Marker Of Good Prognosis Research Articles

Effect of Flow Cytometric MRD Detection at Different Time Points during AML Chemotherapy on Prognosis

To investigate the effect of flow cytometric minimal residual disease (MRD) detection at different time points during AML chemotherapy on prognosis. 130 adult primary AML patients diagnosed and standardized with chemotherapy from March 2018 to March 2022 were retrospectively analyzed, MRD was detected by flow cytometry, Kaplan-Meier curves was used for survival analysis and log-rank test was used for variance analysis, and univariate and multifactor influencing patient survival with COX proportional risk regression model analysis. Cumulative incidence rate (CIR) analysis with competing risk model and variance analysis using Fine-Gray. There were 81 CR1, 26 CR2, 14 PR, and 9 NR patients in 130 patients. OS of the CR1 group was higher than that in the CR2, PR,and NR groups. OS of the CR2 group was higher than that in the PR group, but there was no statistically difference compared to the NR group. There was no statistically difference in OS between the PR and NR groups. 107 patients in CR1 and CR2 were grouped according to MRD detected by flow cytometry, and after the first induction chemotherapy, for patients in the MRD- and MRD+ groups, the 4-year expected RFS rates were 65.3% and 27.9% respectively, the 4-year expected OS rates were 58.7% and 41.4% respectively, and the 4-year expected CIR were 34.7% and 69.7% respectively, with statistically significant differences between 2 groups (χ2=6.639, P =0.010; χ2=6.131, P =0.013 and χ2=6.637， P =0.010). After the second chemotherapy, for patients in the MRD- and MRD+ groups, the 4-year expected RFS rates were 50.8% and 37.9% respectively, the 4-year expected OS rates were 49.2% and 44.5% respectively, and the 4-year expected CIR were 49.2% and 59.5% respectively, with no statistically significant differences between 2 groups (χ2=1.475, P =0.225; χ2=2.432, P =0.119 and χ2=1.416， P =0.234). During consolidation therapy, for patients in the MRD - and MRD+ groups, the 4-year expected RFS rates were 51.9% and 29.6% respectively, the 4-year expected OS rates were 67.5% and 24.6% respectively, and the 4-year expected CIR were 48.1% and 70.4% respectively, with statistically significant differences between 2 groups (χ2=20.982, P < 0.001; χ2=17.794, P < 0.001 and χ2=19.879， P < 0.001). For patients with MRD- at all three time points and positive at either time point, the 4-year expected RFS rates were 69.9% and 33.3% respectively, the 4-year expected OS rates were 59.1% and 44.7% respectively, and the 4-year expected CIR were 30.1% and 65.1% respectively, with statistically significant differences between 2 groups (χ2=7.367, P =0.007; χ2=6.042, P =0.014 and χ2=7.662， P =0.006). Univariate analysis showed that karyotype at high risk of chromosome was an unfavorable factor affecting patients' RFS and OS, while 2 cycles of induction chemotherapy achieved CR, MRD- after the first induction chemotherapy and MRD- after the second induction chemotherapy was a protective factor affecting patients' RFS and OS. MRD- during consolidation therapy and MRD- at all three time points were all protective factors affecting patients' RFS, OS and CIR. Multivariate analysis showed that induction chemotherapy for 2 cycles achieved CR was a protective factor affecting patients' RFS and CIR, and MRD- during consolidation therapy was a protective factor affecting patients' RFS, OS and CIR. Early achievement of CR and MRD- in adult AML patients, especially MRD- during consolidation therapy, is a marker of good prognosis, and flow cytometry is the most commonly used method for MRD detection in AML patients.

Treatment-Related Lymphopenia is Possibly a Marker of Good Prognosis in Nasopharyngeal Carcinoma: a Propensity-Score Matching Analysis

Treatment-Related Lymphopenia is Possibly a Marker of Good Prognosis in Nasopharyngeal Carcinoma: a Propensity-Score Matching Analysis

Abstract 4634: Inhibitory-κB kinase alpha as a biomarker and therapeutic target in colorectal cancer

