scholarly journals The Presence of SETBP1, RUNX1 or EZH2 Mutation in MDS/MPN Is Associated with Absence of Response to Hypo-Methylating Agents

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1520-1520
Author(s):  
Theodoros Karantanos ◽  
Hua-Ling Tsai ◽  
Mark Levis ◽  
Ravi Varadhan ◽  
Richard J. Jones ◽  
...  
Keyword(s):  
Overall Survival ◽  
Logistic Regression ◽  
Regression Analysis ◽  
Research Funding ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Median Number ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Methylating Agents

Abstract INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN) remains challenging due to their molecular complexity. Hypo-methylating agents (HMA) have been used for cytoreduction and preparation of patients for allogeneic blood or marrow transplantation (BMT). However, less than 50% patients have a meaningful response to HMA and predictive factors for response remain unknown. The aim of our study is to examine molecular predictors of response to HMA in patients with MDS/MPN. PATIENTS AND METHODS: We performed a retrospective analysis of 150 patients evaluated at our center for chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MDS/MPN-U) between 1/1/2010 and 12/31/2020. Forty-three individuals who were treated with HMA during chronic phase and had next generation sequencing (NGS) using the established 63-genes panel were identified. Complete and partial remission (CR and PR), and marrow response (MR) were assessed based on the MDS/MPN International Working Group response criteria. Univariate logistic regression analysis was used to associate the number of somatic mutations or high-risk (HR) mutations (NRAS, SETBP1, RUNX1, EZH2, TP53, ASXL1, STAG2), and other disease specific factors at the time of the initiation of HMA with response categories. Multivariable analysis for modeling response were conducted via Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression approach, where the predictors were selected based on 5-fold cross validation with turning parameter selected to minimize deviance of logistic regression model. Kaplan-Meier was used to assess the overall survival based on the CR/PR status at 6 months from the initiation of HMA in landmark analysis. Cox-regression analysis considering the occurrence of CR/PR as a time-varying covariate was used to assess the impact of CR/PR on overall survival. RESULTS: Fifteen women and 28 men with a median age 67 years (range: 45 - 85 years) and a median follow up of 1.5 years (range: 91 days - 5.2 years) were included. Twenty five (58.1%) had CMML, 15 (34.9%) had MDS/MPN-U and 3 (7%) had aCML. Thirty-four patients (79.1%) received azacitidine (median number of cycles: 4.5, range: 1 - 65) and 9 patients (20.9%) received decitabine (median number of cycles: 4, range: 3 - 21). Seventeen patients (39.5%) underwent BMT following HMA therapy. The incidence of AML transformation was 16%. No patients had CR while 56% achieved a PR and 42% had an MR. Univariate analysis showed that ≥2 HR mutations (OR 0.19, 95% CI 0.05-0.67), SETBP1 mutation (OR 0.16, 95% CI 0.02-0.76), RUNX1 mutation (OR 0.1, 95% CI 0.01-0.48) and a mutation in at least one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.05, 95% CI 0.01-0.21) were associated with absence of PR. ≥2 HR mutations (OR 0.23, 95% CI 0.05-0.9), and the presence of a mutation in one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.16, 95% CI 0.03-0.62) were associated with absence of MR on univariate analysis. Finally, older age as a continuous variable was associated with PR (OR 1.09, 95% CI 1.01-1.19) and MR (OR 1.12, 95% CI 1.03-1.24). Presence of a mutation in one of the SETBP1, RUNX1 and EZH2 genes with age adjusted was selected from LASSO approach and significantly predicted the absence of PR (OR 0.05, 95% CI 0.01-0.27), and MR (OR 0.19, 95% CI 0.04-0.91) (Table 1). Using the landmark of 6 months after the initiation of treatment, Kaplan-Meier analysis showed that PR at 6 months was associated with superior overall survival (P=0.010) compared to patients with no response (Figure 1). Similarly, Cox-regression analysis revealed that the occurrence of PR following the initiation of treatment was associated with better overall survival (HR 0.26, 95% CI 0.9-0.13, P=0.010). CONCLUSIONS: Mutations in SETBP1, RUNX1 or EZH2 genes predicted absence of response to HMA among patients with MDS/MPN independent of other factors including karyotype, blast percentage and R-IPSS. These findings suggest that the molecular profile of MDS/MPN patients can potentially identify patients with HMA-refractory phenotype. Multi-institutional studies of larger cohorts are required to verify these results and develop novel treatment strategies especially for patients with high-risk mutations in MDS/MPN. Figure 1. Kaplan-Meier estimates of OS by PR status at 6 months in landmark analysis. P-value was based on log-rank test. Figure 1 Figure 1. Disclosures Levis: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas and FujiFilm: Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Jain: Syneos Health: Research Funding; CTI Biopharma: Research Funding; CareDx: Other: for advisory board participation; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy.

