Prognostic Biomarker In Patients Research Articles

Age-dependent molecular variations in osteosarcoma: implications for precision oncology across pediatric, adolescent, and adult patients.

Osteosarcoma is a leading subtype of bone tumor affecting adolescents and adults. Comparative molecular characterization among different age groups, especially in pediatric, adolescents and adults, is scarce. We collected samples from 194 osteosarcoma patients, encompassing pediatric, adolescent, and adult cohorts. Genomic analyses were conducted to reveal prevalent mutations and compare molecular features in pediatric, adolescent, and adult patients. Samples from 194 osteosarcoma patients across pediatric to adult ages were analyzed, revealing key mutations such as TP53, FLCN, NCOR1, and others. Children and adolescents showed more gene amplifications and HRD mutations, while adults had a greater Tumor Mutational Burden (TMB). Mutations in those over 15 were mainly in cell cycle and PI3K/mTOR pathways, while under 15s had more in cell cycle and angiogenesis with higher VEGFA, CCND3, TFEB mutations. CNV patterns varied with age: VEGFA and XPO5 amplifications more in under 25s, and CDKN2A/B deletions in over 25s. Genetic alterations in genes like MCL1 and MYC were associated with poor prognosis, with VEGFA mutations also indicating worse outcomes. 58% of patients had actionable mutations, suggesting opportunities for targeted therapies. Age-specific patterns were observed, with Multi-TKI mutations more common in younger patients and CDK4/6 inhibitor mutations in adults, highlighting the need for personalized treatment approaches in osteosarcoma. In a small group of patients with VEGFR amplification, postoperative treatment with multi-kinase inhibitors resulted in a PR in 3 of 13 cases, especially in patients under 15. A significant case involved a 13-year-old with a notable tumor size reduction achieving PR, even with other genetic alterations present in some patients with PD. This study delineates the molecular differences among pediatric, adolescent, and adult osteosarcoma patients at the genomic level, emphasizing the necessity for precision diagnostics and treatment strategies, and may offer novel prognostic biomarkers for patients with osteosarcoma. These findings provide a significant scientific foundation for the development of individualized treatment approaches tailored to patients of different age groups.

The Association Between Serum Levels of Glial Biomarkers, Clinical Severity and Electro-encephalography Features in Idiopathic West and Lennox-Gastaut Syndromes.

Although the contribution of enhanced glial activity in seizure induction is increasingly recognized, the role of glia-induced neuroinflammation in the physiopathology of epileptic encephalopathy (EE) has been scarcely investigated. To delineate the contribution of glial activity in EE, we measured levels of glia-derived mediators with previously described biomarker value, including glial fibrillary acidic protein (GFAP), high mobility group box 1 (HMGB1), chitinase-3-like protein 1 (CHI3L1), soluble CD163 (sCD163) and triggering receptor expressed on myeloid cells 2 (TREM2) by ELISA in sera of patients with idiopathic West syndrome (WS, n=18), idiopathic Lennox-Gastaut syndrome (LGS, n=13) and healthy controls (n=31). Patients with EE showed significantly higher CHI3L1 levels compared to healthy controls. Levels of HMGB1, CHI3L1, sCD163 and TREM2 were higher in LGS patients than WS patients and/or healthy controls. One or more of the investigated mediators were associated with treatment responsiveness, disease severity and presence of pathological features on electroencephalography (EEG). To our knowledge, our findings provide the initial patient-based evidence that astrocyte- and microglia-mediated neuroinflammation might be involved in the pathogenesis of LGS and WS. Moreover, glial mediators may serve as prognostic biomarkers in patients with idiopathic EE.

Matrix Metalloproteinases and Their Inhibitors as Potential Prognostic Biomarkers in Head and Neck Cancer after Radiotherapy.