Abstract Introduction/Aims: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality. The canonical NF-κB pathway driven by IKKβ has been implicated in CRC development and progression, however less research has focused on non-canonical NF-κB signaling, regulated by inhibitory-κB kinase alpha (IKKα). This project aimed to assess IKKα, phospho-IKKα (pIKKαs176) and IKKβ expression in a retrospective CRC cohort to establish association with survival outcomes. Subsequently, this project aimed to determine the effect of abrogating IKKα activity without perturbing the canonical NF-κB pathway controlled by IKKβ using a first-in-class selective IKKα inhibitor in vitro/ex vivo. Methods: Immunohistochemical staining for IKKα/pIKKα s176/IKKβ was performed using tissue microarrays from a CRC patient cohort (n=787). QuPath® software was used to semi-quantitively assess expression levels and scores were analyzed for association with cancer-specific survival (CSS). CRC cell lines (n=3), patient-derived organoids (PDOs; n=5) and patient-derived explants (n=5) were treated with novel IKKα inhibitor SU1644 and assessed for cell viability and proliferation. Results: Positive staining for IKKα, pIKKαs176 and IKKβ was detected in tumor specimens. High cytoplasmic expression of IKKα within tumor cells was associated with reduced CSS in patients with right-sided colon cancer (HR=3.091, 95%CI; 1.128-9.467, log rank p=0.021). Conversely, high IKKβ expression was a marker of good prognosis (HR=0.627, 95%CI; 0.457-0.861, log rank p=0.004). A high ratio of IKKα to IKKβ was associated with reduced CSS in the full cohort (HR=1.404, 95%CI; 1.050-1.879, log rank p=0.021) and this was potentiated in right-sided colon cases (HR=1.772, 95%CI; 1.107-2.837, log rank p=0.016). Selective inhibition of IKKα using 1µM SU1644 in vitro caused a significant reduction in HT29 colony formation (p=0.012) and cell viability (p=0.039). PDOs showed altered cell morphology, reduced cell viability and proliferation when treated with SU1644. In the patient-derived explant model, Ki67 expression was reduced in tumor explants treated with SU1644. Conclusions: These data establish high cytoplasmic IKKα expression within tumor cells as a marker of poor prognosis in CRC and conversely high IKKβ expression as a marker of good prognosis. This highlights the importance of development of selective IKKα inhibitor SU1644. IKKα inhibition using SU1644 demonstrated anti-cancer activity in recapitulative CRC disease models. Citation Format: Kathryn A. Pennel, Molly McKenzie, Guang-Yu Lian, Jean A. Quinn, Sara Samir Foad Al-Badran, Campbell S. Roxburgh, Simon P. Mackay, Joanna Birch, Joanne Edwards. Inhibitory-κB kinase alpha as a biomarker and therapeutic target in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4634.

Characterization of lymphocyte-rich hepatocellular carcinoma and the prognostic role of tertiary lymphoid structures.

Lymphocyte-rich hepatocellular carcinoma (LR-HCC) is largely unknown and a rare subtype of HCC with immune-rich stroma. Tertiary lymphoid structures (TLS), frequently observed in LR-HCC, are known to be prognostically significant in various malignancies; however, their significance in HCC remains unevaluated. Clinicopathologic data of 191 cases of surgically resected conventional HCC (C-HCC, n = 160) and LR-HCC (n = 31) were retrieved. Immunohistochemistry, multiplex immunofluorescence staining, RNA sequencing and proteomic analysis were conducted. Differences between the subtypes were statistically evaluated. LR-HCC was significantly correlated to larger tumour size, higher Edmondson-Steiner grade, presence of TLS and higher CD3-, CD8- and FOXP3-positive T cell, high PD-1 and PD-L1 expression (p < .001 for all) compared to C-HCC. Patients with LR-HCC exhibited significantly better overall survival (OS) (p = .044) and recurrence-free survival (RFS) (p = .025) than C-HCC. LR-HCC demonstrated TLS signatures with significantly higher proteomic-based immune scores in 14 of 17 types of tumour-infiltrating immune cells. Furthermore, C-HCC with secondary follicles, the most mature form of TLS, exhibited significantly better OS (p = .031) and RFS (p = .033) than those without. Across the global proteome, LR-HCC was well-differentiated from C-HCC and a map of protein-protein interactions between tumour-infiltrating lymphocytes and HCC in tumour microenvironment was completed. LR-HCC is clinicopathologically and molecularly distinct and shows better prognosis compared to C-HCC. Also, the presence of secondary follicle can be an important prognostic marker for better prognosis in both LR-HCC and C-HCC.

Expressions of HuR, Methyl-HuR and Phospho-HuR in Endometrial Endometrioid Adenocarcinoma Are Associated with Clinical Features.

HuR regulates cytoplasmic mRNA stability and translatability, with its expression correlating with adverse outcomes in various cancers. This study aimed to assess the prognostic value and pro-oncogenic properties of HuR and its post-translational isoforms methyl-HuR and phospho-HuR in endometrial adenocarcinoma. Examining 89 endometrioid adenocarcinomas, we analyzed the relationship between HuR nuclear or cytoplasmic immunostaining, tumor-cell proliferation, and patient survival. HuR cytoplasmic expression was significantly increased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001), correlating with worse overall survival (OS) (p = 0.02). Methyl-HuR cytoplasmic expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and correlated with better OS (p = 0.002). Phospho-HuR nuclear expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and non-significantly correlated with increased OS (p = 0.06). Cytoplasmic HuR expression strongly correlated with proliferation markers MCM6 (rho = 0.59 and p < 0.001) and Ki67 (rho = 0.49 and p < 0.001). Conversely, these latter inversely correlated with cytoplasmic methyl-HuR and nuclear phospho-HuR. Cytoplasmic HuR expression is a poor prognosis marker in endometrioid endometrial adenocarcinoma, while cytoplasmic methyl-HuR and nuclear phosphoHuR expressions are markers of better prognosis. This study highlights HuR as a promising potential therapeutic target, especially in treatment-resistant tumors, though further research is needed to understand the mechanisms regulating HuR subcellular localization and post-translational modifications.

