Marker Of Prognosis Research Articles

DTL promotes the growth and migration of melanoma cells through the ERK/E2F1/BUB1 axis

Melanoma is the most dangerous form of skin cancer. Hence, a better understanding of molecular mechanisms in melanoma pathogenesis is urgently needed, which provides a new insight into the therapy of melanoma. DTL gene is screened out in melanoma pathogenesis by integrated bioinformatics analysis, and its expression is validated in the tissue and cell samples of melanoma. Forced DTL expression facilitates the proliferation, invasion, migration and EMT of melanoma cells, while DTL knockdown suppresses the biological behavior of melanoma cells. In addition, DTL promotes the malignancy of melanoma in vivo. Mechanistically, BUB1 is the crucial downstream target of DTL. Reduced DTL expression suppresses BUB1 expression, while enhanced DTL expression induces BUB1 upregulation. Rescue experiments showed that growing and migrating of melanoma cells induced by DTL are partially impaired by BUB1 inhibition. In addition, the expression of phosphorylated ERK (p-ERK) and the downstream transcription factor E2F1 are reduced when DTL expression is blocked. Meanwhile, BUB1 levels are decreased when the expression of p-ERK or E2F1 is repressed. Notably, the growth and migration of melanoma cells by inhibition of ERK and knockdown of E2F1 was rescued by overexpressing BUB1. DTL gene may be a prognosis marker and represent a unique potential target for melanoma patients. DTL supports the biologically malignant activity of melanoma cells via the ERK/E2F1/BUB1 axis.

Epicardial adipose tissue volumes for long-term risk stratification in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement

Abstract Background Accurate risk stratification is important to improve patient selection and outcome of patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). As epicardial adipose tissue (EAT) is discussed to be involved in cardiovascular disease, it could be useful as a marker of poor prognosis in patients with severe AS undergoing TAVR. Purpose We hypothesized that EAT impacts long-term outcome of patients with severe AS undergoing TAVR independently from subtype and other risk factors. Methods A total of 416 patients diagnosed with severe AS by transthoracic echocardiography were assigned for TAVR and enrolled for systematic assessment. Patients underwent clinical surveys and 5-year long-term follow-up, with all-cause mortality as the primary endpoint. EAT volume was quantified on pre-TAVR planning CTs. Patients were retrospectively dichotomized at the median of 74cm3 of EAT into groups with low-EAT and high-EAT volumes. Mortality rates were compared using Kaplan-Meyer plots and uni- and multivariable cox regression analyses. Results A total number of 341 of 416 patients (median age 80.9years, 45% female) was included in the final analysis. Patients with high-EAT volumes had similar short-term outcome (p=0.794) but significantly worse long-term prognosis (p=0.023) compared to patients with low-EAT volumes. Increased EAT volumes were associated with worse long-term outcome (HR1.59;p=0.031) independently from concomitant cardiovascular risk factors, general type of AS and functional echocardiography parameters of AS severity (HR1.69;p=0.013). Conclusion Increased EAT volume is an independent predictor of all-cause mortality in patients with severe AS undergoing TAVR. It can be easily obtained from pre-TAVR planning CTs and may thus qualify as a novel marker to improve prognostication and management of patient with severe AS.Graphical Abstract

CEBPA mutation in acute myeloid leukemia: prognostic impact of bZIP domain mutation

Abstract One of the most important prognostic genes for acute myeloid leukemia (AML) is CEPBA, and its mutation (CEBPAmu) is present in nearly 10%–15% of de novo AML cases. CEBPAdm is associated with a favorable prognosis; however, CEBPAsm does not appear to have a better prognosis than CEBPAdm. We reviewed CEBPAmu-bZIP in 8694 cases across studies for prognostic impact in patients with de novo AML. It was observed that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. CEBPA-bZIP mutations were discovered in 562 (6.46%) of 8694 cases, with 366 (65.1%) harboring a second CEBPA mutation (CEBPA-double-mutated [CEBPAdm]) and 196 (34.9%) having a single CEBPA-bZIP only mutation. Multivariate analysis of three studies consisting of 1028, 4708, and 2958 patients showed that CEBPAmu in bZIP was the most potent predictor of overall survival (OS) with overall survivability of 53%, 62%, and 89%, respectively, independently. However, complete remission of disease with bZIP mutation in the same studies was found to be 80%, 62%, and 78.6%, respectively. These findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis.

