Circulating Mir-16 and Mir-25 As New Prognosticators For Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1853-1853 ◽  
Author(s):  
Flavia Pichiorri ◽  
Alberto Rocci ◽  
Craig C Hofmeister ◽  
Susan Geyer ◽  
Tiffany Talabere ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Prognostic Significance ◽  
Cox Proportional Hazards ◽  
Response To Therapy ◽  
Differentially Expressed ◽  
Prognostic Impact ◽  
Continuous Variables ◽  
Circulating Micrornas ◽  
Non Invasive

Abstract Purpose While international stage (ISS) and the presence of absence of cytogenetic abnormalities on FISH somewhat define the clinical risk of MM patients, additional biomarkers are necessary for more precise risk-based classification. Emerging studies have shown that circulating microRNAs (miRNAs) can be detected in patients with a variety of malignancies, including MM, and they could be non-invasive biomarkers. We measured serum miRNA levels of a large cohort of well-characterized previously untreated MM patients and correlated results with clinical outcome to test their prognostic impact. Methods and Patients To profile the expression of circulating microRNAs in the serum of MM patients, we performed NanoString-nCounter microRNA assays on samples obtained from a discovery cohort of 54 newly diagnosed MM patients enrolled on a randomized GIMEMA phase 3 study comparing Velcade-Melphalan-Prednisone-Thalidomide versus Velcade-Melphalan-Prednisone followed by maintenance with Velcade-Thalidomide. To further analyze the expression of the differentially expressed microRNAs, stem-loop-RT-PCR was performed on a validation cohort of 234 MM patients enrolled in the same trial. The prognostic significance of differentially expressed microRNAs were evaluated in relation to progression-free (PFS) and overall survival (OS) using univariate and multivariate Cox proportional hazards models. The utility of incorporating microRNA expression into a risk score with known risk factors – specifically ISS stage and the presence of del17, t(4;14) or t(14;16) by FISH – was also explored. Results Out of the 800 miRNAs evaluated, only 25 were detectable (≥100 counts) in at least 20% of the patients. The expression of these miRNAs were then measured in a validation set, but only 10 (miRs-92a, 21, 30a, 720, 451, 223, 126, 19b, 25 and miR-16) were validated to be differentially expressed. We found that levels of miR-16 and miR-25, used as continuous variables, had significant impact on OS duration: miR-16 (HR 0.87; p=0.019) and miR-25 (HR 0.81; p=0.0012) where low expression corresponded with worse survival. Based on these observations we generated a microRNA-based risk score which was significantly associated with OS duration (p=0.008). We then integrated this score with ISS stage and presence of high risk features by FISH, generating an integrated-microRNA risk score that was significantly associated with OS (p<0.0001), and was better than a risk score that combined ISS and FISH (p=0.014), see figure. Conclusions Circulating miR-16 and miR-25 can risk stratify elderly, previously untreated, MM patients beyond ISS-stage and high risk genetic features. The opportunity to isolate circulating miRNAs allows us to sequentially sample cancer patients in a relatively non-invasive manner, opening new avenues of investigation for disease stratification and response to therapy. Disclosures: Bringhen: Onyx: Consultancy.

scholarly journals Measurements Methods for the Development of MicroRNA-Based Tests for Cancer Diagnosis

2021 ◽  
Vol 22 (3) ◽  
pp. 1176
Author(s):  
Francesca Precazzini ◽  
Simone Detassis ◽  
Andrea Selenito Imperatori ◽  
Michela Alessandra Denti ◽  
Paola Campomenosi
Keyword(s):  
Expression Profiling ◽  
Clinical Stage ◽  
Response To Therapy ◽  
Clinical Settings ◽  
Molecular Tools ◽  
Altered Expression ◽  
Circulating Micrornas ◽  
Non Invasive ◽  
Mirna Expression Profiling ◽  
Technological Limitations

