Clinical Relevance of Gastroesophageal Cancer Associated SNPs for Oncologic Outcome After Curative Surgery

Abstract Background Gastric and esophageal cancers are malignant diseases with rising importance in Western countries. To improve oncologic outcome after surgery, it is essential to understand the relevance of germline mutations. The aim of the study was to identify and distinguish clinically relevant single-nucleotide polymorphisms (SNPs). Patients and Methods In total, 190 patients with curative oncological resections of gastric and distal esophageal adenocarcinomas at Heidelberg University Hospital were eligible for this study. Outcome differences were determined for each SNP by analysis of clinical variables, survival, and mRNA expression levels. Results Significant survival differences were found on univariate analysis for usual prognostic variables (such as pTNM) and for six SNPs. On multivariate survival analysis, the SNPs rs12268840 (intron variant of MGMT, p = 0.045) and rs9972882 (intron variant of STARD3 and eQTL of PGAP3, p = 0.030) were independent and significant survival predictors along with R status and pT/pN category. Group TT of rs12268840 had the highest rate of second primary carcinoma (30.4%, p = 0.0003), lowest expression of MGMT based on cis-eQTL analysis in normal gastroesophageal tissue (p = 1.99 × 10−17), and worst oncologic outcome. Group AA of rs9972882 had the highest rate of distant metastases pM1 (42.9%, p = 0.0117), highest expression of PGAP3 (p = 1.29 × 10−15), and worst oncologic outcome. Conclusions Two intron variant SNPs of MGMT and STARD3 were identified that were significant survival predictors and may influence tumor biology. The data indicate that DNA methylation (MGMT) and malfunction of GPI anchoring (PGAP3) are distinct mechanisms that are relevant for tumor progression and relapse.

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Prognostic impact of polymorphisms of caspase genes on survival in patients with operated invasive ductal breast cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e22020 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e22020-e22020

Author(s):

H. Park ◽

J. Jung ◽

Y. Eun ◽

J. Kim ◽

Y. Chae ◽

...

Keyword(s):

Breast Cancer ◽

Histological Grade ◽

Univariate Analysis ◽

Breast Conserving Surgery ◽

Prognostic Impact ◽

Nucleotide Polymorphisms ◽

Curative Surgery ◽

Curative Intent ◽

Invasive Ductal Breast Cancer ◽

Ductal Breast Cancer

e22020 Background: Since the apoptosis induced by caspases may play a role in the prognosis of breast cancer, the present study analyzed the polymorphisms of caspase genes and their impact on the survival in patients with operated invasive ductal breast cancer. Methods: Two hundred eighty patients with breast cancer who underwent surgery with curative intent were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue, and 7 single nucleotide polymorphisms (SNPs) of 6 caspase genes were determined using a PCR-RFLP assay. Results: The median age was 49 (range, 24–82) years, and 157 (56.1%) patients were premenopause at the time of diagnosis. Thirty-six (12.9%) patients underwent breast-conserving surgery. Pathologic stages after surgery were as follows: stage I (n=86, 30.7%), stage II (n=129, 46.1%), and stage III (n=63, 22.5%). Among the target SNPs, CASP6 (rs2301717, +5095G>T) and CASP7 (rs11593766, +11G>T) were found to correlate with relapse-free survival (RFS) after curative surgery in an univariate analysis adjusted to age, stage, histological grade, and the immunohistochemical expression of estrogen receptor and HER2. Meanwhile, multivariate analysis showed that the combined GT and TT genotype of CASP6 (rs2301717) was associated with a better RFS than the GG genotype (HR=0.39; 95% CI=0.19–0.79; p=0.009). However, there was no significant association with overall survival. Conclusions: The CASP6 (rs2301717) polymorphism may be considered as a possible prognostic factor for survival in patients with operated invasive breast cancer. No significant financial relationships to disclose.

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PSV-13 Genetic parameters and quantitative trait loci for heat stress related traits in sheep

Journal of Animal Science ◽

10.1093/jas/skaa054.289 ◽

2020 ◽

Vol 98 (Supplement_3) ◽

pp. 163-164

Author(s):

Devin R Jacobs ◽

Claudia E Silvera-Rojas ◽

Jennifer M Bormann ◽

Terry A Gipson ◽

Arthur L Goetsch ◽

...