Head and neck cancer (HNC) is among the ten most frequent tumours, with 5-year survival rates varying from 30% to 70% depending on the stage and location of the tumour. HNC is traditionally known as head and neck squamous cell carcinoma (HNSCC), since 90% arises from epithelial cells. Metastasis remains a major cause of mortality in patients with HNSCC. HNSCC patients with metastatic disease have an extremely poor prognosis with a survival rate of less than a year. Matrix metalloproteinases (MMPs) have been described as biomarkers that promote cell migration and invasion. Radiotherapy is widely used to treat HNSCC, being a determining factor in the alteration of the tumour's biology and microenvironment. This review focuses on analysing the current state of the scientific literature on this topic. Although few studies have focused on the role of these proteinases in HNC, some authors have concluded that radiotherapy alters the behaviour of MMPs and tissue inhibitors of metalloproteinases (TIMPs). Therefore, more research is needed to understand the roles played by MMPs and their inhibitors (TIMPs) as prognostic biomarkers in patients with HNC and their involvement in the response to radiotherapy.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

Significance of Preoperative Modified Nutritional Risk Index in Patients With Gastric Cancer After Curative Resection.

A new modified nutritional risk index (mNRI), calculated using serum albumin (g/l)+body mass index (BMI) [weight (kg_/height2 (m2)], is a good predictor of postoperative complications and cancer survival. However, no study has used this index in patients with gastric cancer (GC). Therefore, we aimed to investigate the clinical significance of the preoperative mNRI values in patients with GC who underwent curative resection. We examined 449 patients who underwent curative resection for GC at Kanagawa Cancer Center between 2013 and 2017. The mNRI cutoff value obtained using a receiver operating characteristic analysis was 23.31. Patients were divided into high and low mNRI groups according to the cutoff value, and the clinicopathological characteristics and outcomes were compared between the two groups. In terms of clinicopathological characteristics, the high mNRI group had a higher proportion of men, higher BMI, and a higher proportion of patients with American Society of Anesthesiologists physical status class 2/3 compared with the low mNRI group; the low mNRI group had significantly worse 5-year recurrence-free survival (RFS) and overall survival (OS) than the high mNRI group (OS, p=0.005) (OS, p=0.006; RFS, p=0.018) did. In the multivariate analysis, a low mNRI was an independent predictor of OS (p=0.006) and RFS (p=0.013). Preoperative mNRI may be a useful recurrence and prognostic biomarker in patients with GC who have undergone curative resection.

Prognostic value of lncRNA LINC01018 in prostate cancer by regulating miR-182-5p (The role of LINC01018 in prostate cancer)

LncRNAs are abnormally expressed in a variety of cancers and play unique roles in therapy. Based on this, the prognostic value of lncRNA LINC01018 in prostate cancer was discussed in this study. LINC01018 was underexpressed in prostate cancer tissues and cells, while miR-182-5p was elevated (***p < 0.001). Overexpression of LINC01018 may inhibit the progression of prostate cancer by targeting miR-182-5p. This study revealed that upregulated LINC01018 may prolong the overall survival of patients with prostate cancer (log-rank p = 0.042), and LINC01018 may become a prognostic biomarker for patients with prostate cancer, which brings a new direction for the treatment of patients.

Serum heme oxygenase-1 as a prognostic biomarker in patients with acute exacerbation of interstitial lung disease

Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.

CSGALNACT2 restricts ovarian cancer migration and invasion by modulating MAPK/ERK pathway through DUSP1.

Ovarian cancer is one of the leading causes of cancer-related death among women. CSGALNACT2 is a vital Golgi transferase and is related to a variety of human diseases. However, its expression pattern and function in ovarian cancer remain uncertain. The Cancer Genome Atlas and GEPIA databases were used to assess the expression of CSGALNACT2 in ovarian cancer patients. RNA-seq, qRT-PCR, and IHC were used to verify the expression of CSGALNACT2 in ovarian cancer tissues. Then, in vivo and in vitro experiments were conducted to evaluate the role of CSGALNACT2 in the progression of ovarian cancer. RNA-seq and GSEA were used to reveal the potential biological function and oncogenic pathways of CSGALNACT2. We demonstrated that the mRNA expression and protein level of CSGALNACT2 were significantly downregulated in ovarian cancer and ovarian cancer metastatic tissues. CSGALNACT2 can significantly inhibit the migration, invasion, and clonogenic growth of ovarian cancer in vitro and is progressively lost during ovarian cancer progression in vivo. CSGALNACT2 suppresses ovarian cancer migration and invasion via DUSP1 modulation of the MAPK/ERK pathway through RNA-seq, KEGG analysis, and Western blotting. Moreover, CSGALNACT2 expression was correlated with immune cell infiltration and had prognostic value in different immune cell-enriched or decreased ovarian cancer. In addition, patients with CSGALNACT2 downregulation are less likely to benefit from immunotherapy. As an ovarian cancer suppressor gene, CSGALNACT2 inhibits the development of ovarian cancer, and it might be used as a prognostic biomarker in patients with ovarian cancer.

