scholarly journals A Polygenic DNA Damage Repair Pharmacogenomics (DDR_PGx8) Score Predicts GO Response in AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3456-3456
Author(s):  
Vivek M. Shastri ◽  
Lata Chauhan ◽  
Todd A. Alonzo ◽  
Yi-Cheng Wang ◽  
Richard Aplenc ◽  
...  

Abstract Gemtuzumab Ozogamicin (GO) is a CD33-directed antibody conjugated to calicheamicin used in AML immunotherapy. Children's Oncology Group led pediatric AML phase II trial COG-AAML03P1 (NCT00070174) established that GO could be safely added to the standard chemotherapy regimen consisting of ara-C, daunorubicin and etoposide (ADE+GO) and improved outcome(Cooper et al., 2012). Subsequent COG-AAML0531 phase III trial (NCT00372593) randomized patients to receive either standard chemotherapy alone (ADE) or with addition of two doses of GO (ADE+GO) and showed that addition of GO improved outcome in newly diagnosed AML patients (Gamis et al., 2014). Our group previously established that CD33 genetic variation impacts GO response in AML patients (Lamba et al., 2017). Given that the antileukemic effect of GO is primarily driven by calicheamicin induced DNA damage, in this study we investigated pharmacogenomic impact of SNPs in DNA damage response (DDR) pathway genes on GO treatment response. We genotyped 132 SNPs in 42 genes involved in DNA damage repair pathway in DNA samples from 470 patients treated with standard chemotherapy in AAML0531 trial (ADE arm) and 755 patients treated with addition of GO to standard therapy in AAML03P1 and AAAML0531 trials (ADE+GO arm). Univariate analysis to test for association between OS, EFS, DFS and RR after induction 1 in both ADE+GO and ADE arms identified 20 SNPs in 16 genes that were significantly associated with at least one of the clinical endpoints tested in the only ADE+GO arm but not in ADE arm of the trials. We tested these 20 SNPs in all possible combinations with a maximum of 3 SNP/model using multivariable Cox proportional hazard models for association with EFS and OS in patients treated with ADE+GO. Drastically increased number of models arising from higher SNP combination numbers was a computational challenge thus we restricted our analysis to a maximum of 3 SNP combinations. We performed 1000 permutation tests per model to determine the likelihood of obtaining them falsely. Models were ordered according to their Bayesian Information Criterion (BIC) and weight in favor of each model. Those withleast BIC and a 1000 permutation p≤0.05 were selected for development of DDR pharmacogenomics score. DDR_PGx8 score was defined by adding the genotype scores of 8 SNPs in 7 genes (AKT1, ATR, DDB2, PARP1, PI3KCA, PTEN and RAD51) accounting for mode of inheritance (additive, dominant or recessive) and direction of their association with outcome (positive for beneficial and negative for detrimental association) Fig 1A shows overall study design. The DDR_PGx8 score ranged from -5 to 3 in patients treated with ADE+GO (n=755) or ADE alone (N=470). Based on the distribution, the scores were stratified into high (score ≥0, n=212 in ADE group and n=357 in ADE+GO group) and low score (score <0, n=241 in ADE group and n=329 in ADE+GO group) groups. The distribution of DDR_PGx8 score groups did not differ by risk groups or MRD1 status. However, it differed significantly within race with 81.81% (108/132) of black or African American patients compared to 43.75% (364/832) of white patients in the low DDR_PGx8 score group. Patients with low-DDR-PGx8 score had significantly worse EFS (HR=1.52, 95%CI (1.22-1.90), p<0.001; Fig 1B), OS (HR=1.62, 95%CI(1.24-2.11), p<0.001), DFS (HR=1.88, 95%CI(1.42-2.50), p<0.00001;), and higher RR1 (HR=1.89, 95%CI(1.40-2.40), p<0.00001) compared to high-DDR-PGx8 score patients when treated with GO (ADE+GO cohort). This impact of DDR_PGx8 was not observed in patients treated with standard chemotherapy alone (ADE arm), with no difference between low and high DDR_PGx8 score groups in EFS (Fig 1B), OS, DFS and RR (all p>0.28). In multivariable Cox proportional hazard models for DDR-PGx8 score groups, initial risk group assignment, WBC at diagnosis and age, low-DDR-PGx8 score remained a significant and independent predictor of inferior EFS (HR=1.6, 95%CI=1.21-2.02, p<0.001; Fig 1C) and OS (HR=1.6, 95%CI=1.17-2.22, p=0.003) in ADE+GO arm but not in ADE arm. We establish a DNA damage repair response-based pharmacogenomics score predicting outcome in patients treated with addition of GO to standard chemotherapy. The score was not predictive of outcome in patients treated with standard chemotherapy alone implying its impact is GO-specific. Our results in conjunction with existing CD33 SNPs provide a rationale for use of pharmacogenomics in personalizing GO treatment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