Studies investigating microRNAs as potential biomarkers for cancer, immune-related diseases, or cardiac pathogenic diseases, among others, have exponentially increased in the last years. In particular, altered expression of specific miRNAs correlates with the occurrence of several diseases, making these molecules potential molecular tools for non-invasive diagnosis, prognosis, and response to therapy. Nonetheless, microRNAs are not in clinical use yet, due to inconsistencies in the literature regarding the specific miRNAs identified as biomarkers for a specific disease, which in turn can be attributed to several reasons, including lack of assay standardization and reproducibility. Technological limitations in circulating microRNAs measurement have been, to date, the biggest challenge for using these molecules in clinical settings. In this review we will discuss pre-analytical, analytical, and post-analytical challenges to address the potential technical biases and patient-related parameters that can have an influence and should be improved to translate miRNA biomarkers to the clinical stage. Moreover, we will describe the currently available methods for circulating miRNA expression profiling and measurement, underlining their advantages and potential pitfalls.

scholarly journals A Risk Signature of Nine Autophagy-Related Genes Associated With Immune Microenvironment and Clinical Prognosis in Wilms Tumor

2021 ◽  
Author(s):  
Shaopei Ye ◽  
Wenbin Tang ◽  
Ke Huang
Keyword(s):  
Regression Analysis ◽  
High Risk ◽  
Risk Score ◽  
Cox Regression ◽  
Wilms Tumor ◽  
Risk Group ◽  
High Risk Group ◽  
Differentially Expressed ◽  
Clinical Prognosis ◽  
Cox Regression Analysis

Abstract Background: Autophagy is a biological process to eliminate dysfunctional organelles, aggregates or even long-lived proteins. . Nevertheless, the potential function and prognostic values of autophagy in Wilms Tumor (WT) are complex and remain to be clarifed. Therefore, we proposed to systematically examine the roles of autophagy-associated genes (ARGs) in WT.Methods: Here, we obtained differentially expressed autophagy-related genes (ARGs) between healthy and Wilms tumor from Therapeutically Applicable Research To Generate Effective Treatments(TARGET) and The Cancer Genome Atlas (TCGA) database. The functionalities of the differentially expressed ARGs were analyzed using Gene Ontology. Then univariate COX regression analysis and multivariate COX regression analysis were performed to acquire nine autophagy genes related to WT patients’ survival. According to the risk score, the patients were divided into high-risk and low-risk groups. The Kaplan-Meier curve demonstrated that patients with a high-risk score tend to have a poor prognosis.Results: Eighteen DEARGs were identifed, and nine ARGs were fnally utilized to establish the FAGs based signature in the TCGA cohort. we found that patients in the high-risk group were associated with mutations in TP53. We further conducted CIBERSORT analysis, and found that the infiltration of Macrophage M1 was increased in the high-risk group. Finally, the expression levels of crucial ARGs were verifed by the experiment, which were consistent with our bioinformatics analysis.Conclusions: we emphasized the clinical significance of autophagy in WT, established a prediction system based on autophagy, and identified a promising therapeutic target of autophagy for WT.

scholarly journals Diabetes risk score in the United Arab Emirates: a screening tool for the early detection of type 2 diabetes mellitus

2018 ◽  
Vol 6 (1) ◽  
pp. e000489 ◽  
Author(s):  
Nabil Sulaiman ◽  
Ibrahim Mahmoud ◽  
Amal Hussein ◽  
Salah Elbadawi ◽  
Salah Abusnana ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Risk Factors ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
High Risk ◽  
United Arab Emirates ◽  
Risk Score ◽  
Family History Of Diabetes ◽  
Non Invasive

ObjectiveThe objective of this study was to develop a simple non-invasive risk score, specific to the United Arab Emirates (UAE) citizens, to identify individuals at increased risk of having undiagnosed type 2 diabetes mellitus.Research design and methodsA retrospective analysis of the UAE National Diabetes and Lifestyle data was conducted. The data included demographic and anthropometric measurements, and fasting blood glucose. Univariate analyses were used to identify the risk factors for diabetes. The risk score was developed for UAE citizens using a stepwise forward regression model.ResultsA total of 872 UAE citizens were studied. The overall prevalence of diabetes in the UAE adult citizens in the Northern Emirates was 25.1%. The significant risk factors identified for diabetes were age (≥35 years), a family history of diabetes mellitus, hypertension, body mass index ≥30.0 and waist-to-hip ratio ≥0.90 for males and ≥0.85 for females. The performance of the model was moderate in terms of sensitivity (75.4%, 95% CI 68.3 to 81.7) and specificity (70%, 95% CI 65.8 to 73.9). The area under the receiver-operator characteristic curve was 0.82 (95% CI 0.78 to 0.86).ConclusionsA simple, non-invasive risk score model was developed to help to identify those at high risk of having diabetes among UAE citizens. This score could contribute to the efficient and less expensive earlier detection of diabetes in this high-risk population.

