5, and in patients with t(9;11) and MLL-rearrangements. VIM levels were lower in cytogenetically favorable and higher in unfavorable risk groups. Cumulative survival probability to standard chemotherapy progressively decreased as VIM expression increased (Fig. 1). We tested whether VIM inhibition with Withaferin-A at 50 nM and 100 nM, would affect proliferation or cell survival, finding a significantly stronger anti-proliferative effect (p<0.02) in the high-VIM OCI-3 cell line compared to the low-VIM OCI-2 cell line at 72 and 96 hours after treatment (Fig. 2). Combined with chemotherapy, Withaferin-A lead to greater cell death in the high-VIM OCI-3 cell line as opposed to low-VIM OCI-2 at 72 and 96 hours. For instance, in OCI-3, 100 nM Withaferin-A combined separately with either 1 uM Cytarabine or 50 nM Doxorubicin to decrease proliferation more than either chemotherapeutic agent alone (p=0.007 and p=0.0013). In primary AML samples, proliferation was slightly more inhibited at 72 hours post-treatment when Withaferin-A was paired with individual chemotherapeutics. Conclusions: Proteomic analysis demonstrated that VIM was elevated in numerous leukemia cell subtypes relative to normal CD34+ cells in children and adults and that prognosis worsened as VIM levels increased in pediatric AML. AML cell lines highly expressing VIM such as OCI-3 displayed sensitivity to both Withaferin-A monotherapy and Withaferin-A in combination with Cytarabine and Doxorubicin. Finally, Withaferin-A significantly reduced viability and proliferation after 72 hours of treatment in primary AML samples at select doses in combination with chemotherapeutics. These results suggest that targeting VIM could improve the efficacy of chemotherapy in high VIM expressing subpopulations and potentially improve overall survival. Withaferin-A's efficacy both as a mono-therapeutic and in combination with standard chemotherapeutics used to treat AML patients offers an exciting new area of research that requires further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EPCO-24. MULTI-OMIC PROFILING OF PATIENT-DERIVED SUBCLONES IDENTIFIES AGGRESSIVE CELLULAR SUBPOPULATIONS IN PAEDIATRIC DIFFUSE HIGH GRADE GLIOMAS (PDHGGS)

Abstract Paediatric-type diffuse high-grade gliomas are classified into distinct subgroups based upon their location and defining molecular alterations, with very poor clinical outcomes in patients &amp;gt;3yrs. This extensive inter-tumour heterogeneity is further complicated by a wide diversity of genotypically- and phenotypically-distinct subclonal populations within individual tumours, providing a substantial barrier to developing effective treatments. We aimed to understand the dynamic cellular make-up of PDHGGs such that novel strategies aimed at targeting specific subpopulations based upon their contribution to disease progression as whole may be employed. Two complementary approaches have been undertaken to address this – first by carrying out single-cell profiling of bulk specimens, and the second isolation and propagation of single-cell-derived stem cell-like cultures in vitro. To-date we have studied 10 cases and a total of 218 subclonal colonies from both DMG-H3K27 and DHG-WT. In a spinal metastatic case of DMG-H3K27, lpWGS/FISH highlighted subpopulations driven by mis-segregation of amplified oncogenic ecDNA, and mutually exclusive subpopulations defined by MYCN, PDGFRA and CCND1. Through integrated analysis of scRNA-seq and scATAC-seq, we show distinct chromatin accessibility profiles to underlie gene expression signatures defining unique subpopulations of cells. In addition to cycling populations and those associated with lineage-specificity, we identified ‘aggressive’ subpopulations defined by significant upregulation of immediate early response genes such as FOS/FOSL1/JUN, those associated with promotion of invasion/migration such as SERPINs and MMPs. These subpopulations could be mapped to isolated single-cell-derived subclones with highly proliferative and/or motile phenotypes, defined by comprehensive profiling of expressed and secreted proteins. Differential cis-regulation driving cell identity/tumorigenesis was found in one example to occur via a trans-histone mechanism mediated by an H4-lysine-methyltransferase, KMT5B. Application of functionally-defined interventional strategies aimed at disrupting the interactions between these subpopulations based upon evolutionary biology principles may offer a novel approach to treat these otherwise incurable tumours in children and young adults.

