Stepwise Multivariate Cox Regression Research Articles

Lightweight transvaginal mesh is associated with lower mesh exposure rates than heavyweight mesh.

There has been a scarcity of long-term published data comparing lightweight versus heavier weight transvaginal mesh for prolapse repair. The aim was to ascertain the long-term rates of recurrent prolapse and mesh exposure in a cohort of vaginal repairs utilizing two different weights of transvaginal mesh. Data were prospectively collected on all mesh-augmented vaginal prolapse repairs performed with Apogee® or Perigee® mesh kits (IntePro® or IntePro Lite®) at a single centre over an 11-year period, with patients receiving ongoing annual follow-up. A sequential stepwise univariate and multivariate Cox regression analysis was performed to identify variables that were significantly associated with mesh exposure. Eighty-eight women with 113 mesh kits were reviewed from the original cohort of 158 women. The median length of follow-up was 6.4years (range 1.1-12.5years). Mesh exposure rate per implant in the IntePro® group was 16/40 (40%) versus 4/73 (5.5%) in the IntePro Lite® group (p < 0.0001). A hazard ratio of 4.2 was identified for mesh exposure for IntePro® versus IntePro Lite® (95% CI 3.0-6.8). There was no difference in rates of recurrent prolapse between the heavy- and lightweight mesh groups. Lightweight transvaginal mesh is associated with lower mesh exposure rates than heavyweight mesh at a median follow-up of 6.4years, with no difference in rates of recurrent prolapse.

Alteration and prognostic values of collagen gene expression in patients with gastric cancer under different treatments

Collagen (COL) genes participate in tumor extracellular matrix (ECM)-receptor interactions and focal adhesion pathways, which play a crucial role in tumor invasion and metastasis. The prognostic value of COL genes has been shown for several malignancies. In the present study, we analyzed multiple microarray datasets using the Oncomine database to identify alterations of COL genes in gastric cancer (GC). Gene expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) in GC tissues and matched adjacent tissues. The prognostic value of differentially expressed COL genes in GC was evaluated by Kaplan-Meier survival analysis based on the complete mRNA transcriptomics data from The Cancer Genome Atlas (TCGA). We found that seven COL genes (COL1A2, COL4A1, COL4A2, COL6A1, COL6A2, COL6A3, and COL11A1) were elevated in GC. Among them, stepwise multivariate Cox regression was applied, and it was determined that COL4A1 and COL4A2 were signature and independent prognostic biomarkers in GC patients with obviously different overall survival (OS). High expression of COL4A1, COL4A2, COL6A1, COL6A2, and COL6A3 was correlated with poorer prognosis of GC patients treated by surgery only, while higher expression of COL4A1 and COL11A1 correlated with poorer survival of patients treated by 5-fluorouracil-based adjuvant therapy. Our results indicate that overexpression of COL genes might be utilized as novel prognostic markers for GC and assist with therapy selection.

Glycolysis-Based Genes Associated with the Clinical Outcome of Pancreatic Ductal Adenocarcinoma Identified by The Cancer Genome Atlas Data Analysis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadly tumors in digestive tract tumors. Although there has been advancement in PDAC treatment, its prognosis still remains unsatisfactory, mainly because of dismal diagnosis. This article aims to develop new prognostic factors related to energy metabolism in PDAC and to use these genes for novel risk stratification. Hundred fifty messenger RNA (mRNA) expression profiles and clinicopathological data of PDAC were downloaded from The Cancer Genome Atlas dataset. The glycolysis pathway was the significant pathway based on the gene set enrichment analysis. We chose the glycolysis pathway-related 176 genes for further analysis. Multivariate Cox regression analysis and forward stepwise Cox regression model established a novel three-gene glycolytic signature (including MET, B3GNT3, and SPAG4) for PDAC patients' prognosis prediction. All 150 patients were classified into two groups by the median risk score. High-risk group had a worse outcome compared to the low-risk group. The risk score was also significantly correlated with age and radiotherapy. A nomogram, including the glycolytic gene signature, has shown some clinical net benefit for overall survival prediction. We also validated the validity and reliability in the Puleo dataset. This novel gene expression signature may be involved in the pathophysiology and used for risk stratification and prognosis prediction in PDAC.

Katanin P80 correlates with larger tumor size, lymph node metastasis, and advanced TNM stage and predicts poor prognosis in non-small-cell lung cancer patients.