ICAM2 is related to good prognosis in dendritic cell immunotherapy forcancer.

Objective: To evaluate the behavior of adhesion molecules ICAM-1 and ICAM-2 in dendritic cell (DC) immunotherapy. Materials & methods: 88 female Balb/c mice were divided into experimental groups. Tumors and lymph nodes were evaluated 7 and 14 days after immunotherapy. Results: Higher mean fluorescence intensityof ICAM-1 in the lymph nodes and tumors in the tumor group at14days was observed. Higher mean fluorescence intensity of ICAM-2 in thetumor DC vaccine group was observedafter 14days. A positive correlation was observed in the lymph nodes with ICAM-1 against tumoral volume in the tumor group. Anegative correlation was foundbetween ICAM-2 and tumoral volume in the lymph nodes of the tumor group. Conclusion: An increase in ICAM-2 in tumor DC vaccineand a decrease in ICAM-1 suggests the DC vaccine positively influences the immune system and that ICAM-2 could be a marker of good prognosis.

Bioinformatics analysis of immune characteristics in tumors with alternative carcinogenesis pathways induced by human papillomaviruses

BackgroundHuman papillomaviruses (HPVs) induce a subset of head and neck squamous cell carcinomas (HNSCC) and anogenital cancers, particularly cervical cancer (CC). The major viral proteins that contribute to tumorigenesis are the E6 and E7 oncoproteins, whose expression is usually enhanced after the integration of viral DNA into the host genome. Recently, an alternative tumorigenesis pathway has been suggested in approximately half of HNSCC and CC cases associated with HPV infection. This pathway is characterized by extrachromosomal HPV persistence and increased expression of the viral E2, E4, and E5 genes. The E6, E7, E5, and E2 proteins have been shown to modify the expression of numerous cellular immune-related genes. The antitumor immune response is a critical factor in the prognosis of HPV-driven cancers, and its characterization may contribute to the prediction and personalization of the increasingly used cancer immunotherapy.MethodsWe analyzed the immune characteristics of HPV-dependent tumors and their association with carcinogenesis types. Transcriptomic HNSCC and CC datasets from The Cancer Genome Atlas were used for this analysis.ResultsClustering with immune-related genes resulted in two clusters of HPV16-positive squamous cell carcinomas in both tumor types: cluster 1 had higher activation of immune responses, including stimulation of the antigen processing and presentation pathway, which was associated with higher immune cell infiltration and better overall survival, and cluster 2 was characterized by keratinization. In CC, the distribution of tumor samples into clusters 1 and 2 did not depend on the level of E2/E5 expression, but in HNSCC, most E2/E5-high tumors were localized in cluster 1 and E2/E5-low tumors in cluster 2. Further analysis did not reveal any association between the E2/E5 levels and the expression of immune-related genes.ConclusionsOur results suggest that while the detection of immune responses associated with preserved expression of genes encoding components of antigen processing and presentation machinery in HPV-driven tumors may be markers of better prognosis and an important factor in therapy selection, the type of carcinogenesis does not seem to play a decisive role in the induction of antitumor immunity.

Immunoexpression of HER2 pathway related markers in HER2 invasive breast carcinomas treated with trastuzumab

PurposeWe evaluated the immunoexpression of potential markers involved in the HER2 pathway in invasive breast carcinoma with HER2 amplification treated with trastuzumab. MethodsSamples of ninety patients diagnosed and treated at two public Brazilian hospitals with overexpressed invasive carcinoma between 2009 and 2018 were included. Several markers (Bcl-2, CDK4, cyclin D1, EGFR, IGF1, IGF-1R, MDM2, MUC4, p16, p21, p27, p53, PTEN, RA, TNFα, and VEGF) were immune analyzed in the tumor by immunohistochemistry and then correlated with clinicopathological variables. ResultsTumor sample expression results determined potential markers of good prognosis with statistically significant values: cyclin D1 with a nuclear grade, and recurrence; IGF-1 with tumor size, and death; p16 with a response after treatment; PTEN with a response after treatment, and death. Markers of poor prognosis: p53 with histological, and nuclear grade; IGF-1R with a compromised lymph node. The treatment resistance rate after trastuzumab was 40%; the overall survival was 4.13 years (95% CI 5.1–12.5) and the disease-free survival was 3.6 years (95% CI 5.1–13.1). ConclusionsThe tumor samples profile demonstrated that cyclin D1, IGF-1, p16, and PTEN presented the potential for a good prognosis and p53 and IGF-1R for worse.