Prognostic value of pretreatment lymphocyte-to-monocyte ratio in patients with glioma: a meta-analysis

BackgroundMany studies have explored the prognostic role of the lymphocyte-to-monocyte ratio (LMR) in patients with glioma, but the results have been inconsistent. We therefore conducted the current meta-analysis to identify the accurate prognostic effect of LMR in glioma.MethodsThe electronic databases of PubMed, Web of Science, Embase, and Cochrane Library were thoroughly searched from inception to July 25, 2023. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to estimate the prognostic role of LMR for glioma.ResultsA total of 16 studies comprising 3,407 patients were included in this meta-analysis. A low LMR was significantly associated with worse overall survival (OS) (HR = 1.35, 95% CI = 1.13–1.61, p = 0.001) in glioma. However, there was no significant correlation between LMR and progression-free survival (PFS) (HR = 1.20, 95% CI = 0.75–1.91, p = 0.442) in glioma patients. Subgroup analysis indicated that a low LMR was significantly associated with inferior OS and PFS in glioma when using a cutoff value of ≤ 3.7 or when patients received mixed treatment.ConclusionsThis meta-analysis demonstrated that a low LMR was significantly associated with poor OS in glioma. There was no significant correlation between LMR and PFS in glioma patients. The LMR could be a promising and cost-effective prognostic biomarker in patients with glioma in clinical practice.

Intrathecal Synthesis of Immunoglobulins G (IgG): A Prognostic Biomarker in Patients with Multiple Sclerosis

Intrathecal Synthesis of Immunoglobulins G (IgG): A Prognostic Biomarker in Patients with Multiple Sclerosis

A systematic review of circulating predictive and prognostic biomarkers in patients with oesophageal adenocarcinoma or oesophageal squamous cell carcinoma managed with radiation

A systematic review of circulating predictive and prognostic biomarkers in patients with oesophageal adenocarcinoma or oesophageal squamous cell carcinoma managed with radiation

Array CGH + SNP in ALL Enhances Detection of Complex Cytogenetic Profiles and Suggests That PRSS1 Loss May Play a Role in Leukemogenesis