ObjectiveThe present study aimed to investigate the correlation of katanin P80 expression with clinicopathological features and survival profile in non–small‐cell lung cancer (NSCLC) patients.MethodsTotally, 398 NSCLC patients treated by pulmonary resection were enrolled and their tumor specimens were collected to determine katanin P80 expression by immunohistochemistry (IHC) assay. Clinical data were collected at diagnosis, and survival data including disease‐free survival (DFS) and overall survival (OS) were assessed after treatment.ResultsThere were 195 (49.0%) patients with katanin P80 high expression and 203 (51.0%) patients with katanin P80 low expression, respectively. Meanwhile, katanin P80 high expression was associated with larger tumor size (P = .001), lymph node (LYN) metastasis (P = .005), and advanced TNM stage (P = .001). As for survival data, katanin P80 high expression was correlated with reduced DFS (P < .001) and OS (P < .001). And forward stepwise multivariate Cox's regression revealed that katanin P80 high expression was an independent predictor for decreased DFS (P < .001) and OS (P < .001). Besides, further analysis indicated that DFS (P < .001) and OS (P < .001) were the shortest in patients with katanin P80 high+++ expression, followed by patients with katanin P80 high++ expression and then those with katanin P80 high + expression and katanin P80 low expression.ConclusionKatanin P80 correlates with larger tumor size, LYN metastasis, and advanced TNM stage, and serves as a potential biomarker for predicting poor survival in NSCLC patients.

Vasodilator stress perfusion CMR is feasible and has prognostic value in morbid obese patients without known CAD

Obesity is a growing public health problem. Given the impact of obesity on cardiovascular disease, methods to effectively risk stratify obese patients are needed. Current methods for the detection of myocardial ischemia by single photon emission computed tomography or stress echocardiography remain limited in obese patients. Stress cardiac magnetic resonance (CMR) may be a powerful alternative, but its feasibility and prognostic value in the obese population has not been specifically evaluated. This study sought to determine feasibility and prognostic value of vasodilator stress perfusion CMR in morbid obese patients with body mass index (BMI) ≥ 40 kg/m 2 . Consecutive patients with a BMI ≥ 40 kg/m 2 and without known coronary artery disease (CAD) referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death, non-fatal myocardial infarction or stroke. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR. Of 452 obese patients, 444 (98%) completed the CMR protocol with good diagnostic imaging quality; among those, 404 (91%) completed the follow-up (mean 5.6 ± 2.2 years). Participants averaged 59 ± 11 years in age with 44% of men (mean BMI 43.9 ± 3.8 kg/m 2 , maximum weight 210 kg and maximum BMI 67.1 kg/m 2 ). Stress CMR was well tolerated without severe adverse event. Reasons for failure to complete CMR included claustrophobia ( n = 3), declining participation ( n = 4) and intolerance to stress agent ( n = 1). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (3.3% vs. 12.4% for those with ischemia and vs.11.2% for those with ischemia and LGE). In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, the absence of inducible ischemia was independently associated with a lower incidence of MACE at follow-up (hazard ratio 0.20; 95% confidence interval: 0.11 to 0.36; P < 0.001) ( Fig. 1 ) and cardiac death (hazard ratio 0,11 95% confidence interval: 0.02 to 0.63; P = 0,013); the cardiac death was lesser in the group with no late gadolinium enhancement (hazard ratio 0,12 95% confidence interval: 0.02 to 0.66; P < 0.015). When patients with early coronary revascularization (within 30 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE. Using Kaplan–Meier analyses, myocardial ischemia identified future CV events/survival ( P < 0.001), and this finding was similar in men and women ( P = 0.16). Stress CMR is feasible and of high prognostic value in morbid obese patients, with a very low negative event rate at 5 years in patients without ischemia or infarction as opposed to patients with inducible ischemia and/or presence of myocardial infarct.

566 Myocardial left ventricular mechanical uniformity and adverse cardiac events following myocardial infarction

Abstract Background Despite limitations as a standalone parameter, left ventricular ejection fraction (LVEF) is the preferred measure of myocardial function and marker for post-infarction risk stratification. LV myocardial uniformity may provide superior prognostic information after acute myocardial infarction (AMI), which was subject of this study. Methods and Results: Consecutive patients with AMI (n = 1082; median age 63 years; 75% male) undergoing cardiac magnetic resonance (CMR) in median 3 days after infarction were included in this multicenter, observational study. Circumferential and radial uniformity ratio estimates (CURE and RURE) were derived from CMR feature-tracking as markers of mechanical uniformity (values between 0 and 1 with 1 reflecting perfect uniformity). The clinical endpoint was the 12-month rate of major adverse cardiac events (MACE), consisting of all-cause death, re-infarction, and new congestive heart failure. Patients with MACE (n = 73) had significantly impaired CURE [0.76 (IQR 0.67-0.86) versus 0.84 (IQR 0.76-0.89); p &amp;lt; 0.001] and RURE [0.69 (IQR 0.60-0.79) versus 0.76 (IQR 0.67-0.83); p &amp;lt; 0.001] compared to patients without events. While uniformity estimates did not provide independent prognostic information in the overall cohort, CURE below the median of 0.84 emerged as an independent predictor of outcome in post-infarction patients with LVEF &amp;gt;35% (n = 959) even after adjustment for established prognostic markers (hazard ratio 1.99; 95% confidence interval 1.06-3.74; p = 0.033 in stepwise multivariable Cox regression analysis). In contrast, LVEF was not associated with adverse events in this subgroup of AMI patients. Conclusions CMR-derived estimates of mechanical uniformity are novel markers for risk assessment after AMI and CURE provides independent prognostic information in patients with preserved or only moderately reduced LVEF.