An androgen receptor regulated gene score is associated with epithelial to mesenchymal transition features in triple negative breast cancers

BackgroundAndrogen receptor (AR) is considered a marker of better prognosis in hormone receptor positive breast cancers (BC), however, its role in triple negative breast cancer (TNBC) is controversial. This may be attributed to intrinsic molecular differences or scoring methods for AR positivity. We derived AR regulated gene score and examined its utility in BC subtypes. MethodsAR regulated genes were derived by applying a bioinformatic pipeline on publicly available microarray data sets of AR+ BC cell lines and gene score was calculated as average expression of six AR regulated genes. Tumors were divided into AR high and low based on gene score and associations with clinical parameters, circulating androgens, survival and epithelial to mesenchymal transition (EMT) markers were examined, further evaluated in invitro models and public datasets. Results53% (133/249) tumors were classified as AR gene score high and were associated with significantly better clinical parameters, disease-free survival (86.13 vs 72.69 months, log rank p = 0.032) when compared to AR low tumors. 36% of TNBC (N = 66) were AR gene score high with higher expression of EMT markers (p = 0.024) and had high intratumoral levels of 5α-reductase, enzyme involved in intracrine androgen metabolism. In MDA-MB-453 treated with dihydrotestosterone, SLUG expression increased, E-cadherin decreased with increase in migration and these changes were reversed with bicalutamide. Similar results were obtained in public datasets. ConclusionDeciphering the role of AR in BC is difficult based on AR protein levels alone. Our results support the context dependent function of AR in driving better prognosis in ER positive tumors and EMT features in TNBC tumors.

Expression of IGLL1 Gene and Its Clinical Significance in Pediatric T-ALL

To detect the relative expression of IGLL1 (immunoglobulin lambda-like polypeptide 1) mRNA in bone marrow of children with T-cell acute lymphoblastic leukemia (T-ALL), and analyze its correlation with the clinical characteristics and prognosis of the patients, so as to clarify the clinical significance of IGLL1 in pediatric T-ALL patients. A total of 56 pediatric T-ALL patients hospitalized in Children's Hospital of Soochow University from June 2012 to December 2017 and treated with CCLG-ALL 2008 regimen were selected. Transcriptome sequencing technology was used to detect the transcription level of IGLL1 gene in children with T-ALL. According to 25% of the IGLL1 transcription level (cutoff value:448), the enrolled children were divided into IGLL1 low expression group (17 cases) and IGLL1 high expression group (39 cases). Combined with clinical data, the correlation between the expression level of IGLL1 and prognosis of the patients was analyzed. The comparative analysis showed that the transcription level of IGLL1 was not correlated with the clinical characteristics of the patients, such as sex, age, bone marrow blast, white blood cell (WBC) count at initial diagnosis. The 5-year OS rate of patients with high IGLL1 expression was significantly higher than that of patients with low IGLL1 expression (76.9%±6.7% vs 47.1%±12.1%, P =0.018). Further comparison of relapse-free survival (RFS) rate between the two groups showed that the 5-year RFS rate of patients with high IGLL1 expression was higher than that of patients with low IGLL1 expression, but the difference between the two groups was not statistically significant (P =0.095). Multivariate COX analysis was conducted on common clinical prognostic factors (age, sex, WBC count at diagnosis, prednisone response on the 7th day, bone marrow response on the 15th day after treatment) and IGLL1 expression level, and the results showed that IGLL1 expression (P =0.012) and prednisone response (P =0.017) were independent risk factors for overall survival in pediatric T-ALL patients. In pediatric T-ALL, the OS rate of children with high expression of IGLL1 gene was significantly higher than that of children with low expression of IGLL1 gene, and the expression level of IGLL1 gene was an independent factor affecting the survival of children with T-ALL, which suggests that IGLL1 is a marker of good clinical prognosis of children with T-ALL.

Clinical meaning of stromal tumor infiltrating lymphocytes (sTIL) in luminal early breast cancer.