Long-Term Results of the GIMEMA LAP AIDA 0493 Amended Protocol in Elderly Patients with Acute Promyelocytic Leukemia (APL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 885-885
Author(s):  
R. Latagliata ◽  
M. Breccia ◽  
P. Fazi ◽  
M. Vignetti ◽  
A. Cupri ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Risk Score ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Long Term Results ◽  
Induction Treatment ◽  
Prognostic Impact ◽  
Wbc Count

Abstract In order to reduce toxicity in elderly patients with newly diagnosed APL, since 3/1997 the Italian cooperative group GIMEMA evaluated an amended AIDA protocol for patients aged &gt; 60 years, consisting of the same induction with ATRA and Idarubicin but only 1st consolidation course (Idarubicin + Cytarabine), followed by 2 years maintenance with ATRA alone. Up to now, 56 patients (25 males and 31 females, median age 66.2 years, 46 with PS 0-1 and 10 with PS 2) are fully evaluable. At onset, according to GIMEMA-PETHEMA risk score, 18 were low-risk(32.5%), 31 intermediate risk (55%) and 7 high risk (12.5%). After induction treatment, 54 patients (96.4%) achieved CR and 2 (3.6%) died from haemorrhage (1) and infection (1). ATRA syndrome was documented in 5 patients (9.3%): 13/56 patients (23.2%) showed during induction other toxicities (WHO 3 – 4) not related to ATRA. After CR achievement, 2 patients died in CR from haemorrhage (1) and infection (1) and 52 received the consolidation course: on the whole, during consolidation 4 patients (7.6%) had a toxicity WHO 3 – 4 and 2 of them (3.8%) died from haemorrhage (1) and infection (1). The remaining 50 patients started maintenance treatment: up to now, 12 patients (22.2%) relapsed, after a median time from morphological CR of 19 months (range 7 – 86). Overall survival (OS) was 76.1% and 73.3% at 3 and 5 years, respectively. Disease free survival (DFS) was 64.5% and 61.3% at 3 and 5 years, respectively. At the univariate analysis, PS =2 (p=0.0019), WBC count &gt; 3 x 109 /l (p=0.018) and male gender (p=0.03) had a bad prognostic impact on DFS, while only PS=2 (p=0.05) did it on OS. Age, PLTS count, WBC count &gt; 10 x 109 /l, and risk score did not affect both OS and DFS. At the multivariate analysis on DFS, only PS =2 retained prognostic significance (HR = 3.8). In conclusion, the amended GIMEMA protocol has shown to be effective and safe in elderly APL patients, as the rate of death in CR was reduced when compared with previous results in not amended GIMEMA LAP AIDA 0493: however, to face with a relapse rate &gt; 20%, future strategies might be designed which exploit the use of more targeted approaches including combinations of ATRA, arsenic trioxide, and anti-CD33 monoclonal antibodies.

Global Methylation Provides Independent Prognostic Information in Chronic Lymphocytic Leukemia and Is Associated with a Microrna Signature

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3873-3873
Author(s):  
Alfons Navarro ◽  
Gerardo Ferrer ◽  
Marina Díaz-Beyá ◽  
Carmen Muñoz ◽  
Rut Tejero ◽  
...  
Keyword(s):  
Dna Methylation ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Mirna Expression ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Surrogate Marker ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Global Methylation