Keyword(s):

Heat Stress ◽

Quantitative Trait Loci ◽

Rectal Temperature ◽

Quantitative Trait ◽

Fixed Effects ◽

Univariate Analysis ◽

Average Daily Gain ◽

The United States ◽

Nucleotide Polymorphisms ◽

Trait Loci

Abstract Greater selection emphasis has been placed on efficiency than on fitness in livestock populations over the last several decades. Heat stress is a concern in production systems due to the negative effects on production, reproduction, and immunity. The objective of the study was to estimate variance components and identify quantitative trait loci (QTL) for heat stress related traits in sheep. A total of 125 Dorper, Katahdin, and St. Croix ewes originating from four regions of the United States were selected for the experiment. Animals were separated into four trials due to facility limitations. Data were collected for each trial over four consecutive two-week periods in an environmentally controlled facility with targeted heat load index (HLI) for daytime/nighttime of 70/70, 85/77, 90/77, and 95/81. Body weight was collected three times per week and rectal temperature was collected weekly. Black globe temperature and humidity were measured every 15 minutes. Animals were genotyped using the Illumina OvineSNP50 BeadChip. After quality control, 49,396 effective single nucleotide polymorphisms were included in the univariate analysis performed with the BLUPF90 suite of programs. Fixed effects in the models included region of origin, breed, trial, and age as a covariate. Traits analyzed included rectal temperature at 95 HLI (RT95), feed intake at 95 HLI (FI95), and average daily gain for the period for HLI between 90 and 95 (ADG). Heritabilities for RT95, FI95, and ADG were 0.35, 0.10, and 0.10, respectively. Largest effect QTL were identified on chromosomes 23, 9, and 6 for RT95, chromosomes 9, 2, and 20 for FI95, and chromosomes 6, 1, and 5 for ADG. Many of the regions identified have also been associated with weight and carcass traits in other studies, but few had obvious connections to the heat stress related response. In conclusion, results suggest selection could improve heat tolerance in sheep.

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832. Assessment of Risk Factors Associated with Wide-resistance Gram-negative Bacteria Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1021 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S457-S457

Author(s):

Henry Pablo Lopes Campos e Reis ◽

Ana Beatriz Ferreira Rodrigues ◽

Julio César Castro Silva ◽

Lia Pinheiro de Lima ◽

Talita Lima Quinaher ◽

...

Keyword(s):

Risk Factors ◽

Mechanical Ventilation ◽

Univariate Analysis ◽

Multidrug Resistant ◽

University Hospital ◽

Gram Negative Bacteria ◽

Multiresistant Pathogens ◽

Gram Negative ◽

Contact Isolation ◽

Bladder Catheter

Abstract Background Enterobacteria and multidrug-resistant non-fermenting Gram-negative bacilli present a challenge in the management of invasive infections, leading to mortality rates due to their limited therapeutic arsenal. The objective of this work was to analyze risk factors that may be associated with these infections, for a better situational mapping and assertive decision-making in a university hospital in Brazil. Methods The study was conducted between January and September 2019, with 167 patients in contact isolation at a university hospital in Brazil. Potential outcome-related variables for wide-resistance Gram-negative bacteria (BGN) infections were evaluated. Risk factors were identified from univariate statistical analysis using Fisher’s test. Results 51 (30.5%) out of 167 patients in contact isolation evolved with wide-resistance BGN infection. Risk factors in univariate analysis were age, hospital unit and previous use of invasive devices. Patients aged up to 59 years were more likely to progress to infection than those aged over 60 years (p 0.0274, OR 2.2, 95% CI 1.1-4.5). Those admitted to the oncohematology (p < 0.001, OR 32.5, Cl 9.1-116.3) and intensive care unit (p < 0.001, OR 28.0, Cl 3.5-225.9) units were more likely to develop this type of infection. The least likely were those admitted to a kidney transplant unit (p 0.0034, OR 15.33, Cl 1.8-131.0). Prior use of mechanical ventilation (p 0.0058, OR 12.2, Cl 2.0-76.1) and delayed bladder catheter (p 0.0266, OR 5.0, Cl 1.2-20.1) in patients with respiratory and urinary tract infection, respectively, were also reported as risk factors related to these infections. The gender of the patients was not significant for the study. Conclusion This study determined that variables such as age, hospitalization unit, use of mechanical ventilation and delayed bladder catheter could be considered important risk factors in triggering the infectious process by wide-resistant gram-negative bacteria. Thus, the analysis of these factors becomes a great foundation to prevent the development of multiresistant pathogens through prevention strategies, prophylaxis management and more targeted empirical therapies. Disclosures All Authors: No reported disclosures