Introduction Cytogenetic alterations are essential prognostic biomarkers in patients (pts) with acute lymphoblastic leukemia/lymphoma (ALL), but are limited by the propensity of leukemic blasts to undergo apoptosis in culture, poor-quality chromosomes, and overgrowth by normal cells. Array CGH + SNP has 10,000-fold higher resolution than conventional cytogenetics and can identify submicroscopic gains, losses and copy number neutral loss of heterozygosity (cnLOH) irrespective of mitotic rate. Few studies outside of clinical trials have investigated microarray findings in adults with ALL or correlated microarray findings with clinical outcomes. Methods We retrospectively reviewed pts with ALL and mixed phenotype acute leukemia (MPAL) aged ≥18 years at diagnosis at our institution between 2017 and 2022. Array analysis was performed on diagnostic bone marrow or peripheral blood samples using high resolution CGH + SNP Genetisure cancer array platform (Agilent). Statistical analysis was done using R software (R core team, 2022). Results Baseline characteristics of included pts (n = 60) are shown in Table 1. CGH + SNP analysis identified 93.3% (56/60) of pts with genomic changes with a mean of 7 (range 0 - 28) aberrations per pt. Among pts with a normal karyotype, 81.8% (9/11) had new genomic abnormalities revealed by CGH + SNP, but significantly fewer aberrations were detected per pt compared to those with abnormal karyotypes (mean 3.09 v. 7.67, p = .008). Pts with Ph-like B-ALL/MPAL had significantly more aberrations on array than pts without Ph-like phenotype (mean 12.0 v. 5.85, p.= .002). Among the 78.3% of pts without complex cytogenetics on chromosome analysis, 44.7% (21/47) were found to have a complex genomic profile (≥5 aberrations) with the addition of CGH + SNP. However, there was no difference in CR rates or OS in pts with &amp;lt;5 or ≥5 microarray aberrations (p = .515 and p = .970, respectively). Quantity of copy number alterations (CNAs) as detected on array was not predictive of achieving end of induction CR/CRi/CRh (mean 6.08 in pts who achieved CR/CRi/CRh v. 7.02 in pts with primary refractory disease, p = .310). Hispanic pts had the same number of CNAs as non-Hispanic pts (mean 6.69 v. 6.94, p = .435). On linear regression analysis, there was no correlation between number of CNAs and age (r 2 = -.01, F = 0.1941, p = .661) or BMI (r 2 = 5.21 x10 -5, F = 0.0029, p = .957). The most frequent focal aberrations were detected in CDKN2A/B (n = 19), IKZF1 (n = 17), PRSS1 (n = 11), PAX5 (n = 8), BTG1 (n = 8) and RB1 (n = 8) (Figure 1). RB1 loss was enriched in pts with T-ALL (45.5% v. 6%, p = .003),and occurred at significantly higher rates than previously reported in T-ALL (Schraders, 2009). Loss of PRSS1 was detected in 18.3% (11/60) of the cohort. Homozygous PRSS1 deletions were identified in 3/11 (27.3%) pts. We identified the minimal overlapping deleted region on 7q34 in all 11 pts, which included the PRSS1 gene within the 124 kb region. Five of 6 pts who had repeat arrays performed at the end of induction had resolution of this aberration. The one pt who retained PRSS1 loss after induction had primary refractory disease, but after further treatment and attainment of CR1, this pt cleared the PRSS1 loss. Asparaginase associated pancreatitis, which has been linked to PRSS1 variations, occurred in only 1 pt with PRSS1 loss. Pts harboring PRSS1 loss were significantly less likely to achieve MRD negativity after induction (50% vs. 82%, P = .041) and had numerically more relapses (37.5% vs. 19%, p = .300), but no OS difference was observed (p = .290). Conclusions In our institutional cohort, the addition of CGH + SNP array reclassified almost half (44.7%) of pts without complex cytogenetics to harbor complex genomic changes (≥5 aberrations). Pts with Ph-like ALL had significantly more aberrations on array than those with Ph-positive or -negative B-ALL. Focal PRSS1 loss was associated with reduced rates of MRD clearance at the end of induction. This aberration resolved upon disease remission, raising the possibility that both homozygous and/or heterozygous deletions of 124 kb from the 7q34 chromosomal region of the PRSS1 gene may potentially have a role in ALL pathogenesis. Further studies with larger cohorts utilizing CGH + SNP analyses at additional time points during treatment are needed to explore the potential integration of microarray data for refined ALL risk stratification as well as to elucidate the functional role of PRSS1 in leukemogenesis.

The impact of circulating 25-hydroxyvitamin D and vitamin D receptor variation on leukemia-lymphoma outcome: Molecular and cytogenetic study