572 Background: Luminal breast cancer (BC) is associated with lower immune activation. Although stromal tumor infiltrating lymphocytes (sTIL) are a marker of better prognosis and response in hormone receptor (HR) negative tumors, sTIL predictive and prognostic implications are less clear in luminal BC. Further insights on the clinical correlations of immune microenvironment in luminal disease may facilitate therapeutic improvement and prognostic stratification in these patients. Methods: Observational and single-center cohort of 345 women with early luminal (HR positive, HER2 negative) BC (2012-2020) treated with chemotherapy. Pre-treatment sTIL were determined in the diagnostic biopsy following validated standard methods. The correlation between sTIL and other tumor characteristics were analyzed (Spearman's Rho and Chi-squared tests). Association of sTIL with pathologic complete response (pCR) in patients treated with neoadjuvant chemotherapy (nCT) was evaluated with logistic regression models. Prognostic value of sTIL for overall (OS) or relapse free interval (RFI) was analyzed by Cox regression models. Results: Median age: 50 (range: 24-89); 48.1% premenopausal; 91.3% infiltrating ductal carcinoma; 30.1% grade 3; 87.2% progesterone receptor (PgR)+; 67.5% treated with nCT and 32.8% with adjuvant CT (aCT); 47.6% N0, 32.8% N1, 19.6% N2-3; median ki67: 30% (82.7% &gt;10%). A 29% of patients showed sTIL=0%. Median sTIL infiltration was 5 (Q1-Q3 range [IQR], 0-10), with higher values in premenopausal (p&lt;0.001), grade 3 (p&lt;0.001), N+ (p&lt;0.001) and luminal B tumors (defined as PgR- and/or grade 3 and/or Ki67&gt;15%) (p&lt;0.001). Ki67 was significantly correlated with sTIL (ρ:0.39; p&lt;0.001). The percentage of sTIL was associated with pCR after nCT (OR: 1.045, 95%Ci 1.02-1.07, p=0.001). No prognostic impact of sTIL for OS or RFI was found in luminal A tumors. In luminal B cases (n=286), any grade of lymphocytic infiltration (defined as sTIL &gt; 0%) was associated with a shorter RFI both in univariate (p=0.01) and multivariate Cox models (HR: 4.83, 95%CI 1.28-18.21, p=0.02), with a non-significant trend for poorer OS (p=0.06). Conclusions: In luminal BC, an increased level of sTIL is associated with luminal B subtype characteristics such as higher proliferation, higher tumor grade and nodal involvement. Lymphocytic infiltration has been found to be a predictor of pCR after nCT, but, in contrast with hormone receptor-negative BC, it is also associated with a poorer prognosis for recurrence and a trend towards worse overall survival in luminal B tumors. [Table: see text]

Abstract P2-04-01: Immunoexpression of markers related to the HER2 pathway in cases of pure positive her2 breast carcinoma treated with trastuzumab

Abstract Introduction: Breast cancer is a heterogeneous disease with well-defined molecular subtypes and variable clinical behavior. The overexpressed HER2 subtype represents approximately 20% of all breast carcinomas. It is associated with a poor prognosis, increased risk of systemic and brain metastases, and poor overall survival until the advent of anti-HER2 therapies, such as trastuzumab. Its introduction into clinical practice has improved the prognosis in cases of breast cancer with overexpressing of pure HER2. However, some cases develop resistance to this drug. Objectives: To evaluate immunoexpression of possible markers involved in the HER2 pathway in breast carcinoma with overexpressing of pure HER2 treated with trastuzumab. Methods: We included 90 patients diagnosed with pure positive HER2 breast carcinoma treated with trastuzumab at the IBCC and HSP/Unifesp public hospitals between 2009 and 2018. Through immunohistochemistry, markers involved in the HER2 pathway (MUC4, IGF-1, IGF-1R, EGFR, p21, p27, p53, p16, cyclin D1, PTEN, CDK4, Bcl-2, VEGF, AR, MDM2, and TNFα) were analyzed samples paraffin-embedded of tumor and compromised lymph nodes and then, correlated with clinicopathological variables. The statistics were performed using the SPSS® software, version 25, from the company IBM, values equal to or less than 0.05 were considered significant (p ≤0.05). To verify possible associations between the clinical-pathological variables and the analyzed markers, Pearson’s X2 test, and Fisher’s exact test were used; for survival analysis, the Kaplan-Meier method was used. Results: Treatment resistance of pure HER2-positive breast cancer cases after trastuzumab treatment was 40%; the OS of this series was 4.13 years (95% CI 5.1 - 12.5) and the DFS was 3.6 years (95% CI 5.1 - 13.1). In the tumor samples it was possible to determine potential markers of good prognosis: cyclin D1 with nuclear grade (p=0.049) and recurrence (p=0.038); IGF-1 with tumor size (p= 0.015) and death (p= 0.046); p16 with response to treatment (p= 0.016); PTEN with response to treatment (p= 0.050) and death (p= 0.030). The results also showed possible markers of poor prognosis such as p53 with SBR GH (p= 0.003) and GN (p= 0.048); and IGF-1R with compromised lymph node (p=0.016). In compromised lymph nodes samples, the correlations showed TNFα with tumor size (p=0.043); and CDK4 with the response to treatment (p=0.011) as possible markers of good prognosis; only p53 with GH SBR grade (p= 0.045) maintained its potential for poor prognosis. Conclusions: In tumor samples, it was possible to demonstrate that the markers: cyclin D1, IGF-1, p16, and PTEN had the potential for a good prognosis panel and p53 and IGF-1R for worse. In samples of compromised lymph nodes, p53 remained as a marker of poor prognosis, while TNFα and CDK4 of good prognosis. Citation Format: Andreia Fabiana V. Franco, Angela Flavia L. Waitzberg, Joaquim T. Araujo Neto, Fatima S. Pasini. Immunoexpression of markers related to the HER2 pathway in cases of pure positive her2 breast carcinoma treated with trastuzumab [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-04-01.