2021 ◽  
Vol 20 ◽  
pp. 153303382110049
Author(s):  
Tao Ran ◽  
ZhiJi Chen ◽  
LiWen Zhao ◽  
Wei Ran ◽  
JinYu Fan ◽  
...  

Background and Objective: Gastric cancer (GC) is a common tumor malignancy with high incidence and poor prognosis. Laminin is an indispensable component of basement membrane and extracellular matrix, which is responsible for bridging the internal and external environment of cells and transmitting signals. This study mainly explored the association of the LAMB1 expression with clinicopathological characteristics and prognosis in gastric cancer. Methods: The expression data and clinical information of gastric cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG). And we analyzed the relationship between LAMB1 expression and clinical characteristics through R. CIBERSORTx was used to calculate the absolute score of immune cells in gastric tumor tissues. Then COX proportional hazard models and Kaplan-Meier curves were performed to evaluate the role of LAMB1 and its influence on prognosis in gastric cancer patients. Finally, GO and KEGG analysis were applied for LAMB1-related genes in gastric cancer, and PPI network was constructed in Cytoscape software. Results: In the TCGA cohort, patients with gastric cancer frequently generated LAMB1 gene copy number variation, but had little effect on mRNA expression. Both in the TCGA and ACRG cohorts, the mRNA expression of LAMB1 in gastric cancer tissues was higher than it in normal tissues. All patients were divided into high expression group and low expression group according to the median expression level of LAMB1. The elevated expression group obviously had more advanced cases and higher infiltration levels of M2 macrophages. COX proportional hazard models and Kaplan-Meier curves revealed that patients with enhanced expression of LAMB1 have a worse prognosis. GO/KEGG analysis showed that LAMB1-related genes were enriched in PI3K-Akt signaling pathway, focal adhesion, ECM-receptor interaction, etc. Conclusions: The high expression of LAMB1 in gastric cancer is related to the poor prognosis of patients, and it may be related to microenvironmental changes in tumors.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Hirokazu Honda ◽  
Miho Kimachi ◽  
Noriaki Kurita ◽  
Nobuhiko Joki ◽  
Masaomi Nangaku

Abstract Recent studies have reported that high mean corpuscular volume (MCV) might be associated with mortality in patients with advanced chronic kidney disease (CKD). However, the question of whether a high MCV confers a risk for mortality in Japanese patients remains unclear. We conducted a longitudinal analysis of a cohort of 8571 patients using data derived from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS) phases 1 to 5. Associations of all-cause mortality, vascular events, and hospitalization due to infection with baseline MCV were examined via Cox proportional hazard models. Non-linear relationships between MCV and these outcomes were examined using restricted cubic spline analyses. Associations between time-varying MCV and these outcomes were also examined as sensitivity analyses. Cox proportional hazard models showed a significant association of low MCV (< 90 fL), but not for high MCV (102 < fL), with a higher incidence of all-cause mortality and hospitalization due to infection compared with 94 ≤ MCV < 98 fL (reference). Cubic spline analysis indicated a graphically U-shaped association between baseline MCV and all-cause mortality (p for non-linearity p < 0.001). In conclusion, a low rather than high MCV might be associated with increased risk for all-cause mortality and hospitalization due to infection among Japanese patients on hemodialysis.