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Identification of genetic markers associated with ibrutinib-related cardiovascular toxicity.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7526 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7526-7526

Author(s):

Issam Hamadeh ◽

Ryan Jacobs ◽

Bei Hu ◽

Tamara Kay Moyo ◽

Amy Soni ◽

...

Keyword(s):

Data Extraction ◽

Genetic Risk Score ◽

Univariate Analysis ◽

Fold Increase ◽

Lymphocytic Leukemia ◽

Nucleotide Polymorphisms ◽

Clinical Tool ◽

Specimen Collection ◽

Cardiovascular Side Effects ◽

Buccal Swabs

7526 Background: Cardiovascular side effects (CVSEs: atrial fibrillation, hypertension, etc.) are common in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib and often lead to dose reductions or discontinuation. However, the etiology of ibrutinib related CVSEs has not been elucidated. This study sought to interrogate the association between ibrutinib related CVSEs and polymorphisms in genes of the Bruton Tyrosine Kinase (BTK) signaling pathway (identified through Ingenuity Pathway Analysis) Methods: Newly diagnosed and relapsed patients with CLL who underwent treatment with ibrutinib between December 2019 and November 2020 at Levine Cancer Institute were identified. Buccal swabs were collected through an IRB approved specimen collection protocol. Data extraction included: demographics, CLL stage, cytogenetics, previous treatments, ibrutinib start dates and dose, drug related SEs, and other medications. DNA isolated from buccal swabs was genotyped for 40 single nucleotide polymorphisms (SNPs) in GATA4, SGK1, KCNQ1, KCNA4, NPPA and SCN5A genes using a custom NGS panel. Logistic regression analysis evaluated the association between SNPs and CVSEs. Results: In 50 evaluable patients, the median age was 71 years (range:48-90) and 50% received frontline ibrutinib monotherapy. CVSEs occurred in 20% of patients (n=10). In univariate analysis, 4 SNPs in 3 genes were significantly associated with CVSEs (Table). Because the genes were in the same pathway, a genetic risk score was developed which indicated that patients with at least 2 SNPs had a 12-fold increase in risk of CVSEs (Table). Conclusions: Our findings provide insights into the genetic determinants of ibrutinib related CVSEs. If replicated in a larger study, this will facilitate utility of pharmacogenetic testing (for GATA4, KCNQ1 and KCNA5 polymorphisms ) as a clinical tool to individualize ibrutinib treatment.[Table: see text]

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The Effect of the Change in Lymph Flow Following Gastrectomy for Initial Disease on the Prognosis of Remnant Gastric Cancer

10.21203/rs.3.rs-941649/v1 ◽

2021 ◽

Author(s):

Yoshihiko Kakiuchi ◽

Satoru Kikuchi ◽

Shinji Kuroda ◽

Masahiko Nishizaki ◽

Shunsuke Kagawa ◽

...