Prognostic significance of peritumoral fibrosis after resection of pancreatic head cancer.

Prognostic value of peritumoral fibrosis (PF) in pancreatic head cancer after resection was evaluated. A total of 143 pancreatic cancer patients who underwent tumor resection were enrolled. All patients underwent routine preoperative examination, including contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). Patients receiving preoperative chemoradiation were excluded because it affects the proportion of fibrosis and cancer cells. Histopathological confirmation and classification of pancreatic head cancer (PHC) was made according to the standards of World Health Organization and the American Joint Committee on Cancer (AJCC). The presence of fibrosis was assessed histologically, and correlated with the clinicopathological characteristics and overall survival using univariate Kaplan-Meier analysis and a stepwise multivariable Cox regression model. Vein resection, resection margin, grading, nodal status, preoperative CA19-9 levels and PF were significantly associated with overall survival. Multivariate analysis showed that all the aforementioned were independent predictive factors of survival. In addition, the survival of patients with PF was significantly worse compared to those without (HR 1.392; P=0.027). Tumor necrosis is a valuable prognostic tool that can be included in the routine post-resection histopathological evaluation of pancreatic head cancer patients.

Guideline-Based Critical Care Pathway Improves Long-Term Clinical Outcomes in Patients with Acute Coronary Syndrome

Implementation of a critical care pathway (CCP) for acute coronary syndrome (ACS) has been shown to improve early compliance to guideline-directed therapies and reduce early mortality. Nevertheless its long-term impact on the compliance with medications or clinical outcomes remains unknown. Between 2004 and 2015, 2023 consecutive patients were admitted to our coronary care unit with ACS. We retrospectively compared the outcomes of 628 versus 1059 patients (mean age 66.1 ± 13.3 years, 74% male) managed before and after full implementation of a CCP. Compared with standard care, implementation of the CCP significantly increased coronary revascularization and long-term compliance with guideline-directed medical therapy (both P < 0.01). After a mean follow-up of 66.5 ± 44.0 months, 46.7% and 22.2% patients admitted before and after implementation of the CCP, respectively, died. Kaplan-Meier analyses showed that patients managed by CCP had better overall survival (P = 0.03) than those managed with standard care. After adjustment for clinical covariates and coronary anatomy, CCP remained independently predictive of better survival from all-cause mortality [hazard ratio (HR): 0.75, 95%confidence intervals (CI): 0.62–0.92, P < 0.01]. Stepwise multivariate cox regression model showed that both revascularization (HR: 0.55, 95%CI: 0.45–0.68, P < 0.01) and compliance to statin (HR: 0.70, 95%CI: 0.58–0.85, P < 0.01) were accountable for the improved outcome.

A Five-microRNA Signature as Prognostic Biomarker in Colorectal Cancer by Bioinformatics Analysis.

Mounting evidence has demonstrated that a lot of miRNAs are overexpressed or downregulated in colorectal cancer (CRC) tissues and play a crucial role in tumorigenesis, invasion, and migration. The aim of our study was to screen new biomarkers related to CRC prognosis by bioinformatics analysis. By using the R language edgeR package for the differential analysis and standardization of miRNA expression profiles from The Cancer Genome Atlas (TCGA), 502 differentially expressed miRNAs (343 up-regulated, 159 down-regulated) were screened based on the cut-off criteria of p < 0.05 and |log2FC|>1, then all the patients (421) with differentially expressed miRNAs and complete survival time, status were then randomly divided into train group (212) and the test group (209). Eight miRNAs with p < 0.005 were revealed in univariate cox regression analysis of train group, then stepwise multivariate cox regression was applied for constituting a five-miRNA (hsa-miR-5091, hsa-miR-10b-3p, hsa-miR-9-5p, hsa-miR-187-3p, hsa-miR-32-5p) signature prognostic biomarkers with obviously different overall survival. Test group and entire group shown the same results utilizing the same prescient miRNA signature. The area under curve (AUC) of receiver operating characteristic (ROC) curve for predicting 5 years survival in train group, test group, and whole cohort were 0.79, 0.679, and 0.744, respectively, which demonstrated better predictive power of prognostic model. Furthermore, Univariate cox regression and multivariate cox regression considering other clinical factors displayed that the five-miRNA signature could serve as an independent prognostic factor. In order to predict the potential biological functions of five-miRNA signature, target genes of these five miRNAs were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway and Gene Ontology (GO) enrichment analysis. The top 10 hub genes (ESR1, ADCY9, MEF2C, NRXN1, ADCY5, FGF2, KITLG, GATA1, GRIA1, KAT2B) of target genes in protein protein interaction (PPI) network were screened by string database and Cytoscape 3.6.1 (plug-in cytoHubba). In addition, 19 of target genes were associated with survival prognosis. Taken together, the current study showed the model of five-miRNA signature could efficiently function as a novel and independent prognosis biomarker and therapeutic target for CRC patients.