Epicardial adipose tissue (EAT) is a promising imaging biomarker of subclinical atherosclerosis

Introduction: Identifying markers to discriminate high and low-risk individuals better is essential. Coronary Calcium Score (CAC) is an established marker of subclinical atherosclerosis. Epicardial Adipose Tissue (EAT), a new imaging biomarker, has shown considerable interest in the scientific community. Purpose: Study the impact of EAT volume in discrimination and reclassification of cardiovascular (CV) events when added to CAC score. Investigate whether EAT volume is a good prognosis marker in an asymptomatic population. Methods: A cohort of 1024 individuals without coronary disease were selected and followed prospectively during an extended period. CAC score was evaluated by cardiac tomography. EAT was quantified through a semi-automated technique (TeraRecon Aquarius Workstation). Pearson’s or Spearman’s correlations identified EAT-associated parameters. Harrel C statistics assessed the discriminative ability for events. Categorical free Net Reclassification Improvement (cfNRI) and Integrated Discrimination Index (IDI) reclassified the individuals. Kaplan-Meier evaluated CVD prognosis, and Cox regression identified variables independently associated with CV events. Results: EAT volume was significantly correlated with age, BMI, non-HDL cholesterol, triglycerides, systolic and diastolic blood pressure, and inversely with HDL cholesterol. CAC score and EAT had a C-Statistic of 0.737 (0.651 - 0.823) and 0.662 (0.564-0.760), respectively. When EAT was added to CAC, it increased to 0.777 (0.681 - 0.873) and 60% of the participants were better reclassified (NRI=60%). Higher EAT volume displayed the worst prognosis (p=0.006) and was associated, independently, with CV events, even after adjusting for CV risk factors plus CAC score (p=0.021). Conclusions: EAT may be an essential imaging marker of subclinical atherosclerosis and a potential therapeutic target for primary prevention. Reducing EAT volume with adequate measures (physical exercise, proper diet, pharmacological interventions) could decrease atherosclerosis and improve outcomes.

The Double Face of miR-708: A Pan-Cancer Player with Dissociative Identity Disorder

Over the last decades, accumulating evidence has shown tumor-dependent profiles of miR-708, being either up- or downregulated, and thus, acting as a "Janus" regulator of oncogenic pathways. Herein, its functional duality was assessed through a thorough review of the literature and further validation in silico using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. In the literature, miR-708 was found with an oncogenic role in eight tumor types, while a suppressor tumor role was described in seven cancers. This double profile was also found in TCGA and GEO databases, with some tumor types having a high expression of miR-708 and others with low expression compared with non-tumor counterparts. The investigation of validated targets using miRBase, miRTarBase, and miRecords platforms, identified a total of 572 genes that appeared enriched for PI3K-Akt signaling, followed by cell cycle control, p53, Apellin and Hippo signaling, endocrine resistance, focal adhesion, and cell senescence regulations, which are all recognized contributors of tumoral phenotypes. Among these targets, a set of 15 genes shared by at least two platforms was identified, most of which have important roles in cancer cells that influence either tumor suppression or progression. In a clinical scenario, miR-708 has shown to be a good diagnostic and prognosis marker. However, its multitarget nature and opposing roles in diverse human tumors, aligned with insufficient experimental data and the lack of proper delivery strategies, hamper its potential as a sequence-directed therapeutic.

The Expression of Programmed Death-Ligand 1 on Immune Cells Is Related to a Better Prognosis in Biliary Tract Cancer.

Programmed death-ligand 1 (PD-L1) expression in tumor cells is associated with a poor biliary tract cancer (BTC) prognosis; tumor-infiltrating immune cells in the tumor microenvironment are associated with a better prognosis. The effect of PD-L1 expression on immune cells on survival is unclear. We investigated the relationship between PD-L1 expression in immune cells and BTC prognosis. PD-L1 expression was evaluated using an anti-PD-L1 22C3 mouse monoclonal primary antibody, and its relationships with clinical characteristics and prognosis were analyzed using the Cox proportional hazard model to investigate the prognostic performance of PD-L1 in BTC. Among 144 analyzed cases, patients with positive PD-L1 expression in tumor cells and negative PD-L1 expression in immune cells showed poorer overall survival rates than those exhibiting other expressions (tumor cells: hazard ratio [HR]=1.023, p<0.001; immune cells: HR=0.983, p=0.021). PD-L1 expression in tumor cells was an independent predictor of poor overall survival (HR=1.024, p<0.001). In contrast, PD-L1 expression in immune cells was a predictive marker of good prognosis (HR=0.983, p=0.018). PD-L1 expression in immune cells may be used as an independent factor to evaluate the prognosis of patients with BTC.