Abstract 12102: Concomitance of Diabetes Mellitus and Prior Myocardial Infarction Associated With Poor Clinical Outcomes in Patients With Atrial Fibrillation: The Fushimi AF Registry

Background : Patients with diabetes mellitus (DM) have high risk of cardiovascular events such as cardiovascular death, stroke, heart failure and so on. Patients with history of myocardial infarction (MI) are also at high risk. The outcomes of patients with nonvalvular atrial fibrillation (NVAF) who have both DM and history of MI are unclear. Methods : From the Fushimi AF registry, we obtained NVAF patients who had both DM and history of MI (DM+MI+: N=107), either DM or history of MI (DM-MI+: N=156, and DM+MI-: (N=935), and neither DM nor history of MI (DM-MI-: N=3,197). Major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause mortality were evaluated. MACCE was defined as composite events of cardiovascular death, myocardial infarction, stroke, and admission for heart failure. Results: The median follow-up period was 1,851 (interquartile range: 790-2,924) days. DM+MI+ patients were often male and had more heart failure, chronic renal disease, dyslipidemia, hypertension, and paroxysmal AF than other patients. DM+MI+patients had also higher risk scores (CHADS 2 , CHA 2 DS 2 -VASc and HAS-BLED scores). DM+MI+ patients had significantly higher incidence (% per patient-year) of MACCE and all-cause mortality than others (Figure A and B. MACCE: DM+MI+ 18.8%, DM-MI+ 8.0%, DM+MI- 6.1%, DM-/MI- 4.9%, log rank P&lt;0.001, all-cause mortality: 10.2%, 6.1%, 5.2%, 4.5%, respectively, log rank P&lt;0.001). In multivariate analysis, DM+MI+ was significantly associated with the incidence of MACCE compared with DM-/MI- (adjusted hazard ratio [95% confidence interval], 1.97 [1.36-2.87], P&lt;0.001), although DM-MI+ and DM+MI had no association with it. In addition, DM+MI+ had no significant association with the incidence of all-cause mortality after multivariate adjustment. Conclusion: Patients with NVAF who have both DM and history of MI had more comorbidities and had significant association with adverse cardiovascular events.

Whey protein hydrolysate mitigates both inflammation and endotoxin tolerance in THP-1 human monocytic leukemia cells.

It is important to control both inflammation and immunosuppression after severe insults, such as sepsis, trauma, and surgery. Endotoxin tolerance is one of the immunosuppressive conditions and it has been known that endotoxin tolerance relates to poorer clinical outcomes in patients with severe insults. This study investigated whether whey protein hydrolysate (WPH) mitigates inflammation and endotoxin tolerance in THP-1 human monocytic leukemia cells. Endotoxin tolerance can be experimentally reproduced by two consecutive stimulations with lipopolysaccharide (LPS). THP-1 cells were incubated with LPS and WPH (first stimulation). After collecting the culture supernatant to evaluate the effect on inflammation, the cells were washed and restimulated by 100 ng/ml LPS (second stimulation). The culture supernatant was again collected to evaluate the effect on endotoxin tolerance. Concentrations of LPS and WPH in the first stimulation were adjusted to evaluate their dose dependency. Cytokine levels in the supernatant were determined by enzyme-linked immunosorbent assay. Statistical analysis was performed using the student's t-test or Dunnett's test. Five mg/ml WPH significantly decreased interleukin (IL)-6 (p = .006) and IL-10 (p < .001) levels after the first LPS stimulation (1000 ng/ml). WPH significantly increased tumor necrosis factor-alpha (p < .001) and IL-10 (p = .014) levels after the second LPS stimulation. The suppressive effect of WPH on inflammation and endotoxin tolerance was dependent on the concentrations of LPS and WPH. The effective dose of WPH for endotoxin tolerance was lower than its effective dose for inflammation. WPH mitigated both inflammation and endotoxin tolerance. Therefore, WPH might be a candidate for valuable food ingredients to control both inflammation and immunosuppression after severe insults.