Complete Remissions (CRs) with Azacitidine Regimens Compared to Crs with 7+3 Induction Chemotherapy and the Effect on Overall Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1613-1613 ◽  
Author(s):  
Megan Othus ◽  
Mikkael A Sekeres ◽  
Sucha Nand ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Research Funding ◽  
Cox Regression ◽  
Intensive Therapy ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Curative Intent ◽  
Kaplan Meier ◽  
The Impact

Abstract Background: CR and CR with incomplete count recovery (CRi) are associated with prolonged overall survival (OS) for acute myeloid leukemia (AML) patients (pts) treated with curative-intent, induction therapy. For AML pts treated with azacitidine (AZA), response (CR, partial response, marrow CR, or hematologic improvement) is also associated with prolonged OS. We evaluate whether patients given AZA for myelodysplastic syndromes (MDS) or AML had longer OS if they achieved CR. We also compare the effect size of CR on OS between AZA regimens and 7+3. Patients and Methods: We analyzed four SWOG studies: S1117 (n=277) was a randomized Phase II study comparing AZA to AZA+lenalidomide or AZA+vorinostat for higher-risk MDS and CMML pts (median age 70 years, range 28-93); S0703 (n=133) treated AML pts not eligible for curative-intent therapy with AZA+mylotarg (median age 73 years, range 60-88). We analyzed the 7+3 arms of S0106 (n=301 were randomized to 7+3, median age 48 years, range 18-60) and S1203 (n=261 were randomized to 7+3, median age 48 years, range 19-60). CR was defined per 2003 International Working Group criteria. In S1117 CR was assessed every 16 weeks and patients remained on therapy until disease progression. In S0703, S0106, and S1203 CR was assessed following 1-2 induction cycles; patients not achieving CR (S0106) or CRi (S0703 and S1203) were removed from protocol treatment. OS was measured from date of study registration. To avoid survival by response bias, we performed landmark analyses of OS. We present results based on the study-specific landmark date that 75% of pts who eventually achieved a CR had done so (S1117 144 days, S0703 42 days, S0106 44 days, S1203 34 days). Pts who did not achieve CR by this date were analyzed with pts who never achieved CR. Pts who died or were lost to follow-up before this date were excluded from analyses. As a sensitivity analysis we also analyzed based on the 90% date; results were not materially different. Log-rank tests were used to compare survival curves and Cox regression models were used for multivariable modeling including baseline prognostic factors age, sex, performance status, white blood cell count, platelet count, marrow blast percentage, de novo disease (versus antecedent MDS or therapy-related disease), study arm (for S1117 only), and cytogenetic risk (IPSS criteria for S1117, SWOG criteria for S0703, S0106, and S1203). The following analysis considers morphologic CR only. S0106 treated CR with incomplete count recover (CRi) pts as treatment failures (S0703 and S1203 did not) and CRi was not defined for S1117. Hematologic improvement was only defined for S1117 patients. Results: In univariate analysis, CR was significantly associated with prolonged survival among MDS pts treated with azactidine on S1117 (HR=0.55, p=0.017), confirming the results seen in AML pts treated with azacitidine (and mylotarg, S0703, HR=0.60, p=0.054) and 7+3 (S0106 HR=0.44, p<0.001; S1203 HR=0.32, p<0.0001) (Figure 1). For each study this relationship remained significant in multivariable analysis controlling for baseline prognostic factors (S1117 HR=0.25, p<0.001; S0703 HR=0.64, p=0.049; S0106 HR=0.45, p<0.001; S1203 HR=0.41, p<0.001). There was no evidence that the impact of CR varied across the four cohorts (interaction p-value = 0.76). In the full cohort, the effect of CR was associated with a HR of 0.45 (Table 1). Conclusion: Adjusting for pt characteristics, achievement of morphologic CR was associated with a 60% improvement in OS, on average, compared to that seen in pts who don't achieve a CR, regardless of whether pts were treated with 7+3 or AZA containing regimens, and suggesting that value CR is similar of whether pts receive more or less "intensive" therapy for these high grade neoplasms. Support: NIH/NCI grants CA180888 and CA180819 Acknowledgment: The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Figure 1 Kaplan-Meier plots of landmark survival by response. Figure 1. Kaplan-Meier plots of landmark survival by response. Table 1 Multivariable analysis, N=878 Table 1. Multivariable analysis, N=878 Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Erba:Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Agios: Research Funding; Gylcomimetics: Other: DSMB; Juno: Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Pfizer: Consultancy; Ariad: Consultancy; Jannsen: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Astellas: Research Funding; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau.