2019 ◽  
Vol 8 (9) ◽  
pp. 1273-1281 ◽  
Author(s):  
Dong Cen ◽  
Hui Liu ◽  
Zhe Wan ◽  
Zhongjie Lin ◽  
Yanting Wang ◽  
...  

Purpose Gallbladder neuroendocrine neoplasm (GB-NEN) is a relatively rare neoplasm, accounting for 0.5% of all neuroendocrine neoplasm cases and 2.1% of gallbladder cancers. Because of the limited understanding of GB-NEN, the aim of this study was to explore the clinicopathology and survival of GB-NEN patients selected from the Surveillance, Epidemiology, and End Results (SEER) database. Methods A total of 248 GB-NEN patients from the SEER database diagnosed between 2004 and 2015 were included. Kaplan–Meier curves were used to examine the survival time. Multivariate Cox proportional hazard models were used to estimate hazard ratios with 95% confidence intervals to analyze the impact of factors on overall survival and cancer-specific survival. Results The majority of the GB-NEN patients were women (67.3%), white (77%), and married (61.7%). Most tumors were <2 cm in size (31.0%), G3 stage (25.8%), and distant SEER stage (41.1%). 62.9% and 64.5% of cases showed an absence of lymph node metastasis and tumor metastasis, respectively. Patients who received gallbladder surgery had significantly better survival outcomes (P < 0.001). However, patients who received both gallbladder surgery and lymph node resection did not have better survival outcome compared with patients who received only gallbladder surgery. Multivariate Cox proportional hazard models indicated that older age, unmarried status, large tumor size (>5 cm), and distant SEER stage were significant independent predictors for decreased overall survival time and cancer-specific survival time (P < 0.05). Conclusion Age, marital status, tumor size, and SEER stage were predictors for the survival of GB-NEN patients. Gallbladder surgery was associated with better survival, but the combination of gallbladder surgery and lymphadenectomy had no effect on survival outcomes.


2019 ◽  
Author(s):  
Xiaoling Ye ◽  
Jeroen P Kooman ◽  
Frank M van der Sande ◽  
Jochen G Raimann ◽  
Len A Usvyat ◽  
...  

Abstract Background Evidence indicates that the inverse relationships between phosphate levels and mortality maybe modified by age. Furthermore, malnutrition and inflammation could strengthen the risk associated with phosphate abnormalities. This study aimed to assess the associations between phosphate levels and mortality while accounting for the interactions with age and parameters associated with malnutrition and inflammation in hemodialysis (HD) patients. Methods Adult HD patients (n = 245 853) treated in Fresenius Medical Care North America clinics from January 2010 to October 2018 were enrolled. Baseline was defined as Months 4–6 on dialysis, with the subsequent 12 months as the follow-up period. Univariate and multivariate Cox proportional hazard models with spline terms were applied to study the nonlinear relationships between serum phosphate levels and mortality. The interactions of phosphate levels with albumin, creatinine, normalized protein catabolic rate (nPCR) and neutrophil–lymphocyte ratio (NLR) were assessed with smoothing spline analysis of variance Cox proportional hazard models. Results Older patients tended to have lower levels of serum phosphate, albumin, creatinine and nPCR. Additionally, both low (<4.0 mg/dL) and high (>5.5 mg/dL) phosphate levels were associated with higher risk of mortality across all age strata. The U-shaped relationships between phosphate levels and outcome persisted even for patients with low or high levels of serum albumin, creatinine, nPCR and NLR, respectively. Conclusion The consistent U-shaped relationships between serum phosphate and mortality across age strata and levels of inflammatory and nutritional status should prompt the search for underlying causes and potentially nutritional intervention in clinical practice.