Left atrial volumetric-mechanical coupling index as a marker of subclinical primary heart involvement in systemic sclerosis

Abstract Background Primary heart involvement in systemic sclerosis (SSc) is a common yet often clinically silent marker of poor prognosis. Up to 80% of patients have histopathological evidence of heart involvement, highlighting the need for better screening and diagnostic methods. N-terminal pro-brain natriuretic peptide (NTproBNP), a well-established cardiac biomarker, is often increased in patients with SSc, but with a not fully understood mechanism. Meanwhile, left atrial volumetric-mechanical coupling index (LACI), a new echocardiographic parameter, has been shown to predict cardiovascular outcomes in heart failure patients and the general population, but it has not been studied in SSc. Purpose To identify new echocardiographic parameters, particularly related to left atrial volume and function, as markers of increased NTproBNP in SSc patients without overt heart involvement. Methods Consecutive SSc patients without overt heart disease referred for routine cardiac screening underwent 2D and 3D transthoracic echocardiography, including atrial and ventricular strain analysis. LACI was calculated by both 2D and 3D echocardiography as the ratio between the left atrial volume index and the tissue-Doppler-imaging septal a’ velocity. Patients with significant structural and functional changes suggestive of systolic or diastolic dysfunction or pulmonary hypertension, and those with impaired global left ventricular strain were excluded. Logistic regression, Pearson correlation coefficients, and area under the receiver-operating characteristic curve (AUC) are used to analyze the association and predictive power of LACI for elevated NTproBNP. Results A total of 36 SSc patients (55±10 years old; 34 (94%) women; mean disease duration 14±11 years) were included. Sixteen (44.4%) had diffuse cutaneous involvement (dcSSc). Seventeen (47%) patients had increased NTproBNP levels (i.e. >125 pg/mL). Among all tested variables, 3D LACI had the best correlation with NTproBNP values (r = 0.63, p<0.001). A 3D LACI of >2 associated with NTproBNP of >125 pg/mL (odds ratio 7.33 [95%CI 1.38-38.8]; p=0.01) and predicted these increased values with a sensitivity of 76.9% and a specificity of 81.2% (AUC 0.78). NTproBNP was also correlated with 2D LACI (r=0.55, p<0.001), peak left atrial longitudinal strain (r=-0.42, p=0.01), and left atrial contraction strain (r=0.48, p=0.005). Compared to patients with limited cutaneous involvement, those with dcSSc had higher NTproBNP values (250±139.6 vs 107.2±110.9 pg/mL, p=0.001), higher 3D LACI values (2.6±0.9 vs 1.9±0.5, p=0.02), with similar left atrial and ventricular strain parameters. Conclusion Left atrial volumetric-mechanical coupling index assessed by 3D echocardiography is significantly associated with and predictive of elevated NTproBNP levels in SSc patients without overt heart disease and may be a potentially useful non-invasive marker for screening for early subclinical heart involvement in SSc patients.

The prevalence and prognostic impact of low voltage zone in patients with cardiomyopathy after catheter ablation for atrial fibrillation