NPRL2 down-regulation facilitates the growth of hepatocellular carcinoma via the mTOR pathway and autophagy suppression.

Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA-mediated and shRNA-mediated NPRL2 down-regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down-regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down-regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down-regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease-free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down-regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.

Ectodysplasin A is associated with the presence and severity of coronary artery disease and poor long-term clinical outcome in patients presenting with ST-elevation myocardial infarction

ABSTRACT Objectives Hepatokines are proteins secreted by hepatocytes and many hepatokines such as fetuin A/B, selenoprotein P have been shown to play a role in the pathogenesis of many metabolic dysfunctions such as diabetes, insulin resistance, hypertension, and metabolic syndrome by showing autocrine, paracrine and systemic effects. Ectodysplasin A (EDA) is a recently discovered hepatokine that plays a role in the development of ectodermal structures. In recent studies, it has been revealed that EDA may be associated with the pathogenesis of non-alcoholic liver disease, insulin resistance, Type 2 diabetes mellitus. The close relationship between these metabolic diseases and coronary artery disease (CAD), which may be associated with insulin resistance, has been well documented in previous studies. However, until now, there is no study examining the relationship of EDA with CAD and its effect on long-term outcomes. In this study, we aim to reveal this relationship on patients presenting with ST elevation myocardial infarction (STEMI). Methods EDA levels of 544 patients who applied to the study with STEMI and 544 people without coronary artery disease were included in the control group, and the patients with STEMI were followed for median of 33.7 ± 6.8 months. Results We found that EDA levels were significantly higher in patients with STEMI and that EDA levels were proportional to the severity of CAD (p < 0.001) also EDA levels may be an independent predictor of poor clinical outcome in patients with STEMI. Conclusion These results suggest that EDA is closely related to the presence and severity of CAD.

MET-targeted therapies for the treatment of non-small-cell lung cancer: A systematic review and meta-analysis

Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway. This study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC. We searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (I 2>50%). Safety analysis was performed based on adverse events reported in all studies. Eleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]). MET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.

Association of stress hyperglycemia ratio and in-hospital mortality in patients with coronary artery disease: insights from a large cohort study

BackgroundStress hyperglycemia is strongly associated with poor clinical outcomes in patients with acute coronary syndrome (ACS). Recently, the stress hyperglycemia ratio (SHR) has been proposed to represent relative hyperglycemia. Studies regarding the relationship between SHR and mortality in coronary artery disease (CAD) are limited. This study aimed to clarify the association between SHR and in-hospital mortality in patients with CAD.MethodsA total of 19,929 patients with CAD who were hospitalized in Beijing Hospital were enrolled in this study. Patients with an estimated glomerular filtration rate < 30 ml/min, cancer, or missing blood glucose/HbA1c data were excluded; therefore, 8,196 patients were included in the final analysis. The patients were divided into three groups based on tertiles of SHR: T1 group (SHR < 0.725, n = 2,732), T2 group (0.725 ≤ SHR < 0.832, n = 2,730), and T3 group (SHR ≥ 0.832, n = 2,734). The primary endpoint was in-hospital mortality.ResultsThe overall in-hospital mortality rate was 0.91% (n = 74). After adjusting for covariates, SHR was significantly associated with in-hospital mortality in patients with CAD [odds ratio (OR) = 17.038; 95% confidence interval (CI) = 9.668–30.027; P < 0.001], and the T3 group had a higher risk of in-hospital mortality (OR = 4.901; 95% CI = 2.583–9.297; P < 0.001) compared with T1 group. In the subgroup analysis, the T3 group had an increased risk of mortality among patients with pre-diabetes mellitus (pre-DM) (OR = 9.670; 95% CI = 1.886–49.571; P = 0.007) and diabetes mellitus (DM) (OR = 5.023; 95% CI = 2.371–10.640; P < 0.001) after adjustments for covariates. The relationship between SHR and in-hospital mortality among patients with ACS and chronic coronary syndrome was consistent with the main finding. SHR and in-hospital mortality exhibited a dose-response relationship, and the risk of in-hospital mortality increased when the SHR index was above 1.20. Moreover, the area under the curve of SHR for predicting in-hospital mortality in patients with CAD was 0.741.ConclusionSHR is significantly associated with in-hospital mortality in patients with CAD. SHR may be an effective predictor of in-hospital mortality in patients with CAD, especially for those with pre-DM and DM.