Impact of cytoreductive surgery on outcomes of metastatic appendiceal carcinoma: a real-world, population-based study

2020 ◽  
Vol 9 (6) ◽  
pp. 431-439
Author(s):  
Omar Abdel-Rahman
Keyword(s):  
Overall Survival ◽  
Regression Analysis ◽  
Metastatic Disease ◽  
Cytoreductive Surgery ◽  
Mucinous Adenocarcinoma ◽  
Cox Regression ◽  
Cancer Specific Survival ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Appendiceal Carcinoma

Aim: To evaluate the impact of cytoreductive surgery on the outcomes of patients with metastatic appendiceal carcinoma. Methods: Surveillance, Epidemiology and End Results (SEER) database was accessed and patients with metastatic appendiceal carcinoma diagnosed (2010–2015) were reviewed. Kaplan–Meier survival estimates/log-rank testing were then used to assess overall survival outcomes according to cytoreductive surgery. Multivariable Cox regression analysis was then used to evaluate factors affecting cancer-specific survival. Factors included in this model were age, race, sex, stage and histology and cytoreductive surgery. Results: A total of 1339 patients with metastatic appendiceal carcinoma were included in the current study. Using Kaplan–Meier survival estimates to evaluate overall survival, patients with surgery for metastatic disease have better overall survival compared with patients without surgery for metastatic disease (p < 0.001). Stratifying survival analysis according to histology, the overall survival benefit from surgery for the metastases seems to be limited to patients with mucinous adenocarcinoma (p = 0.002) rather than patients with nonmucinous adenocarcinoma (p = 0.401). Multivariable Cox regression analysis was then conducted to evaluate factors predicting cancer-specific survival. The following factors were associated with worse cancer-specific survival: African-American race (hazard ratio [HR]: 1.356; 95% CI: 1.036–1.774; p = 0.026), more advanced stage (HR: 3.910; 95% CI: 2.735–5.588; p < 0.001), nonmucinous adenocarcinoma (HR for signet ring carcinoma vs mucinous adenocarcinoma: 2.119; 95% CI: 1.674–2.683; p < 0.001) and no surgical resection of metastatic disease (HR: 1.273; 95% CI: 1.067–1.519; p < 0.001). Conclusion: The current study suggests that among patients with metastatic appendiceal carcinoma, surgical cytoreduction of metastatic disease is associated with improved outcomes for patients with mucinous adenocarcinoma but not in patients with nonmucinous adenocarcinoma.

