Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children

2012 ◽  
Vol 30 (13) ◽  
pp. 1422-1428 ◽  
Author(s):  
Henk Visscher ◽  
Colin J.D. Ross ◽  
S. Rod Rassekh ◽  
Amina Barhdadi ◽  
Marie-Pierre Dubé ◽  
...  

Purpose Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. Patients and Methods We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. Results We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10−5 for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate–binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. Conclusion We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20647-e20647
Author(s):  
Martina Torchio ◽  
Benvenuto Franceschetti ◽  
Carla Cavali ◽  
Sonia Zanirato ◽  
Angelo Olgiati ◽  
...  

e20647 Background: Venous thromboembolism (VTE), is a negative predictor of survival in pts with advanced cancer. International guidelines don’t recommend routine prophlaxis but suggest to consider pts, undergoing chemotherapy (CT), with high risk of VTE. Many clinical risk factors for cancer-associated VTE have been evaluated in a 5 parameter-based (body mass index, platelet and leucocyte counts, hemoglobin value and tumor site) scoring system, the Khorana score, utilized to indicate a prophylactic approach. We prospectively applied this score in cancer outpts beginning CT and an implementation based on 6 addictional factors analysis (sex, age, central venous catheter, CT-agents, antiangiogenetic drugs, erithropoiesis stimulating agent) to evaluate their impact in pts assignment into risk groups. Methods: We studied adult pts, followed at our Department from August 2011 to December 2012, with advanced cancers (breast, NSCLC, colorectal, pancreatic/gastric, urogenital, LNH, Hodgkin's disease, HD, and MM), receiving a first or second line standard CT. We stratified pts into three risk groups (score 0= low; score 1-2=intermediate; score 3-4-5=high) considering both the Khorana scoring system and its implementation. Results: We analyzed 169 pts (103F/66M, median age 62.3, range 35-80 yrs), pt population included: 38 breast, 32 colorectal, 31 LNH, HD and MM, 27 urogenital, 22 NSCLC and 19 pancreatic/gastric. With the Khorana score 49 pts were assigned to the low risk, 87 pts to the intermediate risk (57 with score=1, 28 with score=2), 16 pts (9.4%) to the high risk group (9 with score=3, 4 with score=4, 3 with score=5). When we considered 11 parameters 37 pts (21.8%) were assigned to the high risk group. Conclusions: A more comprehensive quantification of VTE risk, also considering new independent factors, is mandatory for a correct decision making of an antithrombotic-prophylactic approach.


Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1215-1215
Author(s):  
Theresa Hahn ◽  
Philip L. McCarthy ◽  
Jeanette Carreras ◽  
Mei-Jie Zhang ◽  
Hillard M. Lazarus ◽  
...  

Abstract Abstract 1215 Poster Board I-237 AHCT is standard therapy for relapsed or refractory Hodgkin Lymphoma (HL). Prognostic risk score models for HL patients receiving AHCT aim to predict post transplant outcomes based on factors measured at the time of AHCT. We performed a comparison of 3 such models from Dana-Farber Cancer Institute (DFCI), Roswell Park Cancer Institute (RPCI) and University of Minnesota (UMinn) in an independent multicenter dataset of 597 relapsed or refractory HL patients receiving AHCT from 1996-2004, reported to the CIBMTR by 150 centers. Patient characteristics at diagnosis: 60% male, 52% stage III-IV, 59% B symptoms, 33% extranodal disease. Patient characteristics at AHCT: median (range) age 32 (7-74) years; 73% KPS≥90; 19% with extranodal disease; 39% had ≥3 prior chemotherapy regimens; 18% had resistant disease; median (range) time from diagnosis to AHCT 22 (3-238) months. High dose therapy regimens were primarily BEAM (72%) or CBV (12%) with 91% receiving peripheral blood stem cells. Progression free (PFS) and overall survival (OS) estimates at 3 years were 59% and 72%, respectively. The 3 prognostic models each measured 3 prognostic variables at AHCT that were combined into a prognostic score and assigned to a risk group (low, intermediate, high). The DFCI model risk factors were: chemo-resistant disease, KPS<90, ≥1 extranodal site; with corresponding risk groups low (0 factors), intermediate, (1 factor) and high (2-3 factors). The RPCI model risk factors were: chemo-resistant disease, KPS<90, ≥3 prior regimens with risk groups low (0-1 factor) and high (2-3 factors). The UMinn model risk factors were: chemo-resistant disease, B symptoms, not in CR at BMT with risk groups low (0-1 factor), intermediate (2 factors) and high (3 factors). Only 1 factor (chemo- resistant disease) was included in all 3 models. We quantified the predictive capabilities of the models using Brier score (B) and R2 for each model. Brier score as a function of time is a measure of the accuracy of the model calculated as the average deviation between the predicted probabilities and the actual outcome. R2 measures goodness of fit based on the observed vs. predicted difference in the regression model. A smaller Brier score and a larger R2 indicate better predictive performance. The models are compared in Table 1 with regards to prediction of 36 month PFS: Table 1 DFCI Model RPCI model UMinn model Brier Score 0.2344 0.2360 0.2394 R2 3.24% 2.57% 1.17% The high risk group PFS (Figure 1) was similar for the DFCI and RPCI models but the DFCI model separated a low and intermediate risk group which were not significantly different from each other. The UMinn model high risk group had a higher PFS than either of the other 2 models' high risk group and the intermediate group in this model was not significantly different from the high risk group. The relative incremental change in R2 was 26% higher for the DFCI than the RPCI model and 120% higher for the RPCI than the UMinn model. From the B and R2 values, the DFCI model had marginal superiority over RPCI model while both performed better than the UMinn model. Newer prognostic systems incorporating other prognostic variables are needed to distinguish lower and intermediate risk patients. Figure 1 Figure 1. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter Piko ◽  
Zsigmond Kosa ◽  
Janos Sandor ◽  
Roza Adany