Abstract Abstract 3873 Introduction: Disruption of normal DNA methylation, including both gene specific hypermethylation and genome-wide hypomethylation, is found in most malignant tumors. Most epigenetic studies in chronic lymphocytic leukemia (CLL) have been focused in CpG islands and gene promoter regions, and have identified hypomethylated genes, such as BCL2 or TCL1, and hypermethylated genes, such as GRM7. However, the quantification of overall methylation measured as levels of 5-methylCytosine (5mC) has been poorly explored. As compared to their normal counterparts (CD19+ B cells), overall hypomethylation has been observed in CLL neoplastic cells. Importantly, the overall methylation varies among patients but its clinical significance has not been widely investigated. In addition, it is known that microRNA (miRNA) expression is altered in CLL, and that and epigenetic mechanisms, such as methylation, can affect miRNA expression. Aim: To investigate the prognostic impact of overall methylation in patients with CLL and to analyze the correlation of 5mC levels with miRNAs expression. Methods: We analyzed 73 CLL patients (median age, 69 [range, 34–86]; 43% males) diagnosed in our institution between 1992 and 2007. The median follow up was 10.5 years. The level of global methylation in total DNA was estimated after determination of percentage of 5mC using anti-5mC monoclonal antibodies (MethylFlash Methylated DNA Quantification Kit, Epigentek). The expression of 377 mature miRNAs was analyzed using TaqMan Array Human MicroRNA A Card v2.0 (Applied Biosystems). Statistical analysis was performed with SPSS version 15.0.1 and R software version 2.9.0. MaxStat package of R were used to determine the optimal cutoffs and Quantitative trail function in BRB array tools to correlate miRNA expression and methylation levels. Results: The analysis of methylation levels showed a wide distribution of methylation degree among patients (median: 3.02%, range: 0.58–6.14%). From the clinical standpoint, methylation levels were only correlated with Binet clinical stage, patients with C stage showing a higher degree of methylation (p=0.015). Using MaxStat, we identified two cutoffs which classified patients as having low, medium or high degree of methylation. Mean progression-free survival (PFS) was 8.4 years (95% CI: 6.4–10.4), 6.2 years (95% CI: 4.7–7.7) and 3.2 years (95% CI: 2.4–4.8) for patients with low, medium, and high methylation levels, respectively (p=0.013). In the multivariate analysis for PFS (including ZAP70, IGHV, Age≤65, cytogenetics and global methylation), high ZAP70 expression (HR: 3; 95%CI: 1.1–7.9; p=0.026) and high global methylation (HR: 5.4 95%CI: 1.7–17.1; p=0.004) were independent unfavorable prognostic factors, while a significant trend was observed for high-risk cytogenetics (17p-, 11q-, +12) (p=0.054). Interestingly, methylation levels retained its prognostic significance in subgroup analysis: clinical stage A (p=0.06) and B/C (p=0.009); mutated (p=0.008) and unmutated IGHV (p=0.028); low (p=0.028) and high ZAP70 (p=0.001); and low-risk (normal karyotype, 13q-)(p=0.008) and high-risk (17p-, 11q-, +12) cytogenetics (p=0.001). Finally, we identified a 4-miRNA signature associated with global methylation levels: miR-103 (Spearman correlation [SC]: −0.821;p=0.03), miR-132 (SC: 0.786;p=0.05), miR-494 (SC: −0.786; p=0.02), and miR-193a-5p (SC: 0.786; p=0.05). Interestingly, miR-103, miR-132 and miR-494 are located in subtelomeric regions, which are known to be more susceptible to overall methylation changes. Conclusions: In this study, the degree of global DNA methylation was an independent prognostic factor for PFS in patients with CLL. The analysis of overall methylation could be useful not only for the prognosis of patients with CLL but also in the monitoring of clinical trials in which hypomethylating agents (e.g., decitabine) are being investigated as CLL therapy. The correlation between overall methylation levels and certain miRNAs may be a surrogate marker of epigenetic lesions and deserves further investigation. Disclosures: No relevant conflicts of interest to declare.

The prognostic signficance of pretreatment leukocytosis in patients with anal cancer treated with radical chemoradiotherapy or radiotherapy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 656-656 ◽  
Author(s):  
Robyn Banerjee ◽  
George Roxin ◽  
Misha Eliasziw ◽  
Kurian Joseph ◽  
Donald Buie ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Patient Group ◽  
Anal Cancer ◽  
Tumor Size ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
Pre Treatment ◽  
Poor Outcomes