Abstract Background The low voltage zone (LVZ) in left atrium (LA) was observed in 20-30% of patients undergoing catheter ablation of atrial fibrillation (AF). Furthermore, LVZ was associated with not only AF recurrence but also prognosis. However, the prevalence and prognostic impact of LVZ in patients diagnosed with cardiomyopathy remained unclear. Purpose In this study, we focused on the patients with cardiomyopathy after AF ablation and investigated the prevalence and prognostic impact of LVZ after AF ablation. Methods This study is a single-center retrospective observational study. We enrolled 125 patients diagnosed with cardiomyopathy. All patients underwent voltage mapping after pulmonary vein isolation. LVZ was defined as regions where bipolar peak-to-peak voltage was <0.5mV. We set 5 cm² as the cutoff of the presence of LVZ. The etiology of cardiomyopathy was divided into arrhythmia-induced cardiomyopathy (AICM) and non-AICM consisting of idiopathic dilated cardiomyopathy (iDCM), hypertrophic cardiomyopathy (HCM), ischemic cardiomyopathy (ICM), transthyretin amyloidosis wild type (ATTRwt) and others (1 Fabry disease, 1 cardiac sarcoidosis, 1 restrictive cardiomyopathy). AICM was defined as patient whose LVEF was recovered above 50% after maintenance of sinus rhythm. We investigated the proportion of LVZ by etiology, and the association between LVZ and the composite endpoint consisting of all cause death, heart failure hospitalization, ventricular assisting device implantation, ventricular arrhythmia and stroke. Results Out of 125 patients [age 68 (58-73), female 32 (25%), LVEF 34.0 (25-43)], 51 (41%) had LVZ. Sixty-four patients were AICM etiology (LVEF pre to post: 30.7±10.7% to 61.1±6.7% ) and 61 was Non-AICM etiology (LVEF: 40.7 ± 18.1 to 44.7±15.7, P=0.0062). The presence of LVZ was lower in AICM than in non-AICM group (20.3% vs. 62.3%, P<0.0001). The etiology of non-AICM was consisting of 26 iDCM, 18 HCM, 7 ICM, 7 ATRRwt and 3 other etiology. The prevalence of LVZ was lower in AICM than in non-AICM (20.3 vs. 62.3%, P<0.0001). Detail is shown in Figure 1. Next, the incidence of composite endpoint was higher in patients with LVZ than in those without (HR 4.6, 95%CI 2.1-10.0, P=0.0001) (Figure 2A). Among 4 groups stratified by AICM/non-AICM and with/without LVZ, there was significant difference in the incidence of the composite endpoint (Figure 2B, P<0.0001). After adjusted with age, gender, Non-AICM, LVZ, LVZ tended to have association with composite endpoint (2.21, 0.87-5.65, P=0.097) and Non-AICM showed strong association (5.58, 1.55-20.12, P=0.0086). LVZ was associated with HF hospitalization (4.35, 1.21-15.61, P=0.024). Conclusions The prevalence of LVZ was 60% in Non-AICM, while it was 20% in AICM. LVZ tended to be associated with poor prognosis of cardiomyopathy after AF ablation. LVZ was associated with HF hospitalization in patients with cardiomyopathy. LVZ might be the marker for poor prognosis in cardiomyopathy cohort.

Impaired retinal micro-vascular function in patients with a systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by widespread and progressive multi-organ fibrosis and vascular abnormalities. Endothelial dysfunction is an early manifestation of SSc and an important contributor to the progression and prognosis of the disease. Dynamic retinal vascular analysis (DVA) is a new method for non-invasive and precise determination of microvascular function. The primary aim was to assess micro- and macro-vascular function in patients with SSc. Methods In this study, vascular function was measured non-invasively with flicker-light induced vasodilation of retinal arterioles (FIDart) and branchial arterial flow-mediated vasodilation (FMD). Patients with SSc were prospectively enrolled in the study (n = 40; mean ± SD age 56±11 years, females 73 %) and compared with age- and sex-matched HC (n = 40; mean age 56±15 years, females 73%). Results Retinal microvascular function was significantly impaired in patients with SSc compared to matched HC (2.3±2.0% versus 3.1±1.9% respectively, p=0.04, figure 1). There was a trend for lower FMD in patients with SSc in comparison to HC (5.0± 3.2% versus 6.2±3.2% respectively, p=0.07). Conclusion Patients with SSc have severe impairment of retinal vascular function compared to matched HC. Thus, microvascular dysfunction in these patients is of systemic nature and retinal vessel analysis may serve as an important marker for SSc disease, severity and prognosis. These results set the stage for further studies on retinal function in SSc patients.Figure 1

Controlling Nutritional Status (CONUT) Score: a new tool for characterization and prognosis of patients with infective endocarditis