Impact of margin status on long-term results of liver resection for hepatocellular carcinoma: single-center time-to-recurrence analysis.

Occult metastasis from the initial tumor and a de novo second primary hepatocellular carcinoma (HCC) were recognized as the main causes for the onset of early and late HCC recurrence, after liver resection (LR). This study aims to compare the time to recurrence after LR for HCC in which a margin ≤ 1mm or > 1mm was achieved. A single-center retrospective study involving 256 patients was conducted from June 2005 to June 2019. HCC patients resected with a radical surgical approach were investigated and stratified into groups A (resection margins ≤ 1mm) and B (> 1mm), as measured on final pathologic assessment. Kaplan-Meier estimators were used to estimate the probability of recurrence, and the log-rank test was used to compare groups. Uni- and multivariable (stepwise) Cox regression models were used to assess the effect of several HCC pathological characteristics. Twenty patients were excluded for the presence of microscopic tumor invasion at pathologic analysis (R1); 236 patients underwent radical (R0) LR, and were included in the study and divided into group A (n = 61, 26%), and group B (n = 175, 74%). No differences between the two groups were detected regarding: epidemiology, tumor characteristics, type of LR, and follow-up. The estimated probability of recurrence for group A and group B at 12 and 24months was 27% and 38%, and, 33% and 46%, respectively. Univariate and multivariable Cox regression model estimates showed that tumor grading (HR 2.1, 95% CI 1.2-3.4, p = 0.006), number of nodules (HR 1.2, 95% CI 1.0-1.4, p = 0.015), and extension of the resection (HR 1.8, 95% CI 1.0-1.1, p = 0.047) were independent risk factors for HCC recurrence, with no significant effect of margin status on time to recurrence. A R0 approach that considers a margin of resection > 1mm does not improve the likelihood of HCC recurrence. Otherwise, our experience confirms that biologic tumor characteristics are the principal factors predictive of local and systemic recurrence.

P5256Vasodilator stress perfusion CMR is feasible and has prognostic value in morbid obese patients without known CAD

Abstract Background Obesity is a growing public health problem. Given the impact of obesity on cardiovascular disease, methods to effectively risk stratify obese patients are needed. Current methods for the detection of myocardial ischemia by single photon emission computed tomography or stress echocardiography remain limited in obese patients. Stress cardiac magnetic resonance (CMR) may be a powerful alternative, but its feasibility and prognostic value in the obese population has not been specifically evaluated. Objectives This study sought to determine feasibility and prognostic value of vasodilator stress perfusion CMR in morbid obese patients with body mass index (BMI) ≥40 kg/m2. Methods Consecutive patients with a BMI ≥40 kg/m2 and without known coronary artery disease (CAD) referred for vasodilating stress CMR were followed for major adverse cardiovascular events (MACE), defined as cardiac death, non-fatal myocardial infarction or stroke. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR. Results Of 452 obese patients, 444 (98%) completed the CMR protocol with good diagnostic imaging quality; among those, 404 (91%) completed the follow-up (mean 5.6±2.2 years). Participants averaged 59±11 years in age with 44% of men (mean BMI 43.9±3.8 kg/m2, maximum weight 210 kg and maximum BMI 67.1 kg/m2). Stress CMR was well tolerated without severe adverse event. Reasons for failure to complete CMR included claustrophobia (n=3), declining participation (n=4) and intolerance to stress agent (n=1). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (3.3% vs. 12.4% for those with ischemia and vs. 11.2% for those with ischemia and LGE). In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, the absence of inducible ischemia was independently associated with a lower incidence of MACE at follow-up (hazard ratio 0.20; 95% confidence interval: 0.11 to 0.36; p&lt;0.001) (Figure) and cardiac death (hazard ratio 0,11 95% confidence interval: 0.02 to 0.63; p=0,013); cardiac death was reduced in the group with no late gadolinium enhancement (hazard ratio 0,12 95% confidence interval: 0.02 to 0.66; p&lt;0.015). When patients with early coronary revascularization (within 30 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE. Using Kaplan-Meier analyses, myocardial ischemia identified future CV events/survival (p&lt;0.001), and this finding was similar in men and women (p=0.16). Conclusion Stress CMR is feasible and of high prognostic value in morbid obese patients, with a very low negative event rate at 5 years in patients without ischemia or infarction as opposed to patients with inducible ischemia and/or presence of myocardial infarct.