Vitamin D (VD) potentially has a crucial function in the development of cancerous cells. This study aims to detect the role of vitamin D concentration and its receptor polymorphisms as possible prognostic biomarkers in patients with leukemia/lymphoma and further will attempt to detect the presence of the Philadelphia chromosome abnormality in chronic myeloid leukemia (CML). Seventy-five patients, in addition to 50 healthy individuals were included. Three single nucleotide polymorphisms of the vitamin D receptor (FokI, Tru91, and ApaI) were identified via Polymerase Chain Reaction- Fragment Length Polymorphism (PCR-RFLP). Sanger sequencing and karyotyping for all patients has been undertaken. Out of 75 patients, 69 (92.0%) were vitamin D deficient. The homozygous genotype TT of FokI is the most commonly found in non-Hodgkin's lymphoma, while the heterozygous CT is observed markedly in CML, chronic lymphoid leukemia, and Hodgkin's lymphoma. The AC and CC genotypes of ApaI are more frequent in patients with CML, while the AC genotype is the most common in HL. In Tru9I, the GG genotype has a wider distribution in individuals diagnosed with leukemia. The PCR-RFLP and Sanger sequencing techniques together confirmed significant genotype respectively. The Philadelphia chromosome, t (9;22) was found in five (17%) cases with CML. There is a marked relationship between FokI, ApaI, and Tru91 polymorphisms and the chance of developing leukemia. In lymphoma, a significant connection between the polymorphisms of FokI and ApaI is frequently detected. Cytogenetic and molecular testing are essential for detection of CML and monitoring therapy response.

Prognostic significance and immunoinfiltration analysis of genes associated with epithelial-mesenchymal transition and energy metabolism in bladder urothelial carcinoma.

Epithelial-mesenchymal transition (EMT) and aberrant energy metabolism are pivotal biological processes in tumor progression, significantly impacting tumor prognosis. However, the relationship between EMT, energy metabolism, and the immune microenvironment in bladder urothelial carcinoma (BLCA) remains inadequately understood. Bladder cancer samples from The Cancer Genome Atlas were categorized into two groups via clustering analysis to elucidate disparities in expression, prognostic significance, and immune infiltration of genes associated with EMT and energy metabolism between these groups. Key genes associated with EMT and energy metabolism in BLCA were identified through Cox multifactorial regression analysis, immune infiltration analysis, etc. Subsequently, their prognostic significance in BLCA was validated. Cluster analysis revealed significant differences in the expression of genes associated with EMT and energy metabolism between the two groups. Group 2 exhibited significantly improved overall survival and progression-free survival compared to Group 1. Chondroitin sulfate proteoglycan 4 (CSPG4) emerged as the most critical gene associated with EMT, energy metabolism, prognosis, and immune infiltration in BLCA. Immunohistochemical assays demonstrated differential expression of CSPG4 in bladder tumors and normal bladder tissues, with high CSPG4 expression correlating with a poorer BLCA prognosis. Furthermore, CSPG4 exhibited an association with the immune checkpoint molecule programmed death-1 (PD1) in BLCA. EMT and energy metabolism exert pivotal influences on the immune microenvironment in BLCA. CSPG4 holds promise as a prognostic biomarker for patients with BLCA, offering valuable insights into potential immunotherapeutic strategies for this patient population.

Capacidad pronóstica del PIV (pan-immune-inflammation value) en pacientes con carcinoma escamoso de cabeza y cuello

IntroductionThe pan-immune-inflammation value (PIV), an index that results from the following ratio: (neutrophils×monocytes×platelets) / lymphocytes, has been proposed as a prognostic biomarker in different tumor models. The aim of this study is to analyze the prognostic capacity of PIV in patients with head and neck squamous cell carcinoma. Patients and methodsRetrospective study of 1,187 patients with head and neck squamous cell carcinoma treated at our center between 2000-2017. PIV value was obtained from an analysis performed within 3 weeks prior to the start of treatment. ResultsPIV value was significantly associated with toxic consumption (0.001), tumor location (0.0001), tumor extension (0.0001), and histological grade (0.016). Four categories were defined based on PIV value using a recursive partitioning analysis: category i: PIV<136.3 (n=118, 9.9%), category ii: PIV 136.3-451.1 (n=594, 50.0%), category iii: PIV 451.1-1,141.2 (n=357, 30.1%), and category iv: PIV>1,141.2 (n=118, 9.9%). A significant and ordered decrease in disease-specific survival was observed as the PIV category increased. This decrease in survival was independent of the type of treatment, tumor extension, or location of the primary tumor. The PIV category was an independent prognostic factor of disease-specific survival in a multivariable study. ConclusionsPIV is a prognostic biomarker in patients with head and neck squamous cell carcinoma.