New R2-CHA2DS2-VASc score predicts no-reflow phenomenon and long-term prognosis in patients with ST-segment elevation myocardial infarction after primary percutaneous coronary intervention.

AimsEvaluating the prognostic validity of new R2-CHA2DS2-VASc score for no-reflow phenomena and long-term prognosis in patients following primary percutaneous coronary intervention (PCI) with ST-elevation myocardial infarction (STEMI).Materials and methodsFrom January 2017 to December 2018, a total of 401 patients with STEMI were continuously enrolled. According to the cut-off value, the patients were separated into two groups: R2-CHA2DS2-VASc < 3 group (n = 275) and R2-CHA2DS2-VASc ≥ 3 group (n = 126).ResultsWith a sensitivity of 52.6% and a specificity of 73.1%, the optimal cut-off value for predicting no-reflow is R2-CHA2DS2-VASc ≥ 3. R2-CHA2DS2-VASc ≥ 3 as the ideal cut-off value for predicting major adverse cardiovascular events (MACE) with an area under the curve (AUC) of 0.781 [95% Confidence interval (CI): 0.738–0.801, P 0.001], a sensitivity of 50%, and a specificity of 91.1%. The incidence of MACE, death from all causes, and worsening heart failure was greater in the R2-CHA2DS2-VASc ≥ 3 group, although there was no significant difference in the incidence of repeated revascularisation procedures following PCI between the two groups. R2-CHA2DS2-VASc ≥ 3 was also an independent predictor of MACE (hazard ratio = 2.48, 95% confidence interval CI: 1.33–4.62, P = 0.04). Moreover, this score has a greater sensitivity (66.7%) and specificity (88.7%) for predicting the progression of heart failure.ConclusionR2-CHA2DS2-VASc ≥ 3 was independently associated with no-reflow phenomenon and poor clinical outcomes for patients in STEMI after primary PCI.

MNX1-AS1 Promotes Phase Separation of IGF2BP1 to Drive c-Myc-Mediated Cell-Cycle Progression and Proliferation in Lung Cancer.

MNX1-AS1 drives phase separation of IGF2BP1 to increase c-Myc and E2F1 signaling and to activate cell-cycle progression to promote proliferation in NSCLC.

LOXL2-dependent deacetylation of aldolase A induces metabolic reprogramming and tumor progression

Lysyl-oxidase like-2 (LOXL2) regulates extracellular matrix remodeling and promotes tumor invasion and metastasis. Altered metabolism is a core hallmark of cancer, however, it remains unclear whether and how LOXL2 contributes to tumor metabolism. Here, we found that LOXL2 and its catalytically inactive L2Δ13 splice variant boost glucose metabolism of esophageal tumor cells, facilitate tumor cell proliferation and promote tumor development in vivo. Consistently, integrated transcriptomic and metabolomic analysis of a knock-in mouse model expressing L2Δ13 gene revealed that LOXL2/L2Δ13 overexpression perturbs glucose and lipid metabolism. Mechanistically, we identified aldolase A, glyceraldehyde-3-phosphate dehydrogenase and enolase as glycolytic proteins that interact physically with LOXL2 and L2Δ13. In the case of aldolase A, LOXL2/L2Δ13 stimulated its mobilization from the actin cytoskeleton to enhance aldolase activity during malignant transformation. Using stable isotope labeling of amino acids in cell culture (SILAC) followed by proteomic analysis, we identified LOXL2 and L2Δ13 as novel deacetylases that trigger metabolic reprogramming. Both LOXL2 and L2Δ13 directly catalyzed the deacetylation of aldolase A at K13, resulting in enhanced glycolysis which subsequently reprogramed tumor metabolism and promoted tumor progression. High level expression of LOXL2/L2Δ13 combined with decreased acetylation of aldolase-K13 predicted poor clinical outcome in patients with esophageal cancer. In summary, we have characterized a novel molecular mechanism that mediates the pro-tumorigenic activity of LOXL2 independently of its classical amine oxidase activity. These findings may enable the future development of therapeutic agents targeting the metabolic machinery via LOXL2 or L2Δ13. Highlight of the studyLOXL2 and its catalytically inactive isoform L2Δ13 function as new deacetylases to promote metabolic reprogramming and tumor progression in esophageal cancer by directly activating glycolytic enzymes such as aldolase A.