P3094Feasibility and prognostic value of vasodilator stress perfusion CMR in elderly patients &gt; 75 years without known CAD

Abstract Background The World's ageing population with a life expectancy that is steadily increasing raises the question of the benefit of screening for coronary artery disease (CAD) in very old patients with high risk of CAD. Current guidelines discourage the performance of stress testing in asymptomatic elderly. Purpose To assess the prognostic value of vasodilator stress perfusion cardiac magnetic resonance (CMR) in elderly patients aged &gt;75 years without previous known CAD. Material Consecutive elderly patients &gt;75 years without known CAD referred for vasodilator stress perfusion CMR were followed for major adverse cardiovascular events (MACE) defined as cardiac death, non-fatal myocardial infarction or stroke. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes. Results Of 754 elderly high risk patients (82.0±3.9 years, 48.4% men), 747 (99%) completed the CMR protocol, and among those 659 (88.2%) completed the follow-up (median follow-up 5.7±2.5 years). Reasons for failure to complete CMR included claustrophobia (n=3), declining participation (n=2) and intolerance to stress agent (n=2). Stress CMR was well tolerated without occurrence of death or severe disabling adverse event. Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (5.5% vs. 9.9% for those with ischemia and vs. 6.9% for those with ischemia and/or LGE). In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, the absence of inducible ischemia was an independent predictor of a lower incidence of MACE at follow-up (hazard ratio 0.46; 95% confidence interval: 0.34 to 0.62; p&lt;0.001) (Figure 1A) and all-cause mortality (hazard ratio 0.67; 95% confidence interval: 0.45 to 0.97; p=0.037). When patients with early coronary revascularization (within 30 days of CMR) were censored on the day of revascularization, both presence of inducible ischemia and ischemia extent per segment maintained a strong association with MACE. Using Kaplan-Meier analyses, the presence of myocardial ischemia identified the occurrence of future CV events (p&lt;0.001). Moreover, the absence of inducible ischemia was a predictor of a lower incidence of MACE less significant in men than in women (p&lt;0.01) (Figure 1B). Conclusion Stress CMR is safe and has discriminative prognostic value in very elderly patients, with a very low negative event rate in patients without ischemia or infarction. Among elderly patients without known CAD, the presence of myocardial ischemia on vasodilator stress CMR was predictive of future CV event or death.

Ten-Year Oncologic Outcomes Following Robot-Assisted Radical Cystectomy: Results from the International Robotic Cystectomy Consortium.

Radical cystectomy is the gold standard for nonmetastatic muscle invasive bladder cancer and for refractory nonmuscle invasive disease. Compared to open radical cystectomy, robot-assisted radical cystectomy has been shown to provide comparable early oncologic outcomes and improved perioperative outcomes. However, there is a paucity of data on long-term oncologic outcomes and concerns about a higher incidence of local recurrence after robot-assisted radical cystectomy. We report 10-year oncologic outcomes following robot-assisted radical cystectomy using a multinational database. We retrospectively reviewed the prospective International Robotic Cystectomy Consortium database. Consecutive patients who underwent robot-assisted radical cystectomy 10 years ago or earlier were included in analysis. Data were reviewed for demographics, and perioperative, pathological and oncologic outcomes. Kaplan-Meier curves were used to depict recurrence-free, disease specific and overall survival. Multivariate stepwise Cox regression models were applied to identify variables associated with recurrence-free, disease specific and overall survival. We identified 446 patients with a median age of 67 years (IQR 59-76). Of the patients 10% received neoadjuvant chemotherapy, 51% experienced any complication, 23% had high grade complications and 4% died within 3 months of robot-assisted radical cystectomy. Disease was pT3 or greater in 43% of patients and pN+ in 24% while a positive soft tissue surgical margin was observed in 7%. At a median followup of 5 years (IQR 2-10, maximum 14) local and distant recurrence had developed in 15% and 29% of patients, respectively. Ten-year recurrence-free, disease specific and overall survival rates were 59%, 65% and 35%, respectively. Patients with pT3 or greater and pN+ disease showed worse recurrence-free, disease specific and overall survival. Long-term oncologic outcomes, and recurrence rates and patterns after robot-assisted radical cystectomy seem comparable to those in open series. Advanced disease stage and positive surgical margins remain the main determinants of survival after radical cystectomy.