Abstract Background malnutrition is a marker of unfavorable prognosis in different medical conditions, however, the association between new objective immunonutritional indexes and outcomes for patients with infective endocarditis (IE) is not fully studied. Purpose the aim of this study was to assess the role of the Controlling Nutritional Status (CONUT) Score in the characterization of patients with IE and its association with prognostic outcomes. Methods a total of 184 cases of confirmed IE were consecutively collected and followed during one year after diagnosis in two tertiary hospitals. CONUT score was calculated using serum albumin, total cholesterol and lymphocyte count [(range 0-12), the higher, the worse] at diagnosis, and patients were categorised as CONUT-high (>=6, n=98), and CONUT-low (<6, n=86) based on the sample median value. Results mean age was 70 [SD 15] years, 64% were men and community-acquired infections were 69%. Median score value was 6 (4). As shown in Table 1 and 2, diabetes and frailty were more prevalent in CONUT-high group, who showed a worse profile of nutritional biomarkers. Overall, the most frequent pathogen was S. viridans (n=43). By groups, S. aureus was predominantly isolated in CONUT-high (20 vs 8%; p 0.02), and non-viridans streptococci in CONUT-low (9 vs 2%, p 0.03). Regarding infection site, IE of aortic bioprostheses was more common in CONUT-high, whereas mechanical aortic valves and mitral bioprostheses were more frequently involved in CONUT-low. Larger vegetations [14 (11) vs 11 (7) mm, p 0.02], and more periannular abscesses (25 vs 13%, p 0.04) were detected in CONUT-high, who presented more acute kidney injury and septic shock during hospitalization. Despite higher predicted surgical risk in CONUT-high, neither the proportion of patients who underwent surgery nor in-hospital mortality, differed between groups. When analyzing according to the therapeutic approach, only among those medically managed patients without surgical indication, in-hospital mortality was higher in CONUT-high. At 1-year follow-up, rehospitalization rate tended to be lower in those with a better nutritional status (35% vs 51%, p 0.07). Conclusions in patients with IE and a high CONUT score, diabetes and frailty were more prevalent. In addition, virulent pathogens, larger vegetations and periannular complications were more frequently reported. Although surgery performance and in-hospital mortality did not differ between groups, a worse nutritional status was associated with a higher rate of clinical complications and higher mortality among patients with conservative management who did not meet surgical criteria.

Characterisation of plasma proteins and circulating microRNAs in out-of-hospital cardiac arrest patients - approaches for predicting outcome

Abstract Rationale: Early prognostication after out-of-hospital cardiac arrest (OHCA) is an unmet clinical need. There is limited data on serial release kinetics of cardiac, brain and systemic biomarkers such as Neuron Specific Enolase (NSE) and S-100B. miRNAs are sensitive biomarker candidates in acute myocardial infarction (MI). Objective The objective was to characterise circulating biomolecules in the early release kinetics after OHCA, compared with a STEMI control group and assessed with clinical outcome. Methods and Results Serial blood samples of patients with OHCA with STEMI (n=20) and STEMI control (n=20) were collected at baseline and at 6, 12, 24 and 48h after admission. Untargeted plasma proteomics were performed using data-independent acquisition–mass spectrometry (DIA–MS). Candidate proteins and miRNAs were quantified. Proteomics returned n=156 proteins with significantly different kinetics between OHCA and STEMI. Six clusters, depicting distinct biological pathways, with characteristic differences between OHCA and STEMI were identified. The most distinct and significant differences between OHCA and STEMI patients were seen for acute phase reactants LBP, AACT, CRP and the lipid metabolite A2GL as well as endothelial and platelet miR-126 and cardiomyocyte-apoptosis/ischemia-reperfusion related miR-320a. Cardiogenic shock was best characterised by differential kinetics of coagulation and complement related proteins FA9, HRG, FHR1 and inflammation related miR-146. The primary endpoint was poor neurological recovery at 30-days. Individuals with good outcome showed distinct differences in adaptive immune response, complement and coagulation cascades and hemostasis. Circulating plasma levels of hypoxia-associated miR-101, miR-210 and S-100B protein were significantly elevated at baseline in OHCA patients. These molecules further showed higher baseline values in patients with poor outcome. For current prognosis marker NSE, this difference only develops after 48h. Cardiac/muscle miRNAs followed an early release-pattern similar to high-sensitivity cardiac troponin-T (hs-cTnT). Machine learning models were used to calculate the AUC for the prediction of poor neurological outcome at baseline. This was highest for hypoxia-induced miR-210 (AUC: 0.854), which performed significantly better than the protein biomarkers NSE (AUC: 0.646) and S-100B (AUC:0.656). Conclusions Untargeted mass spectrometry reveals distinct biological pathways and candidate biomolecules affected in patients suffering from OHCA compared with STEMI controls, in patients developing cardiogenic shock and in those with adverse versus good neurological outcome. Platelet-, inflammation and hypoxia associated miRNAs are associated with OHCA, cardiogenic shock and prognostication of adverse neurological outcome. Pronounced differences in early release kinetics of RNA and protein biomarkers may improve identification of OHCA patients at risk of poor outcome.