S1114 Protein-Calorie Malnutrition Is Associated With Worse Outcomes in Patients Admitted With Acute Cholangitis Undergoing Endoscopic Retrograde Cholangiopancreaticography

Introduction: Acute cholangitis, often caused by biliary obstruction, can lead to sepsis and death due to multiorgan failure. Endoscopic retrograde cholangiopancreatography (ERCP) is the recommended first line therapeutic modality in the management of acute cholangitis. ERCP can be associated with complications such as pancreatitis, perforation, and bleeding. Protein-calorie malnutrition (PCM) is associated with poor clinical outcomes in hospitalized patients. The aim of this study is to elucidate the relationship between PCM and patients undergoing ERCP for acute cholangitis. Methods: Data were extracted from the National Inpatient Sample (NIS) database in the period between 2016 to 2019. Using the International Classification of Diseases, 10th revision, and Clinical Modification (ICD-10-CM) codes to obtain baseline demographic and clinical data, in-hospital mortality, hospital charges, and hospital length of stay (LOS). Statistical analysis was completed using t-test and Chi-squared analyses. Multivariate analysis for the mortality odds ratio (OR) was calculated after adjusting for potential confounders. Results: A total of 123,285 patients with ascending cholangitis underwent ERCP, and 11,135 (9%) of these patients had PCM. The mean age of the PCM group was 68.15 years which was not significantly different from the non-PMN group (p-value 0.86). Most patients in the PCM group were males (56%) and whites (62.6%). More patients in the PCM group were alcoholics, had diabetes mellitus, congestive heart failure (CHF), and cirrhosis compared to the non-PCM group. After controlling for potential confounders, PCM was associated with higher in-hospital mortality (OR 3.4, CI 2.85-4.04; p< 0.01). Moreover, patients with PCM had higher total hospital charges ($175,726 vs. $82,824; P< 0.01), and a longer LOS (12.7 vs 6.1 days; P< 0.01). In addition to malnutrition, age > 65 years, non-white race, cirrhosis, and CHF were independently associated with higher in-hospital mortality (Table). Conclusion: PCM is a strong predictor of poor clinical outcomes in patients with acute cholangitis admitted for ERCP. Systemic comorbidities such as cirrhosis and CHF are often associated with diminished nutritional states which may explain the higher prevalence of in-hospital mortality in the study group. Nutritional status is a modifiable risk factor and should be optimized to improve clinical outcomes in hospitalized patients with cholangitis. Table 1. - Univariate and multivariate analysis of factors affecting in-hospital mortality in patients with acute cholangitis undergoing ERCP Variable Univariate Multivariate OR (CI 95%) P-value OR (CI 95%) P-value Protein-calorie malnutrition 3.66 (3.08-4.34) < 0.01 3.4 (2.85-4.04) < 0.01 Age > 65 1.47 (1.25-1.73) < 0.01 1.38 (1.16-1.64) < 0.01 Female 1.06 (0.91-1.22) 0.41 1.06 (0.91-1.23) 0.436 Non-White 1.24 (1.06-1.44) < 0.01 1.25 (1.07-1.46) < 0.01 Alcoholism 1.4 (1.03-1.9) 0.02 1.32 (0.94-1.84) 0.1 Cirrhosis 2.18 (1.68-2.82) < 0.01 1.89 (1.82-2.6) < 0.01 Congestive heart failure 2.38 (2.02-2.82) < 0.01 2.17 (1.42-2.52) < 0.01 Smoking 0.57 (0.48-0.68) < 0.01 0.6 (0.5-0.71) < 0.01