Aberrant a-to-I RNA Editing and Prognostic Impact of Adar in Multiple Myeloma Patients with 1q Amplification

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 357-357
Author(s):  
Alessandro Lagana ◽  
Deepak Perumal ◽  
Violetta V Leshchenko ◽  
Pei-Yu Kuo ◽  
Brian Kidd ◽  
...  
Keyword(s):  
Overall Survival ◽  
Board Of Directors ◽  
Rna Editing ◽  
Copy Number ◽  
Research Funding ◽  
Cox Regression ◽  
Advisory Committees ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Equity Ownership

Abstract Amplification of 1q is observed in 40% of Multiple Myeloma (MM) patients and is associated with a more aggressive clinical course of the disease. The frequency of 1q21 amplifications has been shown to increase significantly in the transition from monoclonal gammopathy of undetermined significance (MGUS) to overt myeloma and to relapse. Previous studies have reported genes on 1q such as ANP32E and CSK1B that have significant impact on survival. However, the biological mechanisms underlying disease aggressiveness associated to 1q amplification still remain unclear. ADAR (Adenosine Deaminase Acting on RNA) is an enzyme responsible for A-to-I editing, a post-transcriptional modification of double stranded RNA consisting in the conversion of specific Adenosines (A) into Inosines (I) by deamination. As Inosine is structurally similar to Guanosine (G), editing events can result in functional consequences in RNA and protein structure, including non-synonymous changes in protein coding sequences and creation/disruption of miRNA binding sites on UTRs. Dysregulation of A-to-I editing by ADAR has been recently linked to cancer. Since the ADAR gene is located in 1q21.3 (the critical minimally amplified region in MM), we asked whether 1q amplification affected ADAR expression, RNA editing and overall prognosis in MM patients. We identified 44 patients with 1q amplification from the IA6 release of the MMRF CoMMpass dataset. As a control group (wt), we selected an equal number of patients from CoMMpass without any 1q alteration. Gene expression analysis showed significantly higher expression of ADAR in 1q-amp patients compared to wt (q = 3.64e-7) (Fig. 1) and significant correlation between ADAR copy number and its expression (Spearman ρ=0.69, p = 4.52e-14). To evaluate the functional impact of ADAR up-regulation, we applied a computational pipeline based on the tool REDItools and our in-house scripts to detect A-to-I edited sites in RNA-Seq samples. The pipeline identified candidate A-to-G mutations in RNA sequences using corresponding Whole-Exome Sequencing data to filter out actual DNA mutations. We calculated sample-wise mean editing frequency across all edited sites and found significantly increased editing in 1q-amp patients compared to wt (p = 4.3e-5) (Fig. 2). Mean editing frequency was significantly correlated with ADAR expression (ρ = 0.62, p < 2e-16) and ADAR copy number (ρ= 0.5, p= 4.32e-7). Our analysis identified 3,286 sites residing in Alu sequences and 1,303 in non-Alu regions. A-to-I editing has been shown to occur predominantly in Alu elements, repetitive sequences abundantly interspersed throughout the human genome, mostly within introns and untranslated regions (UTRs). As expected, most sites were reported within 3' UTRs (66%) and introns (12%). Overall, at the site level, we observed increased editing in 1q-amp vs wt (p < 2e-16). We found that 2,173 sites (47%) had significant differential editing frequency between 1q-amp and wt patients (FDR < 20%). Next, we sought to assess the prognostic implications of ADAR activity. Cox regression analysis revealed a trend toward higher risk in terms of EFS (Event Free Survival) for 1q-amp vs wt (HR = 1.7, 95% CI = 0.83-3.59, p = 0.13), as well as for patients with higher expression of ADAR (HR = 2.4, 95% CI = 0.79-7.15, p = 0.11) and higher mean editing frequency (HR = 2, 95% CI = 0.72-5.59, p = 0.17). Since survival data in the CoMMpass dataset is not yet mature, we evaluated the effects of ADAR expression on survival on an independent dataset consisting of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658, Shaughnessy et al, Blood 2007; 109:2276-84). Cox regression analysis showed a significant difference in terms of overall survival between patients with low and high ADAR expression, the latter being correlated with higher risk (HR = 2, 95% CI = 1.18-3.66, p = 0.01) (Fig. 3). In conclusion, we found a significant increase in ADAR expression and aberrant A-to-I RNA editing in MM patients with amplification of 1q. These results demonstrate a novel mechanism by which 1q amplification can contribute to MM pathogenesis via induction of A-to-I RNA editing by ADAR. Figure 1 ADAR expression in 1q-amp vs wt patients. Figure 1. ADAR expression in 1q-amp vs wt patients. Figure 2 Difference in mean RNA editing frequency between 1q-amp and wt patients. Figure 2. Difference in mean RNA editing frequency between 1q-amp and wt patients. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by ADAR expression (GSE2658) Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by ADAR expression (GSE2658) Disclosures Chari: Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cho:Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Agenus, Inc.: Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Jagannath:Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Dudley:NuMedii, Inc.: Patents & Royalties; AstraZeneca: Speakers Bureau; Ontomics, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; Ayasdi, Inc.: Equity Ownership; Janssen Pharmaceuticals, Inc.: Consultancy; GlaxoSmithKline: Consultancy; Personalis: Patents & Royalties.