AbstractCardiovascular diseases (CVDs) are the number one cause of death globally, and the early identification of high risk is crucial to prevent the disease and to reduce healthcare costs. Short life expectancy and increased mortality among the Roma are generally accepted (although not indeed proven by mortality analyses) which can be partially explained by the high prevalence of cardiovascular risk factors (CVRF) among them. This study aims to elaborate on the prevalence of the most important CVD risk factors, assess the estimation of a 10-year risk of development of fatal and nonfatal CVDs based on the most used risk assessment scoring models, and to compare the Hungarian general (HG) and Roma (HR) populations. In 2018 a complex health survey was accomplished on the HG (n = 380) and HR (n = 347) populations. The prevalence of CVRS was defined and 10-year cardiovascular risk was estimated for both study populations using the following systems: Framingham Risk Score for hard coronary heart disease (FRSCHD) and for cardiovascular disease (FRSCVD), Systematic COronary Risk Evaluation (SCORE), ACC/AHA Pooled Cohort Equations (PCE) and Revised Pooled Cohort Equations (RPCE). After the risk scores had been calculated, the populations were divided into risk categories and all subjects were classified. For all CVD risk estimation scores, the average of the estimated risk was higher among Roma compared to the HG independently of the gender. The proportion of high-risk group in the Hungarian Roma males population was on average 1.5–3 times higher than in the general one. Among Roma females, the average risk value was higher than in the HG one. The proportion of high-risk group in the Hungarian Roma females population was on average 2–3 times higher compared to the distribution of females in the general population. Our results show that both genders in the Hungarian Roma population have a significantly higher risk for a 10-year development of cardiovascular diseases and dying from them compared to the HG one. Therefore, cardiovascular interventions should be focusing not only on reducing smoking among Roma but on improving health literacy and service provision regarding prevention, early recognition, and treatment of lipid disorders and diabetes among them.


2010 ◽  
Vol 30 (1) ◽  
pp. 58-73 ◽  
Author(s):  
Paul T. Seed ◽  
Lucy C. Chappell ◽  
Michael A. Black ◽  
Katrina K. Poppe ◽  
Yuan-Chun Hwang ◽  
...  

2019 ◽  
Author(s):  
Junxiong Yin ◽  
Chuanyong Yu ◽  
Hongxing Liu ◽  
Mingyang Du ◽  
Feng Sun ◽  
...  

Abstract Objective: To establish a predictive model of carotid vulnerable plaque through systematic screening of high-risk population for stroke.Patients and methods: All community residents who participated in the screening of stroke high-risk population by the China National Stroke Screening and Prevention Project (CNSSPP). A total of 19 risk factors were analyzed. Individuals were randomly divided into Derivation Set group and Validation Set group. According to carotid ultrasonography, the derivation set group patients were divided into instability plaque group and non-instability plaque group. Univariate and multivariable logistic regression were taken for risk factors. A predictive model scoring system were established by the coefficient. The AUC value of both derivation and validation set group were used to verify the effectiveness of the model.Results: A total of 2841 high-risk stroke patients were enrolled in this study, 266 (9.4%) patients were found instability plaque. According to the results of Doppler ultrasound, Derivation Set group were divided into instability plaque group (174 cases) and non-instability plaque group (1720 cases). The independent risk factors for carotid instability plaque were: male (OR 1.966, 95%CI 1.406-2.749),older age (50-59, OR 6.012, 95%CI 1.410-25.629; 60-69, OR 13.915, 95%CI 3.381-57.267;≥70, OR 31.267, 95%CI 7.472-130.83) , married(OR 1.780, 95%CI 1.186-2.672),LDL-c(OR 2.015, 95%CI 1.443-2.814), and HDL-C(OR 2.130, 95%CI 1.360-3.338). A predictive scoring system was created, range 0-10. The cut-off value of prediction model score is 6.5. The AUC value of derivation and validation set group were 0.738 and 0.737.Conclusion:For a high risk group of stroke individual, We provide a model that could distinguishing those who have a high probability of having carotid instability plaque. When resident’s predictive model score exceeds 6.5, the incidence of carotid instability plaque is high, carotid artery Doppler ultrasound would be checked immediately. This model can be helpful in the primary prevention of stroke.