Abstract 3154: Tumor expression of Activin A is associated with clinical outcomes in patients with colorectal cancer

Abstract Background: Activin A is a member of the transforming growth factor β (TGF-β) superfamily. Activin A shows an extensive variety of biological activities, including mesoderm induction, bone remodeling, muscle atrophy. Activin A is also related to Smad 2/3 mediated cancer development and metastasis. The overexpression of Activin A has been reported in several types of cancers and high expression of Activin A leads to poor prognosis. We examined the relationship between tumor expression of Activin A and clinical outcomes in patients with colorectal cancer. Methods: AACR Annual Meeting 2019 We analyzed the association between tumor expression of Activin A and clinicopathological features and patient’s prognosis in 157 primary colorectal cancers, which were curatively resected between 2008 and 2012. The expression level of Activin A was measured in tumor tissue by quantitative RT-PCR. Patients were categorized into the high or low groups based on median expression value of Activin A and Kaplan-Meier survival analyses were performed to display difference in overall survival (OS) and relapse-free survival (RFS) between two groups. The between-group differences were assessed by the log-rank test and stepwise multivariate Cox regression analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for OS. Result: RT-PCR analysis showed that expression of Activin A was significantly higher in tumor areas compared with that in normal (p&amp;lt;0.001). Activin A was highly expressed in the rectal cancer (p=0.015). Other clinicopathological factors were not significantly correlated with Activin A expression. Patients with Activin A high-expressed colorectal cancers showed a significantly shorter OS and RFS than those with activin A low-expressed tumor (5-year OS: Low 79.2% vs High 63.8%, p=0.037). High expression of Activin A is an independent predictor of poor prognosis in patients with colorectal cancers after curative surgery (Low vs High, HR=5.558, 95%CIs=2.229-15.17, AACR Annual Meeting 2019 p=0.003). Conclusion: We concluded that high Activin A expression in tumor is associated with poor prognosis in colorectal patients. Citation Format: Nobuya Daitoku, Yuji Miyamoto, Yuki Sakamoto, Kojiro Etoh, Yukiharu Hiyoshi, Yohei Nagai, Masaaki Iwatsuki, Takatsugu Ishimoto, Yoshifumi Baba, Shiro Iwagami, Naoya Yoshida, Hideo Baba. Tumor expression of Activin A is associated with clinical outcomes in patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3154.

Vasodilator stress perfusion CMR is feasible and has prognostic value in morbid obese patients without known CAD

Obesity is a growing public health problem with an impact on cardiovascular disease. But current methods for the detection of myocardial ischemia remain limited in obese patients and stress cardiac magnetic resonance (CMR) may be a powerful alternative. To determine feasibility and prognostic value of vasodilator stress perfusion CMR in morbid obese patients with body mass index (BMI) ≥ 40 kg/m 2 . Consecutive patients with a BMI > 40 kg/m 2 and without known coronary artery disease (CAD) referred for vasodilating stress CMR were followed for major adverse cardiovascular events MACE, defined as cardiac death, non-fatal myocardial infarction of stroke. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inductible ischemia or late gadolinium enhancement (LGE) by CMR. Of 452 obese patients (mean BMI 43.9 ± 3.8 kg/m 2 , 44% of men), 444 (98%) completed the CMR protocol and among those, 404 (91%) completed the follow-up (mean 5.6 ± 2.2 years). Patients without inductible ischemia or LGE experienced a susbtantially lower annual rate of MACE (3.3% vs. 12.4% for those with ischemia and vs. 11,2% for those with ischemia and LGE). In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, the absence of inducible ischemia was an independent predictor of a lower incidence of MACE at follow-up (Hazard ratio 0.20, 95% confidence interval: 0.11 to 0.36; P < 0.001) ( Fig. 1 ) and cardiac death (hazard ratio 0.11 95% confidence interval: 0.02 to 0.63). Using Kaplan-Meier analyses, myocardial ischemia identified future CV events/survival ( P < 0.001). Stress CMR is feasible and has a high prognostic value in morbid obese patients, with a very low negative event rate in patients without ischemia or infarction as opposed to patients with inducible ischemia and/or presence of myocardial infarct. Kaplan-Meier curves ( Fig. 1 ).