scholarly journals Long-term effects of citric acid-based bicarbonate haemodialysis on patient outcomes: a survival propensity score–matched study in western France

2020 ◽  
Vol 35 (7) ◽  
pp. 1228-1236 ◽  
Author(s):  
Jacky Potier ◽  
Thibault Dolley-Hitze ◽  
Didier Hamel ◽  
Isabelle Landru ◽  
Erick Cardineau ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Patient Outcomes ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Long Term Effects ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Statistical Relevance ◽  
All Cause Mortality

Abstract Background Citric acid–based bicarbonate haemodialysis (CIT-HD) has gained more clinical acceptance over the last few years in France and is a substitute for other acidifiers [e.g. acetic acid (CH3COOH) and hydrochloric acid (HCl)]. This trend was justified by several clinical benefits compared with CH3COOH as well as the desire to avoid the consequences of the corrosive action of HCl, but a nationwide clinical report raised concerns about the long-term safety of CIT-HD. The aim of this study was to assess the long-term effects of CIT-HD exposure on patient outcomes in western France. Methods This is a population-based retrospective multicentre observational study performed in 1132 incident end-stage kidney disease patients in five sanitary territories in western France who started their renal replacement therapy after 1 January 2008 and followed up through 15 October 2018. Relevant data, collected prospectively with the same medical software, were anonymously aggregated for the purposes of the study. The primary goal of this study was to investigate the effects of citrate exposure on all-cause mortality. To provide a control group to CIT-HD one, propensity score matching (PSM) at 2:1 was performed in two steps: the first analysis was intended to be exploratory, comparing patients who received citrate ≤80% of the time (CIT-HD ≤80) versus those who received citrate &gt;80% of the time (CIT-HD &gt;80), while the second analysis was intended to be explanatory in comparing patients with 0% (CIT-HD0) versus 100% citrate time exposure (CIT-HD100). Results After PSM, in the exploratory part of the analysis, 432 CIT-HD ≤80 patients were compared with 216 CIT-HD &gt;80 patients and no difference was found for all-cause mortality using the Kaplan–Meier model (log-rank 0.97), univariate Cox regression analysis {hazard ratio [HR] 1.01 [95% confidence interval (CI) 0.71–1.40]} and multivariate Cox regression analysis [HR 1.11 (95% CI 0.76–1.61)] when adjusted for nine variables with clinical pertinence and high statistical relevance in the univariate analysis. In the explanatory part of the analysis, 316 CIT-HD0 patients were then compared with 158 CIT-HD100 patients and no difference was found using the Kaplan–Meier model (log-rank 0.06), univariate Cox regression analysis [HR 0.69 (95% CI 0.47–1.03)] and multivariate Cox regression analysis [HR 0.87 (95% CI 0.57–1.33)] when adjusted for seven variables with clinical pertinence and high statistical relevance in the univariate analysis. Conclusions Findings of this study support the notion that CIT-HD exposure ≤6 years has no significant effect on all-cause mortality in HD patients. This finding remains true for patients receiving high-volume online haemodiafiltration, a modality most frequently prescribed in this cohort.