Unraveling the proteomic signatures of coronary artery disease and hypercholesterolemia.

Atherosclerosis, a leading cause of coronary artery disease (CAD), is heavily influenced by hypercholesterolemia (HC). Proteomics research has shown promise in identifying biological markers for CAD diagnosis and prognosis. This cross-sectional study aimed to identify novel biomarkers for detecting HC and CAD. Through the analysis of proteome data from healthy controls (n=45) and patients diagnosed with HC (n=51) or CAD (n=32), distinct protein patterns associated with each condition were identified. Significant alterations in protein levels were identified with a false discovery rate (FDR)-corrected q-value of <0.05. Subsequent receiver operating characteristic (ROC) analysis, with an area under the curve (AUC) greater than 0.75, was conducted. CAD patients exhibited significantly increased levels of the cholesterol-metabolizing protein PCSK9 and varied levels of the angiogenesis-related protein SDF-1 compared to controls. In pairwise comparisons among the study groups, 65 proteins showed significant differential expression. Notably, 14 of these proteins had significant correlations with blood cholesterol levels. Additionally, 22 of the identified proteins were associated with CAD or HC pathways, with nine proteins being common to both conditions (Apo E, Apo E3, MMP-3, PCSK9, SDF-1, Apo B, PAFAH, HSP 60, and TAK1-TAB1). Nevertheless, this is an exploratory study, and validation studies are needed to confirm these potential protein biomarkers for CAD in the context of HC.

Pulmonary arterial hypertension: updates and perspective with newer therapies.

Pulmonary arterial hypertension (PAH) is a rare condition for which a remarkable change has been witnessed in the epidemiology, assessment and treatment landscape over the last three decades. Well-established registries from the Western world have not only highlighted the shift in the epidemiology to an older, more comorbid cohort but have also identified markers of prognosis that have been validated as part of risk stratification scores in multiple cohorts. The emphasis on early identification through a systematic assessment pathway and the option of upfront combination therapy with serial risk stratification assessment has laid the foundation for the standard of care and improved prognosis. This review provides an update on the assessment and newer therapies for PAH.

ELEVATED TROPONIN OF NON-CORONARY ETIOLOGY A REVIEW

Elevated troponin levels are traditionally associated with acute myocardial infarction (AMI) and are widely used as a specific marker for the diagnosis of ischemic myocardial injury. However, recent studies have shown that elevated troponin levels can occur in several non-coronary conditions, requiring a more careful diagnostic approach to avoid misinterpretations and inadequate management. This study aimed to perform a systematic review of the literature on the non-coronary causes of elevated troponin levels, seeking to identify the main associated clinical conditions and discuss their prognostic value in different contexts. To this end, a systematic review of articles published between 2014 and 2024 was conducted using the PubMed, Scopus and Web of Science databases. The results revealed that conditions such as sepsis, pulmonary embolism (PE), chronic renal failure (CRF), chronic obstructive pulmonary disease (COPD) and tachyarrhythmias are the main non-coronary causes of elevated troponin levels. It is concluded that elevated troponin levels of non-coronary etiology are an important marker of severity and poor prognosis in several systemic conditions. Troponin levels should be interpreted carefully, taking into account the clinical context and underlying conditions of each patient.