Topical nitroglycerin to detect reversible microcirculatory dysfunction in patients with circulatory shock after cardiovascular surgery: an observational study

Persistent abnormalities in microcirculatory function are associated with poor clinical outcomes in patients with circulatory shock. We sought to identify patients with acutely reversible microcirculatory dysfunction using a low-dose topical nitroglycerin solution and handheld videomicroscopy during circulatory shock after cardiac surgery. Forty subjects were enrolled for the study, including 20 preoperative control and 20 post-operative patients with shock. To test whether microcirculatory dysfunction is acutely reversible during shock, the sublingual microcirculation was imaged with incident dark field microscopy before and after the application of 0.1 mL of a 1% nitroglycerin solution (1 mg/mL). Compared to the control group, patients with shock had a higher microcirculation heterogeneity index (MHI 0.33 vs. 0.12, p < 0.001) and a lower microvascular flow index (MFI 2.57 vs. 2.91, p < 0.001), total vessel density (TVD 22.47 vs. 25.90 mm/mm2, p = 0.005), proportion of perfused vessels (PPV 90.76 vs. 95.89%, p < 0.001) and perfused vessel density (PVD 20.44 vs. 24.81 mm/mm2, p < 0.001). After the nitroglycerin challenge, patients with shock had an increase in MFI (2.57 vs. 2.97, p < 0.001), TVD (22.47 vs. 27.51 mm/mm2, p < 0.009), PPV (90.76 vs. 95.91%, p < 0.001), PVD (20.44 vs. 26.41 mm/mm2, p < 0.001), venular RBC velocity (402.2 vs. 693.9 µm/s, p < 0.0004), and a decrease in MHI (0.33 vs. 0.04, p < 0.001. Thirteen of 20 patients showed a pharmacodynamic response, defined as an increase in PVD > 1.8 SD from shock baseline. Hemodynamics and vasoactive doses did not change during the 30-min study period. Our findings suggest a topical nitroglycerin challenge with handheld videomicroscopy can safely assess for localized recruitment of the microcirculatory blood flow in patients with circulatory shock and may be a useful test to identify nitroglycerin responsiveness.

Alberta Stroke Program Early CT Score applied to hyperdense lesion on noncontrast CT immediately post-thrombectomy is a predictor of poor outcome in acute ischemic stroke: A case-control study.

We aimed to evaluate whether Alberta Stroke Program Early CT Score (ASPECTS) applied to hyperdense lesion on noncontrast CT obtained immediately post-thrombectomy (post-ASPECTS) is useful for predicting poor outcome. We retrospectively reviewed patients who underwent noncontrast CT (NCCT) immediately after mechanical thrombectomy between January 2017 and July 2020 in our comprehensive stroke center. We collected baseline NCCT and post-ASPECTS score. The sensitivity, specificity, and positive and negative predictive values of the post-ASPECTS in predicting clinical outcome were calculated. A total of 223 patients were included. The hyperdense lesion on NCCT immediately after endovascular thrombectomy presented in 85.7% (191/223) patients, poor clinical outcome was in 56.1% (112/191) of hyperdense lesion patients. Low post-ASPECTS was associated with poor outcome (OR 0.390; 95% CI 0.258-0.589; P = .001), with an AUCROC curve of 0.753 (95% CI 0.684-0.822), while baseline NCCT-ASPECTS was not (OR 0. 754; 95% CI 0. 497-1.144; P = .185). A score ≤ 7 in post-ASPECTS was the best cut-off to poor clinical outcome (sensitivity 84.8%; specificity 52.7%; positive predictive value 68.4%; negative predictive value 73.8%). Our results point to the proportion of patients who present hyperdense lesion on NCCT is very high, post-ASPECTS could predict poor clinical outcomes in patients with stroke treated with endovascular mechanical thrombectomy, and post-ASPECTS may achieved better predictive value than baseline ASPECTS.