scholarly journals The relationship between RECK Gene Polymorphisms and the prognosis of cholangiocarcinoma

2020 ◽  
Author(s):  
Ning Wang ◽  
Yanni Li ◽  
Yanfang Zheng ◽  
Huoming Chen ◽  
Xiaolong Wen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Overall Survival Rate ◽  
Chi Square ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Chi Square Test ◽  
The Relationship

Abstract Background The study was designed to examine the reversion inducing cysteine rich protein with Kazal motifs (RECK) levels in patients with cholangiocarcinoma (CCA) and assess its role in CCA prognosis. Methods Quantitative real-time PCR (qRT-PCR) was used to determine the expression of RECK mRNA in 127 pairs of CCA samples and controls. Chi-square test was conducted to analyze the effects of clinical features on RECK expression. Kaplan-Meier curves were plotted to determine the overall survival rate of CCA patients with different RECK expression. The prognostic biomarkers for CCA patients were identified using the Cox regression analysis. Results Significantly down-regulated expression of RECK mRNA was determined in CCA tissues compared to noncancerous controls (P < 0.05). Chi-square test suggested reduced RECK expression was related with invasion depth (P = 0.026), differentiation (P = 0.025), lymphatic metastasis (P = 0.010) and TNM stage (P = 0.015). However, age, sex, tumor size and family history had no significant links with RECK expression (all, P > 0.05). The survival curves showed that patients with low RECK expression had a shorter overall survival rate than those with high RECK expression. Both the univariate analysis (P = 0.000, HR = 5.290, 95%CI = 3.195–8.758) and multivariate analysis (P = 0.000, HR = 5.376, 95%CI = 2.231–8.946) demonstrated that RECK was an independent biomarker for predicting the outcomes of CCA patients. Conclusions Taken together, the expression of RECK was down-regulated in CCA and it might be an efficient biomarker for CCA patients.

Cisplatin-Based versus Carboplatin-Based Chemotherapy for Extra-Pulmonary Neuroendocrine Carcinomas; A Real-World Study.

2021 ◽  
Author(s):  
Omar Abdel-Rahman ◽  
Sheryl L. Koski
Keyword(s):  
Overall Survival ◽  
Regression Analysis ◽  
Cox Regression ◽  
Survival Outcomes ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Platinum Agent ◽  
Extra Pulmonary ◽  
The Impact ◽  
Neuroendocrine Carcinomas

Objective: To assess the survival differences between cisplatin/etoposide versus carboplatin/etoposide chemotherapy regimens in the management of extra-pulmonary neuroendocrine carcinomas (NECs). Methods: Administrative cancer care databases in the province of Alberta, Canada were reviewed, and patients with extra-pulmonary NECs (including those with small cell and large cell neuroendocrine carcinomas) who were treated with either cisplatin/ etoposide or carboplatin/ etoposide, 2004-2019, were reviewed. Kaplan-Meier survival estimates were used to compare the survival outcomes according to the type of platinum agent, and multivariable Cox regression analysis was used to assess the impact of the type of platinum agent on overall survival outcomes. Results: A total of 263 eligible patients were included in this analysis. These include 176 patients who received cisplatin/ etoposide and 87 patients who received carboplatin/etoposide. Using Kaplan-Meier survival estimates, patients treated with cisplatin have better overall survival compared to patients treated with carboplatin (P=0.005). Multivariable Cox regression analysis suggested that the following factors were associated with worse overall survival: higher Charlson comorbidity index (HR: 1.17; 95% CI: 1.05-1.30), gastrointestinal primary site (HR: 1.55; 95% CI: 1.12-2.14), stage IV disease (HR: 1.75; 95% CI: 1.28-2.38) and use of carboplatin (HR: 1.40; 95% CI: 1.02-1.92). Conclusions: The current study suggested that cisplatin/etoposide might be associated with better overall survival compared to carboplatin/etoposide among patients with extra-pulmonary NECs. It is unclear if this is related to differences in inherent responsiveness to the two platinum agents, or due to differences in comorbidity burden between the two treatment groups.