656 Background: There are emerging data showing prognostic significance of pre-treatment leukocytosis (elevated white blood cell count) in cervical cancer patients. However the prognostic impact of leukocytosis in anal cancer patients has not been previously reported. The purpose of this study was to determine the association of pre-treatment leukocytosis on outcome in patients with anal cancer treated with radical chemoradiotherapy (CRT) or radiotherapy (RT). Methods: 126 patients with anal cancer, treated with radical CRT (91.3%) or RT (8.7%) from 2 major Canadian cancer centers (University of Calgary, n=65 and University of Alberta, n=61), between 2000 and 2008 were evaluated. Demographic, clinical, hematologic and treatment factors were retrieved from retrospective review of the patients’ records. The association of clinical factors and hematologic status with overall survival (OS) and disease-free survival (DFS) was analyzed using Cox proportional hazards regression models. Results: Median follow-up was 24 months. Median tumor size was 4 cm. Mean age was 59 years and M:F was 29:97. Pre-treatment leukocytosis (WBC count greater than 10^9/L) was identified in 16% (20/126) of patients. After adjusting for gender, tumor size and stage in a multivariate analysis, leukocytosis remained significantly associated with worse 2-year OS [HR 2.9 (95% CI 1.1-7.9), p=0.036] and worse DFS [HR 2.2 (95% CI1.1-4.8), p=.045]. The patient group with both pre-treatment hemoglobin (Hgb) less than 125 g/L (lowest quartile) and leukocytosis had very poor outcomes, 2-year OS 61% versus 89% for patients without these factors; more than doubling the hazard for DFS [HR2.7 (95% CI 1.1-6.8), p=0.033] and for OS [4.5 (95% CI 1.5-13.2), p=.006]. Conclusions: Pre-treatment leukocytosis is associated with worse OS and DFS in patients with anal cancer treated with radical CRT or RT. Patients with both low Hgb and leukocytosis had very poor outcomes. These hematologic parameters represent potential biomarkers for prognosis and treatment response, and warrant further investigation to uncover the underlying biologic mechanisms and therapeutic strategies in this patient group.

scholarly journals Comparing non-invasive diabetes risk scores for detecting patients in clinical practice: a cross-sectional validation study

2021 ◽  
Vol 4 ◽  
pp. 70
Author(s):  
Sinéad Flynn ◽  
Seán Millar ◽  
Claire Buckley ◽  
Kate Junker ◽  
Catherine Phillips ◽  
...  
Keyword(s):  
Risk Score ◽  
Characteristic Curve ◽  
Diabetes Risk ◽  
Detection Methods ◽  
Risk Scores ◽  
Continuous Variables ◽  
Irish Population ◽  
Cross Sectional ◽  
Non Invasive ◽  
Diabetes Risk Score

Background: Type 2 diabetes (T2DM) is a significant cause of morbidity and mortality, thus early identification is of paramount importance. A high proportion of T2DM cases are undiagnosed highlighting the importance of effective detection methods such as non-invasive diabetes risk scores (DRSs). Thus far, no DRS has been validated in an Irish population. Therefore, the aim of this study was to compare the ability of nine DRSs to detect T2DM cases in an Irish population. Methods: This was a cross-sectional study of 1,990 men and women aged 46–73 years. Data on DRS components were collected from questionnaires and clinical examinations. T2DM was determined according to a fasting plasma glucose level ≥7.0 mmol/l or a glycated haemoglobin A1c level ≥6.5% (≥48 mmol/mol). Receiver operating characteristic curve analysis assessed the ability of DRSs and their components to discriminate T2DM cases. Results: Among the examined scores, area under the curve (AUC) values ranged from 0.71–0.78, with the Cambridge Diabetes Risk Score (AUC=0.78, 95% CI: 0.75–0.82), Leicester Diabetes Risk Score (AUC=0.78, 95% CI: 0.75–0.82), Rotterdam Predictive Model 2 (AUC=0.78, 95% CI: 0.74–0.82) and the U.S. Diabetes Risk Score (AUC=0.78, 95% CI: 0.74–0.81) demonstrating the largest AUC values as continuous variables and at optimal cut-offs. Regarding individual DRS components, anthropometric measures displayed the largest AUC values. Conclusions: The best performing DRSs were broadly similar in terms of their components; all incorporated variables for age, sex, BMI, hypertension and family diabetes history. The Cambridge Diabetes Risk Score, had the largest AUC value at an optimal cut-off, can be easily accessed online for use in a clinical setting and may be the most appropriate and cost-effective method for case-finding in an Irish population.