Clinicopathological Implications of ASAP1 Expression in Hepatocellular Carcinoma

Background: The expression of ArfGAP with SH3 domain ankyrin repeat and PH domain 1 (ASAP1) is increased in various types of cancer, showing potential as a prognostic marker. The clinicopathological implications of ASAP1 expression in patients with hepatocellular carcinoma (HCC) remain unclear. We thus investigated the clinicopathological significance and prognostic effect of ASAP1 expression in HCC patients. Materials and Methods: ASAP1 expression was assessed in 149 HCC tissue samples using immunohistochemistry (IHC). The associations between ASAP1 expression and clinicopathological characteristics were analyzed. The prognostic effect of ASAP1 expression in patients with HCC was evaluated based on survival analyses and confirmed using a web-based tool. Results: ASAP1 expression was observed in the cytoplasm of tumor cells. High ASAP1 expression was observed in 89 (59.7%) of 149 cases. High ASAP1 expression was significantly associated with male patients (p = 0.018), higher histological grade (p = 0.013), vessel invasion (p = 0.021), and higher stage (p = 0.020). High ASAP1 expression was associated with shorter overall survival (OS; p = 0.041) and recurrence-free survival (RFS; p = 0.008) based on Kaplan-Meier survival analyses. Web-based analysis using Kaplan-Meier (KM) plotter showed high mRNA ASAP1 expression to be associated with short OS (p = 0.001). Conclusion: High ASAP1 expression was associated with aggressive clinicopathological characteristics and poor clinical outcomes in patients with HCC. ASAP1 can be considered a prognostic biomarker in HCC patients.

ASPECTS-based net water uptake predicts poor reperfusion and poor clinical outcomes in patients with ischemic stroke.

To investigate the value of automated Alberta Stroke Program Early CT Score (ASPECTS)-based net water uptake (NWU) to predict tissue-level reperfusion status and 90-day functional outcomes in acute ischemic stroke (AIS) patients after reperfusion therapy. One hundred and twelve patients with AIS who received reperfusion therapy were enrolled. ASPECTS-NWU was calculated from admission CT (NWUadmission) and follow-up CT (NWUFCT), and the difference (ΔNWU) was calculated. Tissue-level reperfusion status was evaluated via follow-up arterial spin labeling imaging. The relationship between ASPECTS-NWU and tissue-level reperfusion was evaluated. Predictors of 90-day unfavorable outcomes (modified Rankin Scale score > 2) were assessed by multivariate logistic regression analysis and receiver operating characteristic (ROC) curves. Poor reperfusion was observed in 40 patients (35.7%) after therapy. Those patients had significantly elevated NWUFCT (median, 14.15% vs. 8.08%, p = 0.018) and higher ΔNWU (median, 4.12% vs. -2.03%, p < 0.001), compared to patients with good reperfusion. High ΔNWU was a significant marker of poor reperfusion despite successful recanalization. National Institutes of Health Stroke Scale score at admission (odds ratio [OR], 1.11; 95% confidence interval [CI] 1.03-1.20, p = 0.007) and ΔNWU (OR, 1.07; 95% CI 1.02-1.13, p = 0.008) were independently associated with unfavorable outcomes. An outcome prediction model including both parameters yields an area under the curve of 0.762 (sensitivity 70.3%, specificity, 84.2%). Elevated NWUFCT and higher ΔNWU were associated with poor tissue-level reperfusion after therapy. Higher ΔNWU was an independent predictor of poor reperfusion and unfavorable neurological outcomes despite successful recanalization. • ASPECTS-NWU may provide pathophysiological information about tissue-level reperfusion status and offer prognostic benefits for patients with AIS after reperfusion therapy. • Elevated NWUFCT and higher ΔNWU were correlated with poor tissue-level reperfusion after therapy. • A higher ΔNWU is an independent predictor of poor reperfusion and 90-day unfavorable outcomes despite successful recanalization.

Combined systemic inflammatory immunity index and prognostic nutritional index scores as a screening marker for sarcopenia in patients with locally advanced gastric cancer.