2021 ◽  
pp. neurintsurg-2020-016985
Author(s):  
Jin Liu ◽  
Jing Tang ◽  
Zuchao Gu ◽  
Yu Zhang ◽  
Shenghui Yu ◽  
...  

BackgroundIt is unclear whether the sandwich vertebra, is at higher risk of new symptomatic fractures (NSFs), and whether prophylactic augmentation might benefit patients with sandwich vertebrae.ObjectiveTo compare fracture-free probabilities of sandwich, ordinary-adjacent, and non-adjacent vertebrae, and identify predictors of NSFs.MethodsData were retrospectively analyzed for patients who had undergone vertebral augmentation resulting in sandwich vertebrae. NSF rates were determined and predictors were identified using Cox proportional hazard models.ResultsThe analysis included 1408 untreated vertebrae (147 sandwich, 307 ordinary-adjacent, 954 non-adjacent vertebrae) in 125 patients. NSFs involved 19 sandwich, 19 ordinary-adjacent, and 16 non-adjacent vertebrae. The NSF rate was significantly higher in the patients with sandwich vertebrae (27.2%) than among all patients (14.8%). At the vertebra-specific level, the NSFs rate was 12.9% for sandwich vertebrae, significantly higher than 6.2% for ordinary-adjacent and 1.7% for non-adjacent vertebrae. The corresponding fracture-free probabilities of sandwich, ordinary-adjacent, and non-adjacent vertebrae were 0.89, 0.95, and 0.99 at 1 year, and 0.85, 0.92, and 0.98 at 5 years (p<0.05). Cox modeling identified the following as predictors for occurrence of an NSF in a given vertebra: vertebra location, type of vertebrae, number of augmented vertebrae, and puncture method.ConclusionSandwich vertebrae are at higher risk of NSFs than ordinary-adjacent and non-adjacent vertebrae, and several NSF risk factors were identified. Since 85% of sandwich vertebrae are fracture-free for 5 years and NSF risk increases with the number of augmented vertebrae, prophylactic augmentation of every sandwich vertebra may be unnecessary.


Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Richard A Takx ◽  
Amparo L Figueroa ◽  
Megan H MacNabb ◽  
Amr Abdelbaky ◽  
Zachary R Lavender ◽  
...  

Introduction: While the relationship between obesity and cardiovascular disease (CVD) is well-established, mechanisms underlying this relationship are not well elucidated. Hypothesis: Our hypothesis is that visceral adipose tissue (VAT) volume, aortic inflammation and the risk of subsequent cardiovascular events are linked together. Methods: Individuals who underwent 18F-FDG PET/CT imaging were included. VAT volume, subcutaneous adipose tissue (SAT) volume and aortic FDG uptake were measured while blinded to clinical data. Cardiovascular events were adjudicated by independent cardiologists. Thereafter, the relationship between VAT volume and aortic FDG activity and cardiovascular events was evaluated using Cox proportional hazard models. Results: The final analysis included 415 patients with a median age of 55 (P25-P75: 45-65) years and a median BMI of 26.4 (P25- P75: 23.4-30.9) kg/m2. VAT and SAT volume were significantly higher in obese individuals. 32 subjects experienced cardiovascular event during a median follow-up of 4 years. Cox proportional hazard models showed that VAT volume was a associated with cardiovascular events (hazard ratio, HR (95% CI): 1.15 (1.06-1.25, p<0.001). This remained significant after correcting for age, BMI and aortic TBR (p<0.05). SAT was not predictive of cardiovascular events. VAT volume was associated with arterial inflammation (r=0.29, p<0.001, Figure 1). The combination of high aortic inflammation and high VAT volume was associated with significant worse survival (p<0.05). Conclusions: We observed that VAT volume is a predictor of subsequent cardiovascular events. Moreover, our results indicate a link between visceral adipose tissue volume and arterial inflammation, which may explain some of VAT's association with cardiovascular events.


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