Feasibility and prognostic value of vasodilator stress perfusion CMR in elderly patients > 75 years without known CAD

The World's ageing population raises the question of the benefit of screening for coronary artery disease (CAD) in very old patients. To assess the prognostic value of vasodilator stress perfusion cardiac magnetic resonance (CMR) in elderly patients aged > 75 years without previous known CAD. Consecutive elderly patients > 75 years without known CAD referred for vasodilator stress perfusion CMR were followed for major adverse cardiovascular events (MACE) defined as cardiac death, non-fatal myocardial infarction or stroke. Univariable and multivariable Cox regressions for MACE were performed to determine the prognostic association of inducible ischemia or late gadolinium enhancement (LGE) by CMR beyond traditional clinical risk indexes. Of 754 elderly high risk patients (82 ± 4 years, 48.4% men), 747 (99%) completed the CMR protocol, and among those 659 (88.2%) completed the follow-up (median follow-up 5.7 ± 2.5 years). Patients without inducible ischemia or LGE experienced a substantially lower annual rate of MACE (5.5% vs. 9.9% for those with ischemia and vs. 6.9% for those with ischemia and/or LGE). In a multivariable stepwise Cox regression including clinical characteristics and CMR indexes, the absence of inducible ischemia was an independent predictor of a lower incidence of MACE at follow-up (hazard ratio 0.46; 95% confidence interval: 0.34 to 0.62; P < 0.001) ( Fig. 1 ) and all-cause mortality (hazard ratio 0.67; 95% confidence interval: 0.45 to 0.97; P = 0.037). Using Kaplan-Meier analyses, the presence of myocardial ischemia identified the occurrence of future CV events ( P < 0.001). Stress CMR is safe and has discriminative prognostic value in very elderly patients without known CAD, with a very low negative event rate in patients without ischemia or infarction, and with a higher rate of future CV event or death in patients with ischemia. Kaplan Meier curves ( Fig. 1 )

Early serum tumor marker dynamics predict progression-free and overall survival in single PD-1/PD-L1 inhibitor treated advanced NSCLC—A retrospective cohort study

ObjectivesTo evaluate serum tumor markers (STM) as biomarkers for treatment monitoring and prognosis in advanced non-small cell lung cancer (NSCLC) treated with single-agent PD-1/PD-L1-directed immune checkpoint inhibitor (ICI) therapy. Materials and MethodsCarcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), cytokeratin-19 fragments (CYFRA 21-1) and neuron specific enolase (NSE) were routinely measured at NSCLC diagnosis, initially elevated markers were used for follow-up. Leading STM change between ICI initiation and first subsequent restaging as well as corresponding computed tomography evaluations according to response evaluation criteria in solid tumors (RECIST) were retrospectively analyzed regarding progression-free (PFS) and overall survival (OS). In uni- and multivariate stepwise Cox-regression analyses, STM and RECIST response were analyzed for their impact on PFS and OS together with other known prognostic patient and tumor characteristics. ResultsAmong 84 patients (61% men, mean age 68 years), median PFS was significantly (p < 0.001) longer, when STM decreased (11 M (7,19) N = 37) than in case of increases (<2-fold: 6 M (3,8) N = 31; ≥2-fold: 2 M (1,2) N = 16). Patients with initial STM decrease had longer (p < 0.001) median OS (not reached) than with STM increase (<2-fold: 14 M (12,26); ≥2-fold: 4 M (3,7)). Patients with stable or progressive disease by RECIST and concomitant STM decrease had longer (p < 0.001) PFS and OS (8 M (4,14) and 18 M (10,n.e.) N = 24) than upon STM increase (PFS: 2 M (2,4); OS: 10 M (6,13) N = 42). Significant impact on PFS was shown for STM response (p < 0.001), RECIST response (p = 0.003) and PD-L1 status (p = 0.003). For OS, STM response (p < 0.001), presence of cerebral metastases (p = 0.036) and therapy line ≥3 (p = 0.001) were identified. ConclusionDecreasing leading STM at first restaging predict longer PFS and OS and identify patients with favorable outcomes among initial radiological non-responders in ICI treated NSCLC patients.

Baseline platelet counts and derived inflammatory biomarkers: prognostic relevance in metastatic melanoma patients receiving Endostar plus dacarbazine and cisplatin.

Background: The clinical efficacy and safety of Endostar combined with chemotherapy in the treatment of metastatic malignant melanoma (MM) were analyzed and the indicators capable of predicting the efficacy of the regimen were identified to guide clinical practice.Patients and methods: The clinical data of 55 patients with metastatic MM without gene mutations who were treated with Endostar combined with dacarbazine and cisplatin were retrospectively analyzed. Efficacy was assessed using RECIST 1.1, and adverse events (AEs) were graded according to NCI-CTCAE 4.0. The log-rank test was used to compare the survival curves of patients in different subgroups, and stepwise multivariate Cox regression analysis was used to determine significant prognostic factors. Differences were considered statistically significant at P<0.05.Results: Of the 55 patients, seven showed a partial response, 20 showed stable disease, and 28 showed progressive disease. The median progression-free survival was 17.9 months. AEs were controllable. Univariate analysis identified biotherapy, clinical stage, clinical classification, low baseline platelet count, platelet to albumin ratio (PAR), and platelet to globulin ratio (PGR) as factors affecting drug efficacy. Multivariate Cox regression analysis identified clinical stage and PAR as independent factors predicting the efficacy of the regimen.Conclusions: Endostar combined with chemotherapy showed a curative effect on metastatic MM without gene mutations, and AEs were controllable. The baseline platelet count and derived PAR and PGR values were associated with the efficacy of the regimen. The potential value of efficacy prediction remains to be further verified by prospective random experiments.