scholarly journals Identification of Aging-Related Genes Associated With Clinical and Prognostic Features of Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingte Chen ◽  
Lei Wang ◽  
Liang Hong ◽  
Zhixiong Su ◽  
Xiaohong Zhong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regression Analysis ◽  
High Risk ◽  
Risk Score ◽  
Cancer Genome ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Survival Prediction ◽  
Lasso Regression ◽  
Prognostic Features

Background: Aging is a well-studied concept, but no studies have comprehensively analyzed the association between aging-related genes (AGs) and hepatocellular carcinoma (HCC) prognosis.Methods: Gene candidates were selected from differentially expressed genes and prognostic genes in The Cancer Genome Atlas (TCGA) database. A gene risk score for overall survival prediction was established using the least absolute shrinkage and selection operator (LASSO) regression analysis, and this was validated using data from the International Cancer Genome Consortium (ICGC) database. Functional analysis was conducted using gene ontology enrichment, Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis, and immune microenvironment and tumor stemness analyses.Results: Initially, 72 AGs from the TCGA database were screened as differentially expressed between normal and tumor tissues and as genes associated with HCC prognosis. Then, seven AGs (POLA1, CDK1, SOCS2, HDAC1, MAPT, RAE1, and EEF1E1) were identified using the LASSO regression analysis. The seven AGs were used to develop a risk score in the training set, and the risk was validated to have a significant prognostic value in the ICGC set (p &lt; 0.05). Patients with high risk scores had lower tumor differentiation, higher stage, and worse prognosis (all p &lt; 0.05). Multivariate Cox regression analyses also confirmed that the risk score was an independent prognostic factor for HCC in both the TCGA and ICGC sets (all p &lt; 0.05). Further analysis showed that a high risk score was correlated with the downregulation of metabolism and tumor immunity.Conclusion: The risk score predicts HCC prognosis and could thus be used as a biomarker not only for predicting HCC prognosis but also for deciding on treatment.

scholarly journals Circulating MicroRNAs as Non-invasive Biomarkers for Canine Cushing's Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Karin Sanders ◽  
Anouk Veldhuizen ◽  
Hans S. Kooistra ◽  
Adri Slob ◽  
Elpetra P. M. Timmermans-Sprang ◽  
...  
Keyword(s):  
Decision Making ◽  
Cushing’S Syndrome ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Cushing's Syndrome ◽  
Differentially Expressed ◽  
Circulating Micrornas ◽  
Blood Samples ◽  
Non Invasive ◽  
Healthy Dogs

Canine Cushing's syndrome (hypercortisolism) can be caused by a pituitary tumor (pituitary-dependent hypercortisolism; PDH) or a cortisol-secreting adrenocortical tumor (csACT). For both cases, non-invasive biomarkers that could pre-operatively predict the risk of recurrence after surgery would greatly impact clinical decision making. The aim of this study was to determine whether circulating microRNAs (miRNAs) can be used as diagnostic (presence of PDH or csACT) and/or prognostic (disease recurrence, histological grade) non-invasive biomarkers for canine Cushing's syndrome. After a pilot study with 40 miRNAs in blood samples of healthy dogs (n = 3), dogs with PDH (n = 3) and dogs with a csACT (n = 4), we selected a total of 20 miRNAs for the definitive study. In the definitive study, these 20 miRNAs were analyzed in blood samples of healthy dogs (n = 6), dogs with PDH (n = 19, pre- and post-operative samples) and dogs with a csACT (n = 26, pre-operative samples). In dogs with PDH, six miRNAs (miR-122-5p, miR-126-5p, miR-141-3p, miR-222-3p, miR-375-3p and miR-483-3p) were differentially expressed compared to healthy dogs. Of one miRNA, miR-122-5p, the expression levels did not overlap between healthy dogs and dogs with PDH (p = 2.9x10−4), significantly decreased after hypophysectomy (p = 0.013), and were significantly higher (p = 0.017) in dogs with recurrence (n = 3) than in dogs without recurrence for at least one year after hypophysectomy (n = 7). In dogs with csACTs, two miRNAs (miR-483-3p and miR-223-3p) were differentially expressed compared to healthy dogs. Additionally, miR-141-3p was expressed significantly lower (p = 0.009) in dogs with csACTs that had a histopathological Utrecht score of ≥ 11 compared to those with a score of &lt;11. These results indicate that circulating miRNAs have the potential to be non-invasive biomarkers in dogs with Cushing's syndrome that may contribute to clinical decision making.