2020 ◽  
Author(s):  
Jihang Luo ◽  
Puyu Liu ◽  
Leibo Wang ◽  
Yi Huang ◽  
Yuanyan Wang ◽  
...  

Abstract Background Colon cancer is the most common type of gastrointestinal cancer and has high morbidity and mortality. Colon adenocarcinoma(COAD) is the main pathological type of colon cancer. There is a lot of evidence describing the correlation between the prognosis of COAD and the immune system. The objective of the current study was the development of a robust prognostic immune-related gene pairs (IRGPs) model for estimating overall survival of COAD. Methods The gene expression profiles and clinical information of patients with colon adenocarcinoma come from TCGA and GEO databases and are divided into training and validation cohorts. Immune genes were selected which show significantly association with prognosis. Results Among 1647 immune genes, a 17 IRGPs model was built which was significantly associated with OS in the training cohort. In the training and validation data set, the IRGPs model divided patients into high-risk groups and low-risk groups, and the prognosis of the high-risk group was significantly worse( P <0.001). Univariate and multivariate Cox proportional hazard analysis confirmed the feasibility of this model. Functional analysis confirmed that multiple tumor progression and stem cell growth-related pathways in high-risk groups were up-regulated. T cells regulatory and Macrophage M0 were significantly highly expressed in the high-risk group. Conclusion We successfully constructed an IRGPs model that can predict the prognosis of COAD, which provides new insights into the treatment strategy of COAD.


2020 ◽  
Vol 2 (1) ◽  
pp. 1-10
Author(s):  
Murman Kantaria ◽  
Murman Kantaria ◽  
Pavle Machavariani ◽  
Giorgi Ormotsadze ◽  
Giorgi Ormotsadze ◽  
...  

Objective Search of pathogenetic mechanisms and risk factors of atherosclerosis in the employees of the cleaning service in Tbilisi. Materials and Methods As a result of a preliminary survey and examination of 200 employes of Tbilisi cleaning service aged 25-45 years (2014-2016), 22 patients with angina, hypercholesterolemia, intimae-media thickness > 0.65 mm, were selected into I group, and 23 individuals without these disorders into II group. In the blood plasma of the selected patients the intensity of oxidative metabolism parameters, TAA and MDA were determined. The variance and correlation analysis (АNOVA) was used for conducting the comparative analysis of the levels of studied parameters. Results In the combined group (I+II) there are several reliable correlations between the Age -TCol, Age-MDA, BMI-Tg, BMI-MDA, LDLChol-HDLChol, LDLChol–TChol, HDLChol-TChol, LDLChol-MDA, LDLChol-TAA. no correlation between these parameters in individual groups (I and II) was found. That indicates that we have an imaginary correlation related to the large intergroup difference between the average values of the group indicators, that is the values of various indicators change during the development of the pathological process, but there is no causal relationship between these alterations. The reliable TAA-MDA correlation in the combined group (I+II) is related to the high anticorrelation between these parameters and the significantly higher average value of TAA in the low-risk group (II) in comparison to the high-risk group (I). Conclusion The results analysis indicates both the diagnostic value of redox status indicators and their leading role in the atherogenesis processes. In populations with a high risk of atherosclerosis, monitoring of serum TAA is recommended.


2021 ◽  
Vol 105 (1-3) ◽  
pp. 559-563
Author(s):  
Seungmin Lee ◽  
Kwang Yeol Paik

Background The aim of this study is to examine whether pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ) is the better reconstructive method to reduce postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) according to the fistula risk. Methods An institutional database was reviewed for patients undergoing PD between January 2008 and August 2019. A total of 159 patients were stratified into 4 groups according to the Clinical Risk Score-Pancreatic Fistula. POPF according to 4 risk groups was compared between PJ and PG. Results Of the 159 patients, 82 underwent PG (51.6%) and 77 underwent PJ (48.4%) reconstruction. POPF rate was 17.1% (n = 14) in the PG group and 12.9% (n = 10) in the PJ group (P = 0.51). POPF rates were not different in intermediate, low, and negligible risks between 2 reconstructive methods. In the high-risk group (n = 47), there were 4 POPFs (22.2%) in PJ group and 9 (31.0%) in the PG group, respectively (P = 0.74). Conclusion In PD, there was no superior method of reconstruction with regard to POPF, even in high-risk glands.