BackgroundSarcopenia is associated with poor clinical outcomes in patients with locally advanced gastric cancer (LAGC). Currently, the diagnostic criteria for sarcopenia are complex and laborious. Increased evidence suggests the inflammatory state of the body is closely associated with the development of sarcopenia. The systemic immune-inflammatory index (SII) and the prognostic nutritional index (PNI) are representative blood indicators of the status of the systemic inflammatory response, but the clinical significance of the combined testing of these two indicators remains unclear. We aimed to develop a simple and practical risk score (SII-PNI score) to screen patients with LAGC for sarcopenia on admission for early diagnosis.MethodsWe registered a prospective clinical study from January 2011 to May 2016 involving 134 patients with LAGC undergoing radical surgical resection. All patients followed the definition of sarcopenia in the Asian Working Group on Sarcopenia (AWGS) guidelines and were divided into sarcopenia and non-sarcopenia groups. SII-PNI score 0–2 was scored as 2 for high SII (≥432.9) and low PNI ( ≤ 49.5); score 1, either high SII or low PNI; score 0, no high SII or low PNI.ResultsAll patients underwent radical surgery, including 31 patients (23.13%) with sarcopenia according to AWGS criteria. The SII-PNI score was significantly lower in the non-sarcopenic patients than in the sarcopenic patients (p < 0.001). Logistic multivariate analysis showed that the SII-PNI score predicted an independent prognostic factor for sarcopenia (p < 0.001). Patients with high SII-PNI scores had significantly worse prognosis than those with low SII-PNI scores (p < 0.001). The SII-PNI score was an independent prognostic factor for predicting overall survival and disease-free survival (p = 0.016, 0.023).ConclusionPeripheral blood parameters SII-PNI scores accurately identify sarcopenia in patients with LAGC and could be used as potential systemic markers.

RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31

RNF31 (HOIP), RBCK1 (HOIL-1L), and SHARPIN are subunits of the linear ubiquitin chain assembly complex. Their function and specific molecular mechanisms in hepatocellular carcinoma (HCC) have not been reported previously. Here, we investigated the role of RNF31 and RBCK1 in HCC. We showed that RNF31 and RBCK1 were overexpressed in HCC and that upregulation of RNF31 and RBCK1 indicated poor clinical outcomes in patients with HCC. RNF31 overexpression was significantly associated with more satellite foci and vascular invasion in patients with HCC. Additionally, RBCK1 expression correlated positively with RNF31 expression in HCC tissues. Functionally, RBCK1 and RNF31 promote the metastasis and growth of HCC cells. Moreover, the RNF31 inhibitor gliotoxin inhibited the malignant behavior of HCC cells. Mechanistically, RBCK1 interacted with RNF31 and repressed its ubiquitination and proteasomal degradation. In summary, the present study revealed an oncogenic role and regulatory relationship between RBCK1 and RNF31 in facilitating proliferation and metastasis in HCC, suggesting that they are potential prognostic markers and therapeutic targets for HCC.

Time course of beat-to-beat blood pressure variability and outcome in patients with spontaneous intracerebral haemorrhage.

Increased blood pressure variability (BPV) over 24 h or longer was associated with poor clinical outcomes in patients with intracerebral haemorrhage (ICH). However, the characteristics of beat-to-beat BPV, a rapid assessment of BPV and its association with outcome in ICH patients remain unknown. We consecutively and prospectively recruited patients with ICH between June 2014 and December 2020. Five-minute noninvasive beat-to-beat recordings were measured serially at three time points, 1-2, 4-6 and 10-12 days after ICH onset. BPV was calculated using standard deviation (SD) and variation independent of mean (VIM). Favourable outcome was defined as modified Rankin Scale score of less than 2 at 90 days. The analysis included 66 participants (54.12 ± 10.79 years; 71.2% men) and 66 age and sex-matched healthy controls. Compared with that in healthy adults, beat-to-beat BPV was significantly increased 1-2 days after ICH and was completely recovered 10-12 days later. BPV recorded 1-2 days after ICH onset was higher among patients with unfavourable outcomes than among those with favourable outcomes (all P < 0.05) and higher BPV on days 1-2 was independently associated with a 3-month unfavourable outcome after adjustment for major covariates. Beat-to-beat BPV was significantly increased among patients with ICH and could be completely recovered 10-12 days later. In addition, beat-to-beat BPV 1-2 days after ICH was independently associated with prognosis and could be regarded as a potential prognostic predictor and effective therapeutic target in the future.