Prognostic Significance of Combining Cytokeratin-19, E-Cadherin and Ki-67 Analysis in Triple-Negative Breast Cancer with Basal-Like and Non-Basal-Like Phenotype

Triple-negative breast cancer (TNBC) is known to have the worst outcome compared to the other forms of breast cancer. Moreover, molecular markers identified basal-like breast cancer (BLBC) phenotypes to be also related to a worse prognosis. In this study, we evaluated by immunohistochemistry (IHC) the prognostic significance of combining Cytokeratin-19 (CK19), E-cadherin, and Ki-67 tissue expression in triple-negative breast cancer (TNBC) cases presenting a basal-like (BLBC) or a non-basal-like (n-BLBC) phenotype to improve the selection and the monitoring of BC patients with a more aggressive outcome. Herein, when compared to n-BLBC, patients with BLBC showed a positive correlation with lymph node metastasis occurrence and lower survival rates. Immunohistochemistry analysis revealed significantly lower E-cadherin prevalence and higher prevalence of both CK19 and Ki-67 in BLBC when compared to n-BLBC. Spearman correlation showed that E-cadherin is negatively and significantly correlated to CK19 and Ki-67 expressions. Moreover, in BLBC, expressing both CK19 and Ki-67 combined with E-cadherin loss was associated with the worst relapse-free and overall survival. In conclusion, TNBC/BLBC phenotypes simultaneously losing E-cadherin and overexpressing CK19 and Ki-67 markers are the most aggressive forms. This combined analysis could be a predictive marker of poor prognosis.

Circulating miR-18a and miR-532 Levels in Extrahepatic Cholangiocarcinoma.

Background: Cholangiocarcinoma (CCA) is a highly aggressive cancer of the bile ducts with a poor prognosis and limited diagnostic markers. This study aims to investigate the potential of miR-18a and miR-532 as biomarkers for CCA by exploring their correlations with clinical parameters and traditional tumor markers such as CA19.9, CEA, and AFP. Methods: This study involved a cohort of patients diagnosed with CCA. Serum levels of miR-18a and miR-532 were measured and analyzed in relation to various clinical parameters, including age, tumor markers, and histological features. Results: Serum levels of miR-18a and miR-532 were upregulated in patients with extrahepatic cholangiocarcinoma (eCCA) compared to healthy controls (p < 0.05). MiR-18a and miR-532 levels were correlated with each other (p = 0.011, Spearman's rho = 0.482) but showed no significant correlation with age or traditional tumor markers (CA19.9, CEA, AFP). No significant differences in miR-18a and miR-532 levels were observed concerning tumor localization or histological grading. For predicting tumor resectability, miR-532 at a cut-off point of 2.12 showed a sensitivity of 72.73%, specificity of 81.25%, and an AUC of 71.3%, while miR-18a, at a cut-off of 1.83, had a sensitivity of 63.64%, specificity of 75%, and an AUC of 59.7%. ROC curve analysis suggested moderate diagnostic potential for miR-18a and miR-532, with AUC values of 0.64 and 0.689, respectively. Conclusions: Although miR-18a and miR-532 showed significant upregulation in eCCA patients compared to healthy controls, they did not demonstrate significant associations with key clinical parameters, limiting their effectiveness as standalone diagnostic biomarkers. Further research involving larger, multi-center cohorts and additional molecular markers is necessary to validate these findings and explore the broader diagnostic potential of miRNAs in CCA.

The Utility of PRAME and Ki-67 as Prognostic Markers for Cutaneous Melanoma.

Cutaneous melanoma can lead to metastasis, and it is associated with high mortality. Currently, there are no widely accepted immunohistochemistry markers for melanoma prognosis in routine staging. Preferentially expressed antigen in melanoma (PRAME) is a possible biomarker for prognosis in several noncutaneous neoplasms. Ki-67 is a cell proliferation marker correlated with poor outcomes in many cancers. This study assessed PRAME and Ki-67 as potential prognostic markers for sentinel lymph node outcomes and survival among melanoma patients. This is a retrospective study analyzing cutaneous melanoma cases from a Brazilian cancer center (2005-2021). All cases were tested using immunohistochemistry to evaluate PRAME expression and Ki-67 index. Descriptive analysis, Spearman correlations, means comparison, Kaplan-Meier analysis, χ2, and Cox models were performed. In univariate analysis of 123 cutaneous melanoma cases, high extent (P = 0.0267) and elevated intensity (P = 0.043) of PRAME were associated with decreased overall survival. The Ki-67 index was associated with overall survival (P = 0.05) and sentinel lymph node status (P = 0.0403), with a positive correlation between the markers (P = 0.0004) and between Ki-67 and Breslow thickness (P = 0.0001). However, in multivariate analysis, only Breslow thickness significantly influenced overall survival (P = 0.0003). Then, the present results can suggest that elevated PRAME and Ki-67 expression are associated with poor overall survival in cutaneous melanoma; however, in multivariate analysis, only the Breslow thickness had a significant influence. These findings highlight the potential of PRAME and Ki-67 as prognostic markers, opening frontiers that could improve strategies for treating cutaneous melanoma.