2020 ◽  
Vol 41 (21) ◽  
pp. 1988-1999 ◽  
Author(s):  
Neal A Chatterjee ◽  
Jani T Tikkanen ◽  
Gopi K Panicker ◽  
Dhiraj Narula ◽  
Daniel C Lee ◽  
...  

Abstract Aims To determine whether the combination of standard electrocardiographic (ECG) markers reflecting domains of arrhythmic risk improves sudden and/or arrhythmic death (SAD) risk stratification in patients with coronary heart disease (CHD). Methods and results The association between ECG markers and SAD was examined in a derivation cohort (PREDETERMINE; N = 5462) with adjustment for clinical risk factors, left ventricular ejection fraction (LVEF), and competing risk. Competing outcome models assessed the differential association of ECG markers with SAD and competing mortality. The predictive value of a derived ECG score was then validated (ARTEMIS; N = 1900). In the derivation cohort, the 5-year cumulative incidence of SAD was 1.5% [95% confidence interval (CI) 1.1–1.9] and 6.2% (95% CI 4.5–8.3) in those with a low- and high-risk ECG score, respectively (P for Δ &lt; 0.001). A high-risk ECG score was more strongly associated with SAD than non-SAD mortality (adjusted hazard ratios = 2.87 vs. 1.38 respectively; P for Δ = 0.003) and the proportion of deaths due to SAD was greater in the high vs. low risk groups (24.9% vs. 16.5%, P for Δ = 0.03). Similar findings were observed in the validation cohort. The addition of ECG markers to a clinical risk factor model inclusive of LVEF improved indices of discrimination and reclassification in both derivation and validation cohorts, including correct reclassification of 28% of patients in the validation cohort [net reclassification improvement 28 (7–49%), P = 0.009]. Conclusion For patients with CHD, an externally validated ECG score enriched for both absolute and proportional SAD risk and significantly improved risk stratification compared to standard clinical risk factors including LVEF. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT01114269. ClinicalTrials.gov ID NCT01114269.


2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Morten Lindhardt ◽  
Nete Tofte ◽  
Gemma Currie ◽  
Marie Frimodt-Moeller ◽  
Heiko Von der Leyen ◽  
...  

Abstract Background and Aims In the PRIORITY study, it was recently demonstrated that the urinary peptidome-based classifier CKD273 was associated with increased risk for progression to microalbuminuria. As a prespecified secondary outcome, we aim to evaluate the classifier CKD273 as a determinant of relative reductions in eGFR (CKD-EPI) of 30% and 40% from baseline, at one timepoint without requirements of confirmation. Method The ‘Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial’ (PRIORITY) is the first prospective observational study to evaluate the early detection of diabetic kidney disease in subjects with type 2 diabetes (T2D) and normoalbuminuria using the CKD273 classifier. Setting 1775 subjects from 15 European sites with a mean follow-up time of 2.6 years (minimum of 7 days and a maximum of 4.3 years). Patients Subjects with T2D, normoalbuminuria and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2. Participants were stratified into high- or low-risk groups based on their CKD273 score in a urine sample at screening (high-risk defined as score &gt; 0.154). Results In total, 12 % (n = 216) of the subjects had a high-risk proteomic pattern. Mean (SD) baseline eGFR was 88 (15) ml/min/1.73m2 in the low-risk group and 81 (17) ml/min/1.73m2 in the high-risk group (p &lt; 0.01). Baseline median (interquartile range) urinary albumin to creatinine ratio (UACR) was 5 (3-8) mg/g and 7 (4-12) mg/g in the low-risk and high-risk groups, respectively (p &lt; 0.01). A 30 % reduction in eGFR from baseline was seen in 42 (19.4 %) subjects in the high-risk group as compared to 62 (3.9 %) in the low-risk group (p &lt; 0.0001). In an unadjusted Cox-model the hazard ratio (HR) for the high-risk group was 5.7, 95 % confidence interval (CI) (3.9 to 8.5; p&lt;0.0001). After adjustment for baseline eGFR and UACR, the HR was 5.2, 95 % CI (3.4 to 7.8; p&lt;0.0001). A 40 % reduction in eGFR was seen in 15 (6.9 %) subjects in the high-risk group whereas 22 (1.4 %) in the low-risk group developed this endpoint (p&lt;0.0001). In an unadjusted Cox-model the HR for the high-risk group was 5.0, 95 % CI (2.6 to 9.6; p&lt;0.0001). After adjustment for baseline eGFR and UACR, the HR was 4.8, 95 % CI (2.4 to 9.7; p&lt;0.0001). Conclusion In normoalbuminuric subjects with T2D, the urinary proteomic classifier CKD273 predicts renal function decline of 30 % and 40 %, independent of baseline eGFR and albuminuria.


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