Exon-Based Transcriptome Profiling Reveals Genes That Have Prognostic Impact on the Survival of Young High Risk Diffuse Large B-Cell/Follicular Grade 3 Lymphoma Patients Treated with Dose-Dense Chemoimmunotherapy and CNS Prophylaxis. Results From a Nordic Lymphoma Group Phase II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3107-3107
Author(s):  
Satu Koivula ◽  
Minna Taskinen ◽  
Ping Chen ◽  
Harald Holte ◽  
Jan Delabie ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Transcriptome Profiling ◽  
Differentially Expressed ◽  
High Dose ◽  
Prognostic Impact ◽  
Gene Level ◽  
Grade 3 ◽  
Dose Dense

Abstract Abstract 3107 Background: Survival of young high risk diffuse large B-cell lymphoma (DLBCL) is now approaching 80% due to implementation of rituximab and dose-dense chemotherapy protocols but the patients with relapsed or refractory disease continue to have a poor prognosis. Such patients could benefit from additional therapies if their clinical outcome could be more accurately predicted at the time of diagnosis. Recently, several gene-expression signatures with prognostic significance in DLBCL have been identified. To date, the accessibility of exon arrays that interrogate exon-level expression has enabled a new, more sensitive method of analysing gene-expression than the traditional 3′ arrays. In the present study, we have tested the utility of exon profiling to define novel prognostic markers for young high risk DLBCL patients. Patients: Study population consisted of 41 patients (36 DLBCL and 5 follicular lymphoma (FL) grade 3) less than 65 years old with high risk (age adjusted International Prognostic Index (aaIPI) Score 2–3) disease. The selection of the patients was based on the availability of freshly frozen lymphoma tissue containing adequate material for mRNA analyses. All tissue samples were taken before treatments. All patients were treated in the Nordic phase II protocol with six courses of R-CHOEP14 followed by systemic CNS prophylaxis with one course of high-dose methotrexate and one course of high-dose cytarabine. In the present report with a median follow-up of 29 months, (range 15–63 months), ten patients had relapsed and nine died. Relapse free survival (RFS) was 74% and overall survival (OS) 77%. Results: We identified differentially expressed exons between the relapsed patients and the patients in remission using criteria of p ≤ 0.05 and fold change ≥ 1.6. In order to estimate the gene-level expression, and to exclude false positives, the genes were considered as differentially expressed only if at least 20% of all exons were differentially expressed. Accordingly, 646 genes were identified, from which 119 encoded proteins. In a pathway network analysis (Laakso and Hautaniemi, 2010), 23 genes were found likely to be involved in conventional signalling pathways. The identified pathways included important events of lymphoma biology such as antigen processing and presentation, cell adhesion, chemokine signalling as well as TGF-beta, Toll-like receptor, Wnt and MAPK signalling. We also performed a gene level survival analysis with data combined of differentially expressed exons and follow-up information. 12 of the 23 genes were found to associate with RFS (p<0.05). Among these, high expression of HLA-DOA, HLA-DQB1 (both members of MHC class II family), RFXAP (MCH class II transcription regulator), SMAD7 (mediator of TGF-beta signalling), IRF5 (interferon regulatory factor) and CR1 (complement component) had a favourable impact on RFS. In contrast, high IL22 (interleukin 22) and DLG2 (Discs 2) levels were associated with adverse outcome. Similarly, 7 of the 23 genes were predictive for OS (p<0.05). Prognostic impact of one third of the transcripts could be confirmed in an independent gene array based data set of 233 DLBCL patients treated with immunochemotherapy (Lenz et al., 2008). Conclusions: The data suggest that exon-based transcriptome profiling of diagnostic tumor tissue can identify biologically relevant genes that discriminate the outcome of homogenously treated young high risk lymphoma patients. Such genes and involved pathways represent markers for improved patient risk stratification and potential targets for novel DLBCL therapies. Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Leppa:Roche: Honoraria, Research Funding.

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