Keyword(s):

Gastric Cancer ◽

Lymph Node ◽

Poor Prognosis ◽

Malignant Disease ◽

Univariate Analysis ◽

Lymph Flow ◽

University Hospital ◽

Gastric Disease ◽

Remnant Gastric Cancer ◽

Initial Surgery

Abstract Background: Remnant gastric cancer (RGC) has been increasing for various reasons such as longer life span, medical progress, and others. It generally has a poor prognosis, and its mechanism of occurrence is unknown. The purpose of this study was to evaluate the clinicopathological features of and clarify the prognostic factors of RGC.Methods: Between January 2002 and January 2017, 39 patients with RGC following distal gastrectomy underwent curative surgical resection at the Okayama University Hospital; their medical records and immunohistochemically stained extracted specimens were used for retrospective analysis. Results: On univariate analysis, initial gastric disease, pathological lymph node metastasis, and pathological stage were the significant factors associated with a poor overall survival (OS) (p=0.0139, 0.0061, and 0.0158, respectively). Multivariate analysis of these 3 factors showed that only initial gastric disease caused by malignant disease was an independent factor associated with a poor prognosis (p=0.0141, odds ratio [OR]:4.151, 95% confidence interval [CI]:1.333-12.93). In addition, the presence of a left gastric artery (LGA), and tumor-infiltrating CD8+ T cell expression were higher in the benign disease group than in the malignant group (p<0.0001 and p=0.0485, respectively).Conclusion: The lymph flow change caused by lymph node dissection for malignant disease in initial surgery might have an effect on the suppression of tumor immunity and the poor prognosis of RGC.

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Abstract 15318: Association of Single-Nucleotide Polymorphisms with Left Atrial Scar in Patients with Atrial Fibrillation

Circulation ◽

10.1161/circ.130.suppl_2.15318 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Sanghamitra Mohanty ◽

Amelia W Hall ◽

Prasant Mohanty ◽

Chintan Trivedi ◽

Luigi Di Biase ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Left Atrial ◽

Transforming Growth Factor ◽

Univariate Analysis ◽

Scar Formation ◽

Taqman Assay ◽

Inverse Association ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Caveolin 1

Introduction: Earlier studies have demonstrated that some AF patients develop spontaneous atrial scarring that leads to genesis and perpetuation of the arrhythmia. However, it is still unclear why it happens in some and not in others. Therefore, we hypothesized that the atrial scar phenotype is associated with certain specific genetic variants and examined the relationship between AF-related single-nucleotide polymorphisms (SNP) and left atrial scar. Methods: Four hundred AF patients (67% male, 62±12 year, left atrial size 45.3±7 mm, 64% non-paroxysmal) undergoing catheter ablation were prospectively enrolled at our center. DNA extraction and genotyping for 16 AF-associated SNPS identified by GWAS study were performed from the collected blood samples using Qiagen QiaAMP 96 well blood kit and TaqMan assay respectively. Three hundred seventy-two DNA samples were available for genotyping. The Hardy-Weinberg equilibrium was assessed using Chi-square analyses. Multivariable logistic model was utilized to identify predictors of LA scar after adjusting for age, gender, LA size, hypertension and diabetes mellitus and odds ratio (OR) and 95% confidence intervals were computed. Results: Of all 16 SNPs, rs3807989 showed a strong inverse association with LA scar at univariate analysis (0.54 [0.348-0.89] p= 0.014) in the overall population. After adjustment for covariates, the association became highly significant indicating a 50% reduction in scar risk (OR 0.50 (0.30-0.83) p=0.007). When stratified by type of AF, rs3807989 genotype predicted a substantially stronger 69% risk-reduction in the non-PAF population (OR 0.31 (0.15-0.62) p=0.0009). Conclusion: The SNP, rs3807989 on chromosome 7p31, was demonstrated to be associated with reduced risk of left atrial scar formation in AF patients. This genetic variant is located in close proximity to the caveolin-1 gene which is known to have an anti-fibrotic role by inhibiting transforming growth factor-β1, a key mediator in the fibrosis process. Therefore, it can be postulated that by some unknown mechanism the candidate chromosomal variant potentially upregulates caveolin-1 function resulting in attenuation of fibrosis and scar formation.

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Abstract 12905: Gene Expression and Expression Quantifying Trait Loci Analysis of Left Atrium of Patients With Post-operative Atrial Fibrillation

Circulation ◽

10.1161/circ.132.suppl_3.12905 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Martin I Sigurdsson ◽

Mahyar Heydarpour ◽

Louis Saddic ◽

Tzuu-Wang Chang ◽

Stanton K Shernan ◽

...