Correlation of B-cell lymphoma 2 immunoexpression in invasive carcinoma of breast, no special type with hormone receptor status, proliferation index, and molecular subtypes.

B-cell lymphoma 2 is involved in various cancers including breast carcinoma. Its expression in breast cancer has been associated with good prognostic factors such as hormone receptor expression, low Ki-67, low grade, and earlier stage. It is also considered to be an independent prognostic factor for luminal and triple-negative tumors. We aimed to determine the expression of B-cell lymphoma 2 (BCL2) in different molecular subtypes of invasive ductal carcinoma of breast and its association with prognostic indicators. Fifty samples of invasive carcinoma of breast, no special type (NST), were categorized into molecular subtypes according to immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), and Ki-67 and then evaluated for BCL2 expression. The expression of BCL2 was correlated with ER, PR, HER2, and Ki-67 and compared between luminal and nonluminal subtypes. The BCL2 expression was seen in 68% of the cases with a significant association with ER, PR, and luminal subtypes. No significant association of BCL2 expression was seen with grade, HER2 and Ki-67 status of the tumor, or age group of the patients. BCL2 expression is significantly associated with ER, PR, and luminal subtypes in breast cancer. BCL2 is a marker of good prognosis in invasive carcinoma of breast, NST.

HPV infection and 5mC/5hmC epigenetic markers in penile squamous cell carcinoma: new insights into prognostics

BackgroundPenile cancer is one of the most aggressive male tumors. Although it is preventable, the main etiologic causes are lifestyle behaviors and viral infection, such as human papillomavirus (HPV). Long-term epigenetic changes due to environmental factors change cell fate and promote carcinogenesis, being an important marker of prognosis. We evaluated epidemiological aspects of penile squamous cell carcinoma (SCC) and the prevalence of HPV infection using high-risk HPV (hrHPV) and p16INK4A expression of 224 participants. Global DNA methylation was evaluated through 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC).ResultsThe incidence of HPV was 53.2% for hrHPV and 22.32% for p16INK4a. hrHPV was not related to systemic or lymph node metastasis and locoregional recurrence, nor influenced the survival rate. P16INK4a seems to be a protective factor for death, which does not affect metastasis or tumor recurrence. Lymph node and systemic metastases and locoregional recurrence increase the risk of death. An increased 5mC mark was observed in penile SCC regardless of HPV infection. However, there is a reduction of the 5hmC mark for p16INK4a + (P = 0.024). Increased 5mC/5hmC ratio (> 1) was observed in 94.2% of penile SCC, irrespective of HPV infection. Despite the increase in 5mC, it seems not to affect the survival rate (HR = 1.06; 95% CI 0.33–3.38).ConclusionsP16INK4a seems to be a good prognosis marker for penile SCC and the increase in 5mC, an epigenetic mark of genomic stability, may support tumor progression leading to poor prognosis.

The prognostic value of vasoresponse to nitric oxide in patients with chronic thromboembolic pulmonary hypertension

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary artery obstructions due to organized chronic thrombotic material in major pulmonary arteries. In addition, about half of the patients suffer from a small vessel pulmonary arteriopathy that is a strong predictor of outcomes. Currently available treatment of CTEPH includes interventional strategies such as pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA), and non-interventional strategies with PH-specific medications. A simple way of assessing small vessel disease is the degree of vasodilation (“vasoresponse”) in response to inhaled nitric oxide (iNO). In idiopathic pulmonary arterial hypertension vasoresponse serves as the best marker for good prognosis and treatment selection. In CTEPH, the prognostic value of vasoresponse remains unclear. Purpose We investigated the prognostic value of three definitions of vasoresponse to nitric oxide in patients with CTEPH. Methods We studied 325 CTEPH patients who underwent baseline diagnostic right heart catheterization (RHC) with 40ppm iNO testing at a general hospital (AKH) between 1995 and 2019. Cox regression models, adjusting for covariates including age, sex, comorbidities, and markers for disease severity at baseline, such as proBNP, GFR, NYHA functional class, were used to determine the risk of death or lung transplantation with respect to vasoresponse. We analysed three currently used definitions of vasoresponse to nitric oxide – the classical definition (CD) as a 10mmHg reduction in mPAP to a level below 40mmHg; an absolute definition (AD) as a 10mmHg reduction in mPAP regardless of resulting mPAP; and the percent definition (PD) as a 10% reduction in mPAP regardless of resulting mPAP. Results Patients had a median age of 62 (interquartile range [IQR]: 50, 71) at time of baseline right heart catheterization and 50% were female. During a median observation time of 5 years (IQR: 2.2, 9.0), the combined endpoint of death or lung transplantation occurred in 88 cases (27%). In the cox regression model PD vasoresponders, showed improved survival when undergoing PEA (p=0.0019). In PD vasoresponsive patients who were not given PEA surgery (n=66), PH medication therapy was associated with improved survival (p=0.0053), whereas BPA had no association with survival (p=0.58). In PD non-vasoresponsive patients who were not given PEA surgery (n=107) BPA improved survival (p&amp;lt;0.0001), whereas PH medication therapy did not improve survival (p=0.08). Conclusion The PD vasoresponse to iNO carries valuable prognostic information about freedom from death or lung transplantation in patients with CTEPH. In patients who are not eligible for PEA, PD vasoresponse can improve optimal therapy selection. Funding Acknowledgement Type of funding sources: None.