Excessive daytime sleepiness, morning tiredness, loud snoring, and prognostic biomarkers in patients with chronic coronary syndrome

Abstract Background Sleep-related breathing disorders (SRBD) are related to cardiovascular outcomes in patients with chronic coronary syndrome (CCS). Whether SRBD-related symptoms are associated with prognostic biomarkers in patients with CCS is not established. Methods Associations between frequency (never/rarely, sometimes, often, always) of self-reported SRBD-relatedsymptoms (excessive daytime sleepiness [EDS]; morning tiredness [MT]; loud snoring [LS]; multiple awakenings/night; gasping, choking, or apnea when asleep) and levels of biomarkers related to cardiovascular prognosis (high-sensitivity C-reactive protein [hs-CRP], interleukin 6 [IL-6], high-sensitivity cardiac Troponin T [hs-cTnT], N-terminal pro B-type natriuretic peptide [NT-proBNP], cystatin C, growth differentiation factor 15 [GDF-15] and lipoprotein-associated phospholipase A2 activity) were assessed at baseline in 15,640 patients with CCS on optimal secondary preventive therapy in the STABILITY trial. Cross-sectional associations were assessed by adjusted linear regression models with never/rarely as reference. Results EDS was associated (geometric mean ratio, 95% confidence interval) with increased levels of IL-6 (often 1.07 [1.03-1.10], always 1.15 [1.10-1.21]), GDF-15 (often 1.03 [1.01-1.06], always 1.07 [1.03-1.11]), NT-proBNP (always 1.22 [1.12-1.33]), and hs-cTnT (always 1.07 [1.01-1.12]). MT was associated with increased levels of IL-6 (often 1.05 [1.01-1.09], always 1.09 [1.04-1.15]), and GDF-15 (always 1.06 [1.03-1.10]). LS was associated with decreased levels of NT-proBNP (sometimes 0.94 [0.90-0.98], often 0.92 [0.87-0.97], always 0.87 [0.81-0.92]), and hs-cTnT (always 0.94 [0.91-0.98]). Conclusions In patients with CCS, gradually increased frequency of SRBD-related symptoms, such as EDS, MT, and LS, were independently and consistently associated with varying levels of IL-6, GDF-15, and NT-proBNP, each reflecting distinct pathophysiological pathways or underlying pathology of cardiovascular disease. Figure 1. Adjusted analysis of associations between sleep-related breathing disorder-related questions and geometric mean ratios of prognostic biomarkersFigure 1A.Excessive Daytime SleepinessFigure 1B.Loud Snoring

Novel miRNAs are key predictors of heart failure and mortality in functional tricuspid regurgitation