Keyword(s):

Gene Expression ◽

Atrial Fibrillation ◽

Left Atrium ◽

High Throughput ◽

Specific Gene ◽

Eqtl Analysis ◽

Gene Variants ◽

Nucleotide Polymorphisms ◽

Novel Genes ◽

Trait Loci

Introduction: The majority of information on the genetic background of atrial fibrillation (AF) results from genomic DNA variant analysis without consideration of tissue expression. Hypothesis: Analysis of tissue-specific gene expression in left atrium (LA) can further understanding of the molecular mechanism of identified AF risk variants, and identify novel genes and gene variants associated with AF. Methods: We isolated mRNA from samples of the LA free wall taken during mitral valve surgery in 62 Caucasian individuals. Gene expression in the LA was compared between patients who did and did not have post-operative AF (poAF) using high-throughput RNA expression. Using genotypes of 1.4 million single nucleotide polymorphisms (SNP) we performed cis expression quantifying trait loci (eQTL) analysis, correlating gene expression of each gene with the genotypes of adjacent (<1Mbp) SNPs. Results: We identified 23 differentially expressed genes in the LA of patients with poAF, including three potassium channel genes (KCNA7, KCNH8 and KCNK17). The largest expression difference was in LOC645323, a long non-coding RNA. The expression of PITX2, ZFHX3 and KCNN3, previously shown to be associated with AF, did not differ between patients with and without poAF. We identified 12,476 cis eQTL relationships in the LA, several of those included genetic regions and genes previously associated with AF. We confirmed an eQTL relationship between rs3744029 genotype and the expression of MYOZ1. Furthermore we describe a novel eQTL relationship between rs6795970 genotype and the expression of the SCN10A gene. Conclusions: We have analysed the human LA expression via high-throughput RNA sequencing, and identified novel genes and gene variants likely involved in the molecular pathophysiology of AF.

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Preoperative and Intraoperative Predictors of Cardiac Adverse Events after General, Vascular, and Urological Surgery

Anesthesiology ◽

10.1097/aln.0b013e318190b6dc ◽

2009 ◽

Vol 110 (1) ◽

pp. 58-66 ◽

Cited By ~ 145

Author(s):

Sachin Kheterpal ◽

Michael O’Reilly ◽

Michael J. Englesbe ◽

Andrew L. Rosenberg ◽

Amy M. Shanks ◽

...

Keyword(s):

Myocardial Infarction ◽

Mean Arterial Pressure ◽

Adverse Events ◽

Arterial Pressure ◽

Univariate Analysis ◽

Noncardiac Surgery ◽

University Hospital ◽

Improvement Program ◽

Urological Surgery ◽

Cardiac Adverse Events

Background The authors sought to determine the incidence and risk factors for perioperative cardiac adverse events (CAEs) after noncardiac surgery using detailed preoperative and intraoperative hemodynamic data. Methods The authors conducted a prospective observational study at a single university hospital from 2002 to 2006. All American College of Surgeons-National Surgical Quality Improvement Program patients undergoing general, vascular, and urological surgery were included. The CAE outcome definition included cardiac arrest, non-ST elevation myocardial infarction, Q-wave myocardial infarction, and new clinically significant cardiac dysrhythmia within the first 30 postoperative days. Results Four years of data demonstrated that of 7,740 noncardiac operations, 83 patients (1.1%) experienced a CAE within 30 days. Nine independent predictors were identified (P < or = 0.05): age > or = 68, body mass index > or = 30, emergent surgery, previous coronary intervention or cardiac surgery, active congestive heart failure, cerebrovascular disease, hypertension, operative duration > or = 3.8 h, and the administration of 1 or more units of packed red blood cells intraoperatively. The c-statistic of this model was 0.81 +/- 0.02. Univariate analysis demonstrated that high-risk patients experiencing a CAE were more likely to experience an episode of mean arterial pressure < 50 mmHg (6% vs. 24%, P = 0.02), experience an episode of 40% decrease in mean arterial pressure (26% vs. 53%, P = 0.01), and an episode of heart rate > 100 (22% vs. 34%, P = 0.05). Conclusions In comparison with current risk stratification indices, the inclusion of intraoperative elements improves the ability to predict a perioperative CAE after noncardiac surgery.