Retinol-binding protein type 1 expression predicts poor prognosis in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide, with high incidence and poor survival rates. RBP1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the relationship between RBP1 and HNSCC were analyzed based on The Cancer Genome Atlas (TCGA) database.Materials and methodsRBP1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. Tumor tissue and adjacent normal tissue of 6 HNSCC patients were collected to analyze the RBP1 mRNA expression level by quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of RBP1 and clinical data in HNSCC. A nomogram was also established to predict the impact of RBP1 on prognosis based on Cox multivariate results. The methylation level of RBP1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of RBP1 were investigated using gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA).ResultsThe mRNA expression levels of RBP1 were highly expressed in HNSCC tissue. The Cox analyses demonstrate that highly-expressed RBP1 is an independent prognosis marker(P < 0.05). ROC curve analysis showed that performances of RBP1 (area under the ROC curve: 0.887, sensitivity: 84.1%, specificity: 79.9%). The methylation was increased in HNSCC patients compared with normal subjects(P < 0.05) and was associated with better prognosis at sites cg06208339, cg12298268, cg12497564, cg15288618, cg20532370, cg23448348. Additionally, RBP1 expression is mildly associated with immune cell infiltration and immunological checkpoints.ConclusionRBP1 is overexpressed and associated with poor patient prognosis in head and neck squamous cell carcinoma.

The Expression of miR-211-5p in Sentinel Lymph Node Metastases of Malignant Melanoma Is a Potential Marker for Poor Prognosis

Metastatic primary cutaneous melanoma is a frequently fatal disease despite recent therapeutic advances. Biomarkers to stratify patients’ prognosis are lacking. MicroRNAs (miRNAs) are small, non-coding RNAs. We aimed to determine the expression of miR-211-5p in primary tumors and metastases of malignant melanoma and its potential use as a prognostic biomarker. We performed in situ hybridization for miRNA-211-5p on 109 FFPE melanoma samples from 76 patients, including 31 paired primary tumor/metastasis samples. For validation, we performed in silico analyses of TCGA skin cutaneous melanoma (SKCM) cohort. High miR-211-5p expression was more frequent in primary tumors (70.8%) compared to metastases (39.3%). In metastases, it was associated with a significantly worse overall survival. Data from TCGA SKCM cohort confirmed that high miR-211-5p expression in melanoma metastases, but not primary tumors, is associated with worse overall survival. MiR-211-5p expression in metastases is associated with a shorter survival, emphasizing the potential of miR-211-5p as a risk predictor for a less favorable clinical outcome in metastatic disease. In situ hybridization could be implemented in a routine laboratory workflow and can be performed on diagnostic tissue.

ITGA5 is associated with prognosis marker and immunosuppression in head and neck squamous cell carcinoma

BackgroundHead and neck squamous cell carcinoma (HNSCC) is a major tumor that seriously threatens the health of the head and neck or mucosal system. It is manifested as a malignant phenotype of high metastasis and invasion caused by squamous cell transformation in the tissue area. Therefore, it is necessary to search for a biomarker that can systematically correlate and reflect the prognosis of HNSCC based on the characteristics of head and neck tumors.MethodsBased on TCGA-HNSCC data, R software was used to analyze gene expression, correlation, Venn diagram, immune invasive and immunosuppressive phenotypes respectively. The intrinsic effect of ITGA5 on the malignant phenotype of HNSCC cells was verified by cell experiments. Immunohistochemical images from The Human Protein Atlas (THPA) database display the differences in the expression of related proteins in HNSCC tissues. Based on functional enrichment and correlation analysis, the prognostic value of ITGA5 for HNSCC was explored, and the expression level of ITGA5 may affect the chemotherapy of targeting the PI3K-AKT.ResultsIn this study, the target gene ITGA5 may be identified as a valuable prognostic marker for HNSCC. The results of enrichment analysis showed that ITGA5 was mainly involved in the dynamic process of extracellular matrix, which may affect the migration or metastasis of tumor cells. Meanwhile, ITGA5 may be closely related to the infiltration of M2 macrophages, and its secretory phenotypes TGFB1, PDGFA and PDGFB may affect the immunosuppressive phenotypes of tumor cells, which reflects the systemic influence of ITGA5 in HNSCC. In addition, the expression levels of ITGA5 were negatively correlated with the efficacy of targeting PI3K-AKT chemotherapy.ConclusionITGA5 can be used as a potential marker to systematically associate with prognosis of HNSCC, which may be associated with HNSCC malignant phenotype, immunosuppression and chemotherapy resistance.