A Genetic Risk Score englobing variants associated with coronary artery disease is a good marker for prognosis in an asymptomatic population

Abstract Genome-wide association studies have identified several loci linked to coronary artery disease, and coronary atherosclerosis progression. However, the impact of the genetic contribution to MACE occurrence in sub-clinical atherosclerosis is unknown. Purpose This study intended to assess the relationship between a set of single nucleotide popymorphism (SNP) associated with CAD by GWAS and the MACE occurrence in an asymptomatic population. After that evaluate whether a wGRS englobing these variants is useful to estimate the prognostic. Methods Prospective study performed in an asymptomatic cohort from GENEMACOR population-based sample of 1114 subjects aged 51.7±8.3, 74.2 male, without prior coronary artery disease. Coronary Artery Calcium (CAC) score was assessed by coronary computed tomography (Agatston method), and two categories were considered 1–99 and &amp;gt;100. 33 SNP were evaluate to assess the significantly associated with prognostic. A weighted (wGRS) was constructed as the sum of the risk alleles weighted by the corresponding effect size (HR). Cox regression analysis adjusted for the main risk factors, calcium score (CAC) and wGRS to assess the risk of MACE during follow-up. Kaplan Meier assessed the survival. Results Of the studied 33 SNPs previously associated with CAD (GWAS), only 4 presented the significant association with MACE occurrence: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675. After Cox regression analysis the wGRS remained in the equation (HR=2.834); p=0.012, together with CAC score (HR 3.35); p=0.012; diabetes (HR=2.398); p=0.032 and age (HR=1.056; p=0.049. WGRS above the median presented a worst survival rate (p=0.006). Conclusion The wGRS englobing: CDKN2B-AS1 rs4977574, HNF4A rs1884613, APOE rs7412/rs429358A and GJA4A rs 618675 is independently associated with cardiovascular events in an asymptomatic population. CDKN2B-AS1 rs4977574 gene expression modulates the progression and severity of vascular calcification in vascular smooth muscle cells (VSMCs), HNF1α-AS1 is an important regulatory molecule in cancer biology and cardiovascular disease (its expression may regulate VSMCs, and high expression promotes atheroprotection). More research is crucial for understand prognosis in asymptomatic population. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): SESARAM EPE

AML-487 Prognostic Significance of Residual Disease Detected by Flow Cytometry in Acute Myeloid Leukemia With Normal Karyotype and Negative FLT3-ITD/ D835

Complete remission in patients with AML is still cytomorphological, representing a highly heterogeneous state with a wide range of tumor burden and diverse clinical findings. To evaluate prognostic significance of residual disease detected by flow cytometry in acute myeloid leukemia with normal cytogenetics and negative FLT3-ITD/D835. This is a prospective study, spanning a period of five years from January 2017 to December 2021. Our patients were followed for 25 months. The study is carried out in the context of hospitalized care for better management of LAM. We followed 54 adult patients diagnosed with AML according to the 2016 WHO criteria in the hematology and pediatric oncology department of the August 20 Hospital in Casablanca, of which 30 patients achieved complete cytological remission after induction. Any patient presenting a therapeutic failure in post induction and salvage therapy was excluded from the study. After that, we selected patients with normal karyotype for FLT3 gene mutational analysis. Quantification of minimal residual disease (MRD) and leukemic stem cells (LSC) using a six-color Navios type flow cytometer and the cxp acquisition and analysis software. A large panel of monoclonal antibodies was used to determine leukemia-associated immunophenotypes in most patients. Molecular analysis of FLT3-ITD/D835 was performed by PCR/RFLP (restriction fragment length polymorphism). The hypothesis of our study was that the group of patients with favorable and intermediate prognosis will have a relatively better relapse-free survival (RFS) than those with a poor prognosis. The intermediate risk group was predominant with a rate of 83%, of which 67% (20/30) had a normal karyotype. MRD and LSC positivity in this group was predominant with considerable decrease in hematogone count frequency as a marker of good prognosis. Non-mutated FLT3 gene in this group conferred a more improved relapse-free survival compared to that of the negative MRD in all our patients studied. MRD, LSC and are FLT3 gene analysis are powerful prognostic factors for relapse that should be integrated routinely to guide our clinicians in risk stratification, especially in patients with normal karyotype.