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Frequency of dementia among elderly admitted to a Geriatrics Inpatients Sector of a Brazilian public hospital

Dementia & Neuropsychologia ◽

10.1590/1980-57642018dn12-010005 ◽

2018 ◽

Vol 12 (1) ◽

pp. 35-39 ◽

Cited By ~ 2

Author(s):

Rafael Thomazi ◽

Liciana Vaz de Arruda Silveira ◽

Paulo José Fortes Villas Boas ◽

Alessandro Ferrari Jacinto

Keyword(s):

Univariate Analysis ◽

The Elderly ◽

Sociodemographic Factors ◽

University Hospital ◽

Chi Square ◽

Diagnosis Of Dementia ◽

Elderly Inpatients ◽

Chi Square Test ◽

Student’S T ◽

Clinical Conditions

ABSTRACT Patients with dementia are commonly admitted to inpatient sectors. The aim of this study was to describe the frequency of dementia among elderly inpatients admitted to the Geriatrics Sector of a Brazilian Tertiary University Hospital, and to identify associations between dementia and clinical and sociodemographic factors. Methods: All patients admitted to the Geriatrics Sector of a public Brazilian university-hospital from March 1st 2014 to January 31st 2015 were assessed by geriatricians. The patients were divided into groups "with or without diagnosis of dementia". Univariate analysis was performed between these two groups using the Chi-Square Test, Student's t-test or the Mann-Whitney Test. Results: One hundred and three elderly inpatients, with a mean age of 82 (±7.9) years, were assessed. Overall, 74.7% had low educational level (<4 years), 66% used polypharmacy, 57.2% developed delirium during hospitalization and 59% were totally dependent for basic activities of daily living. The diagnosis of dementia was observed in 59 (57%) subjects. Conclusion: The frequency of dementia was high among the elderly inpatients evaluated. The association between dementia and certain clinical conditions, such as incontinence, delirium and use of psychoactive drugs, was in line with the medical literature.

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Established the first clinical prediction model regarding the risk of hyperuricemia in IgA nephropathy

10.21203/rs.3.rs-888732/v1 ◽

2021 ◽

Author(s):

Yin-Hong Geng ◽

Zhe Zhang ◽

Jun-Jun Zhang ◽

Bo Huang ◽

Zui-Shuang Guo ◽

...

Keyword(s):

Risk Factors ◽

Iga Nephropathy ◽

Interstitial Fibrosis ◽

Characteristic Curve ◽

Univariate Analysis ◽

Curve Analysis ◽

University Hospital ◽

Prediction Ability ◽

Decision Curve Analysis ◽

Incidence Risk

Abstract Objective. To construct a novel nomogram model that predicts the risk of hyperuricemia incidence in IgA nephropathy (IgAN) . Methods. Demographic and clinicopathological characteristics of 1184 IgAN patients in the First Affiliated Hospital of Zhengzhou University Hospital were collected. Univariate analysis and multivariate logistic regression were used to screen out hyperuricemia risk factors. The risk factors were used to establish a predictive nomogram model. The performance of the nomogram model was evaluated using an area under the receiver operating characteristic curve (AUC), calibration plots, and a decision curve analysis. Results. Independent predictors for hyperuricemia incidence risk included sex, hypoalbuminemia, hypertriglyceridemia, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), 24-hour urinaryprotein (24h TP), Gross and tubular atrophy/interstitial fibrosis (T). The nomogram model exhibited moderate prediction ability with an AUC of 0.834 ((95% CI 0.804–0.864)). The AUC from validation reached 0.787 (95% CI 0.736-0.839). The decision curve analysis displayed that the hyperuricemia risk nomogram was clinically applicable.Conclusion. Our novel and simple nomogram containing 8 factors may be useful in predicting hyperuricemia incidence risk in IgAN.

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