The First Comprehensive Evaluation of Immuno-Inflammatory Markers for Prognosis in Esophageal Cancer Patients: A South Asian Perspective.

Background: Esophageal cancer (EC) remains a significant health challenge in South Asia, with poor prognosis despite advancements in diagnostics and treatment. Identifying and validating prognostic factors is essential for improving patient outcomes. Methods: A prospective study was conducted with 146 biopsy-confirmed EC patients at the Dr. Ruth K.M. Pfau Civil Hospital, Karachi, Pakistan. Clinical and laboratory data were collected and analyzed using descriptive statistics, receiver operating characteristic (ROC) analysis, and the Chi-square test. Survival outcomes were assessed using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models for univariate and multivariate regression analyses, with statistical significance set at p ≤ 0.05. Results: Bivariate analysis showed significant associations of the neutrophil lymphocyte ratio (NLR) (p = 0.017), C-reactive protein to albumin ratio (CAR) (p = 0.033), red cell distribution width to platelet ratio (RPR) (p = 0.020), and systemic immune-Inflammation index (SII) (p = 0.009) with patient survival. Univariate analysis identified tumor length >10 cm (p = 0.016), T4 stage (p = 0.015), metastasis (p < 0.001), surgery not performed (p < 0.001), and SII (p = 0.022) as significant factors for survival, with higher SII linked to poorer overall survival (p = 0.020). Interestingly, in the multivariate model, only metastasis (p < 0.001) and surgery not performed (p = 0.011) remained significant. Conclusions: Immuno-inflammatory markers may be less pertinent prognostic factors for EC in the South Asian population.

Copeptin as an inflammatory marker in diagnosis and prognosis of neonatal sepsis

BackgroundCopeptin is an immediate biomarker of individual stress response; many life-threatening diseases are causing a high elevation of its concentration in plasma, such as myocardial infarction and cardiovascular shock. Moreover, copeptin is a promising marker in sepsis. We aimed to evaluate copeptin as a diagnostic and prognostic marker in neonatal sepsis for the early initiation of appropriate therapy and the prediction of mortality. A prospective case-control study involved 237 neonates (165 cases had neonatal sepsis, and 72 served as controls). Cases were admitted to the neonatal intensive care unit (NICU) and followed up for symptoms and signs of sepsis confirmed by laboratory data: complete blood count (CBC), c-reactive protein (CRP), and cultures. Serum copeptin level by the enzyme-linked immunosorbent assay (ELISA) was measured for all included neonates. We observed that the copeptin level was significantly higher in cases than control (3.51 ± 1.4, 1.61 ± 0.51 pmol/liter, respectively). The cut-off value of copeptin at which we can discriminate between cases and controls was above 2.065 pmol/liter. Among cases, copeptin was higher in early-onset sepsis (EOS) than late-onset sepsis (LOS) neonates, and there was a significant correlation between its level and all the following: age at admission, birth weight, gestational age, history of perinatal asphyxia, maternal chorioamnionitis, and premature rupture of membrane (PROM). Also, copeptin was strongly associated with CRP level and the poor prognosis of patients. Copeptin can predict the death of cases at a cut-off value above 2.995 pmol/liter.ConclusionSerum copeptin level can be used as a diagnostic and prognostic marker in neonatal sepsis.

Transpulmonary Plasma Endothelin-1 Arterial:Venous Ratio Differentiates Survivors from Non-Survivors in Critically Ill Patients with COVID-19-Induced Acute Respiratory Distress Syndrome.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.