Identification of Prognostic Alternative Splicing Signature in Breast Carcinoma.

BackgroundIncreasing evidence indicated a close relationship between aberrant splicing variants and carcinoma, whereas comprehensive analysis of prognostic alternative splicing (AS) profiling in breast cancer (BRCA) is lacking and largely unknown.MethodsRNA-seq data and corresponding clinical information of BRCA patients were obtained and integrated from The Cancer Genome Atlas (TCGA). Then SpliceSeq software was used to assess seven AS types and calculate the Percent Spliced In (PSI) value. Univariate followed by stepwise multivariate Cox regression analyses identified survival associated AS events and constructed the AS signature, which were further sent for enrichment analysis, respectively. Besides, the splicing correlation network was constructed. Additionally, nomogram incorporating AS signature and clinicopathological characteristics was developed and its efficacy was evaluated with respect to discrimination, calibration and clinical utility.ResultsA total of 45,421 AS events were detected, among which 3071 events were found associated with overall survival (OS) after strict filtering. Parent genes of these prognostic events were involved in BRCA-related processes including NF-kappaB and HIF-1 signaling pathway. Besides, the final prognostic signature built with 20 AS events performed well with an area under the curve (AUC) of receiver operating characteristic (ROC) curve up to 0.957 for 5 years. And gene set enrichment analysis (GSEA) also confirmed the candidate 20 AS events contributed to progression of BRCA. Moreover, the nomogram that incorporated 20-AS-event-based classifier, age, pathological stage and Her-2 status showed good calibration and moderate discrimination, with C-index of 0.883 (95% CI, 0.844–0.921). Decision curve analysis (DCA) confirmed more benefit was added to survival prediction with our nomogram, especially in 5 or 8 years with threshold probability up to 80%. Finally, splicing correlation network revealed an obvious regulatory pattern of prognostic splicing factors (SF) in BRCA.ConclusionThis study provided a systematic portrait of survival-associated AS events involved in BRCA and further presented a AS-clinicopathological nomogram, which could be conveniently used to assist the individualized prediction of long-term survival probability for BRCA patients. And a series of bioinformatic analysis provided a promising perspective for further uncovering the underlying mechanisms of AS events and validating therapeutic targets for BRCA.

03:45 PM Abstract No. 330 Assessing outcomes of Yttrium-90 radioembolization for biphenotypic hepatocellular-cholangiocarcinoma

Biphenotypic hepatocellular-cholangiocarcinoma (HCC-CC) is a rare type of primary liver cancer that carries a poor prognosis. Since most patients present at a stage too advanced for surgical resection, loco-regional liver directed therapy is often performed for palliative or downstaging purposes. The purpose of this study is to evaluate patient outcomes after Yttrium-90 radioembolization (Y90) in patients with HCC-CC. A retrospective review of patients with biopsy-confirmed HCC-CC treated with Y90 between 2012 and 2018 was performed. Hepatic response to Y90 was assessed on follow-up CT or MR using modified RECIST criteria. Univariate and multivariable stepwise cox regression analyses were used to evaluate the association between demographic and clinical factors and survival. Logistic regression was used to evaluate associations between clinical factors and response to treatment (complete/partial response vs stable/progressive disease), overall response, and disease control. 22 patients with HCC-CC (median age 67.1 years, 17 male) underwent a total of 29 Y90 treatments (5 with resin, 24 with glass microspheres). Survival data was available in 21 patients and hepatic response data available in 20 patients. Hepatic response was 15% complete response, 35% partial response, 20% stable disease, and 30% progressive disease (50% response rate, 70% disease control rate). Two patients were successfully downstaged or bridged to transplant and one to resection. Median overall survival was 9.3 months (range 2.5-31.0 months) from time of Y90. Bilobar disease was found to have a 3-fold increase in the hazard of survival (p = 0.03, HR: 3.252 95% CI 1.098, 9.361) on univariate analysis. The final multivariable stepwise cox regression model found nonresponse to treatment after Y90 to be associated with a 4-fold increase in the hazard of survival (p = 0.0274, HR: 4.649, 95% CI 1.187, 18.207). Y90 is a viable option for loco-regional control of HCC-CC with good response and disease control rates. Nonresponse to treatment and bilobar disease were associated with reduced survival after treatment.