scholarly journals Multiplex Immunoassay of Cytokines for The Short-Term Prognosis Predictive Value of Patients With Acute-on-Chronic Liver Failure

2021 ◽  
Author(s):  
Yongyuan Zheng ◽  
Genglin Zhang ◽  
Lina Wu ◽  
Jing Xiong ◽  
Lu Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Regression Analysis ◽  
Hepatitis B ◽  
Cox Regression ◽  
Curve Analysis ◽  
Chronic Liver Failure ◽  
Roc Curve Analysis ◽  
Cox Regression Analysis ◽  
Multiplex Immunoassay ◽  
Kaplan Meier

Abstract Background: Since the systemic inflammation has been found to be associated with disease progression and mortality in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (HBV-ACLF), the objective of this study was to detect inflammatory factors in ACLF patients by a Luminex-based multiplex immunoassay system for high throughput screening of the cytokine with the most prognostic value.Methods: Luminex-based multiplex immunoassay technology was used to determine the concentrations of 48 cytokines in total at once in serum samples from 40 patients with HBV-ACLF, 30 patients with chronic hepatitis B (CHB) and 25 healthy volunteers as normal controls (NC). Then, the receiver operating characteristic (ROC) curve analysis was applied to evaluate the prognostic prediction accuracy. Besides, Kaplan–Meier curves was used to analyze survival, while the Cox regression analysis to determine the mortality predictors.Results: The level of IL-6, IL-10, IL-15, IL-18, M-CSF, IP-10 and CXCL9 were significantly higher in patients with HBV-ACLF than in either patients with CHB or NC subjects, while the level of EGF, PDGF-AA, PDGF-AB/BB, MDC and sCD40L were significantly lower. The concentrations of IL-6, CXCL9, and IL-15 was higher in non-surviving patients with HBV-ACLF than in surviving patients while MDC was lower. Increased serum IL-6 was positively correlated with disease severity. The ROC curve analysis showed that IL-6 and CXCL-9 accurately predicted 90-day survival in patients with HBV-ACLF, with an accuracy equivalent to those of the Model for End-Stage Liver Disease (MELD), MELD-Na. Kaplan–Meier analysis showed an association between the increase in serum concentration of IL-6 as well as CXCL9 and poor overall survival in patients with HBV-ACLF. Moreover, the multivariate Cox regression analysis showed that only serum IL-6 was an independent predictor of overall survival in patients with HBV-ACLF.Conclusion: Although HBV-related ACLF patients have significantly increased serum levels of multiple cytokines, only serum IL-6 levels could be an independent prognostic biomarker in patients with HBV-ACLF.

scholarly journals Identification of a Seven-Gene Signature and Establishment of a Nomogram Predicting Overall Survival in Head and Neck Squamous Cell Carcinoma