Abstract Background Functional tricuspid regurgitation (FTR) is associated with high risk of cardiovascular events, in particular heart failure (HF), but optimal timing for intervention remains controversial. Surgery is often performed late mainly because symptoms might go unnoticed until advance stage of the disease. While microRNA have been recently identified as prognostic biomarkers in different cardiovascular conditions, no study has been focus on patients with TR. Purpose To evaluate the potential role of circulating miRNAs as prognostic biomarkers in patients with severe FTR. Methods Consecutive patients with severe FTR evaluated in the Heart Valve Clinic were prospectively included and underwent a comprehensive clinical protocol. Patients with non-valvular permanent atrial fibrillation (and no TR) undergoing anticoagulant therapy unit were prospectively recruited as a control group. The experimental design included a first screening phase in 16 subjects (8 atrial FTR and 8 AF controls) to identify candidate miRNAs differentially expressed in a miRNA qPCR panel containing 192 specific miRNAs, and a second validation phase in which selected miRNAs were screened for further validation by qRT-PCR in 118 additional patients (77 FTR and 41 controls). A combined endpoint of hospital admission due to HF and all-cause mortality at follow-up was defined. Results The initial screening revealed 16 differentially expressed miRNAs in atrial FTR vs. AF subjects matched by age, gender and atrial dimensions. The candidate miRNAs were subsequently validated in 118 subjects. After a median follow up of 20.4 months (ICR 8-35 months), 25 (32%) reached the combined endpoint. Patients with events showed different levels of miR-15a-5p, miR-152-3p, miR101-3p, miR-92a-3p, miR-363-3p, miR-324-3p and miR-22-3p (Table 1, p&amp;lt;0.05 for all). Based on the high or low relative expression of selected miRNAs (below or above the median value) patients were stratified; those patients with low relative expression of miR-15a-5p, miR-92a-3p, miR101-3p, and miR-363-3p, miR-324-3p and miR-22-3p, showed significantly higher rates of events (log rank test for all p &amp;lt; 0.01, figure). In a multivariate cox regression the analysis, the level of miR-15a-5p (HR: 3.97 [1.58-9.96], miR-92a-3p (HR: 2.64 [1.13-6.13] , and miR-363-3p (HR: 2.41 [1.04-5.60] were predictive of events independently of NYHA functional class and RV dimensions (p &amp;lt; 0.05 for all). Conclusions We identify for the first time circulating miRNAs in patients with severe FTR. We further show that several miRNA predict heart failure and all-cause mortality independently of RV dimension and symptomatic status. These novel biomarkers may help to identify those patients that benefit from earlier valve interventions.Differences in patients with eventsKaplan Meier Curves

Role of Circulating Tumor DNA As a Prognostic Biomarker in Patients with Diffuse Large B-Cell Lymphoma

Introduction: Nearly 50-60% of the patients withDiffuse large B-cell lymphoma (DLBCL) can be cured by front line chemoimmunotherapy. Current risk stratification modalities include cell-of-origin (germinal center (GCB) or non-GCB (activated B-cell [ABC])) subtyping, use of the revised International Prognostic Index (R-IPI), Ki-67 proliferation index assessment, and cytogenetic aberration detection. However, a novel approach for molecular residual disease (MRD) detection and treatment monitoring is needed to improve patient outcomes. Methods: A personalized and tumor-informed multiplex PCR assay (Signatera™ bespoke mPCR NGS assay) was used for the detection and quantification of ctDNA in a prospective clinical cohort of patients with DLBCL. Serial ctDNA testing was performed at various time points collected at the treating physician's discretion, including pretreatment (baseline), during first-line therapy, during and post-salvage therapy, at the end of treatment, and during surveillance, up to the last clinical follow-up. ctDNA clearance was defined as change in ctDNA status (positive to negative) from the pre-treatment time point to the subsequent time point. Event-free survival (EFS) was defined as the time elapsed since the initial ctDNA clearance or PET imaging, for those without ctDNA clearance, during which the patient did not experience progression, death or treatment with salvage therapy. EFS was censored at the last date of followup if the patient was alive and without an event. Overall survival (OS) was defined as the elapsed time after primary treatment until death from any cause. Univariate and multivariable models were analyzed using Cox proportional models. Results: In this retrospective evaluation of commercial ctDNA testing in patients with stage I-IV DLBCL, a total of 50 patients (I:3, II:12, III: 4, and IV: 29;median age: 59 years) were analyzed. Patients were followed up for a median of 12.68 months (inter quartile range: 7.9-17.7 months). Of the 50 patients, 41 had pre-treatment (baseline) time points available and ctDNA was detected in 95% (39/41) of patients. Since the majority of the patients had stage IV disease, median ctDNA detection levels were observed to be high (overall median: 534 MTM/ml, range: 0-5957 MTM/ml; I median: 9.6 MTM/mL [range: 0.2-2822 MTM/mL], II median: 53 MTM/mL [range: 0.8-862 MTM/mL], III median: 368 [range: 2-940 MTM/mL], IV median: 1011 MTM/mL [range: 74-5958 MTM/mL]). Clearance of ctDNA at any point during first-line therapy was associated with improved outcomes (EFS, HR: 8.3, 95% CI: 2.56-27.0, p&amp;lt;0.0001 and OS, HR: 15.2, 95% CI: 1.53-149, p=0.0021), compared to patients who remained ctDNA-positive. Furthermore, 48% (13/27) of patients were found to clear their ctDNA upon the completion of the first cycle of treatment. On comparing baseline ctDNA levels with other clinicopathological risk factors, high ctDNA levels were observed to be strongly correlated with higher R-IPI scores (0-2 vs. 3-5; p=0.0008) and higher stage (I-II vs. III-IV; p=0.0007). Additionally, multivariate analysis determined that ctDNA clearance significantly outperformed all other clinicopathologic risk factors associated with EFS (HR: 48.8, 95% CI:1.2-2005, p=0.04). Finally, ctDNA clearance predicted complete response (CR)/no evidence of disease (NED) on average 95 days (range: 0-14.7 months) ahead of PET imaging or biopsy. Conclusions: In this study utilizing a real-world cohort of patients with stage I-IV DLBCL, ctDNA clearance during first-line therapy was prognostic for EFS and OS and preceded clinical response. ctDNA testing in patients with DLBCL may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Inhibition of the Cyclin K-CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer.

Androgen deprivation therapy (ADT) is the mainstay of the current first-line treatment concepts for patients with advanced prostate carcinoma (PCa). However, due to treatment failure and recurrence investigation of new targeted therapeutics is urgently needed. In this study, we investigated the suitability of the Cyclin K-CDK12 complex as a novel therapeutic approach in PCa using the new covalent CDK12/13 inhibitor THZ531. Here we show that THZ531 impairs cellular proliferation, induces apoptosis, and decreases the expression of selected DNA repair genes in PCa cell lines, which is associated with an increasing extent of DNA damage. Furthermore, combination of THZ531 and ADT leads to an increase in these anti-tumoral effects in androgen-sensitive PCa cells. The anti-proliferative and pro-apoptotic activity of THZ531 in combination with ADT was validated in an ex vivo PCa tissue culture model. In a retrospective immunohistochemical analysis of 300 clinical tissue samples we show that Cyclin K (CycK) but not CDK12 expression correlates with a more aggressive type of PCa. In conclusion, this study demonstrates the clinical relevance of the CycK-CDK12 complex as a promising target for combinational therapy with ADT in PCa and its importance as a prognostic biomarker for patients with PCa.

Interleukin-6 and Epidermal Growth Factor as non-invasive biomarkers of progression in chronic glomerulonephritis.

Several cytokines and chemokines are involved in the pathogenesis and progressive injury of renal tissues in patients with primary chronic glomerulonephritis (CGN). The objective of this study was to determine whether the urinary excretion of interleukin-6 (IL-6), transforming growth factor β1 (TGFβ1), monocytes chemoattractant protein (MCP-1), soluble tumor necrosis factor receptor 1 (sTNFR1) and epidermal growth factor (EGF) in patients with newly recognized CGN can serve as prognostic biomarkers in patients with newly recognized CGN and whether they can be effective in predicting a progressive reduction of renal function in prospective observation. The study included 150 Caucasian patients. UIL-6, UTGFβ1, UMCP-1 and UsTNFR1 and UEGF were measured using ELISA methods (Quantikine R&D System). UIL-6, UTGFβ1, UMCP-1 and UsTNFR1 were significantly higher, yet UEGF excretion was significantly lower in nephrotic patients, in patients with estimated glomerular filtration rate (eGFR) < 60/min/1,73m2 at presentation, as well as in the progressor (PG) subgroup. In a multivariate regression analysis basal eGFR correlated with UsTNFR1, UIL-6 and UEGF excretion, although in the follow-up, ΔeGFR (delta estimated glomerular filtration rate) significantly correlated only with UEGF excretion. A logistic regression analysis showed that the most significant independent risk factors for the deterioration of renal function with time are initial high (>11.8 pg/mgCr) UIL-6 excretion, initial low (<15.5 ng/mgCr) urinary UEGF excretion and male gender. In patients with newly diagnosed CGN, UIL-6 and UEGF can serve as prognostic biomarkers for the progression of the disease.