2020 ◽  
Author(s):  
Haige Zheng ◽  
Xiangkun Wu ◽  
Huixian Liu ◽  
Yumin Lu ◽  
Hengguo Li
Keyword(s):  
Overall Survival ◽  
Squamous Cell Carcinoma ◽  
Regression Analysis ◽  
High Risk ◽  
Cell Carcinoma ◽  
Cox Regression ◽  
Risk Groups ◽  
Gene Signature ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Abstract Background: Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous tumor with high incidence and poor prognosis. Therefore, effective predictive models are needed to evaluate patient outcomes and optimize treatment. Methods: Ten gene microarray datasets were obtained from the gene expression omnibus (GEO) database. Level 3 mRNA expression and clinical data were obtained in The Cancer Genome Atlas (TCGA) database. We identified highly robust differentially-expressed genes (DEGs) between HNSCC and normal tissue in nine GEO and TCGA datasets using Robust Rank Aggregation (RRA) method. Univariate Cox regression analysis and lasso Cox regression analysis were performed to identify DEGs related to the Overall-survival (OS) and to construct a prognostic gene signature. External validation was performed using GSE65858. Moreover, gene set enrichment analyses (GSEA) analysis was used to analyze significantly rich pathways in high-risk and low-risk groups, and tumor immunoassays were used to clarify immune correlation of the prognostic gene. Finally, integrate multiple forecast indicators were used to build a nomogram using the TCGA-HNSCC dataset. Kaplan–Meier analysis, receiver operating characteristic (ROC), a calibration plot, Harrell’s concordance index (C-index), and decision curve analysis (DCA) were used to test the predictive capability of the seven genetic signals and the nomogram. Results: A novel seven-gene signature (including SLURP1, SCARA5, CLDN10, MYH11, CXCL13, HLF, and ITGA3) was established to predict overall survival in HNSCC patients. ROC curve performed well in the training and validation data sets. Kaplan–Meier analysis demonstrated that low-risk groups had a longer survival time. The nomogram containing seven genetic markers and clinical prognostic factors was a good predictor of HNSCC survival and showed a certain net clinical benefit through the DCA curve. Further research demonstrated that the infiltration degree of CD8 + T cells, B cells, neutrophils, and NK cells were significantly lower in the high-risk group.Conclusion: Our analysis established a seven-gene model and nomogram to accurately predict the prognosis status of HNSCC patients, immune relevance was also described, which may provide a new possibility for individual treatment and medical decision-making.

scholarly journals Development and Validation of a Robust Ferroptosis-Related Prognostic Signature to Predict Overall Survival in Clear Cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Yen-ting Lin ◽  
Can-Xuan Li ◽  
Jie Chen
Keyword(s):  
Overall Survival ◽  
Regression Analysis ◽  
Roc Curve ◽  
Prognostic Value ◽  
Cox Regression ◽  
Expression Patterns ◽  
The Cancer Genome Atlas ◽  
Entire Group ◽  
Cox Regression Analysis ◽  
Kaplan Meier

Abstract Background: Ferroptosis is a novel defined type of programmed cell death (PCD) with widespread functions involved in physical conditions or multiple diseases including malignancies. However, the relationship between ccRCC and ferroptosis-related regulators remains poorly known. Herein, we investigate the prognostic values and potential mechanisms of ferroptosis-related genes (FRGs) in ccRCC.Methods: Ferroptosis-related genes were obtained from FerrDb database, GeneCards database and previously published literatures. The gene expression profile of ferroptosis-related regulators and corresponding clinicopathological information were downloaded from The Cancer Genome Atlas (TCGA). Differentially expressed ferroptosis-related genes (DE-FRGs) were screened between ccRCC specimens and noncancerous specimens. Among these genes, prognostic DE-FRGs were identified using univariate COX analysis and LASSO regression analysis. Further multivariate COX regression was employed to identify prognosis-related hub DE-FRGs and establish a prognostic model. Results: We identified seven hub genes (HMGCR, MT1G, BID, EIF4A1, FOXM1, TFAP2C and CHAC1) from the DE-FRGs using univariate Cox regression analysis, LASSO and multivariate Cox regression analysis, and used them to establish a novel clinical predictive model in the TCGA train cohort (n = 374). Subsequently, we assessed the prognostic value of the model. Survival analysis showed that high-risk patients had a reduced overall survival (OS), the time-dependent receiver operating characteristic (ROC) curve analysis confirmed the signature's diagnostic performance. Additionally, multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor. Additionally, we verified the prognostic performance of the risk model in the testing cohort (n=156), and the entire group (n=530) using Kaplan-Meier curve and ROC curve analyses. Functional analysis indicated that several carcinogenic pathways were enriched, and tumor-infiltrating immune cell abundances, and the expression levels of immunosuppressive molecules were different between two risk groups. Finally, external databases (ONCMINE, GEPIA, HPA, Kaplan-Meier plotter and cbioportal) were used to confirm the expression patterns, prognostic value, and genetic mutations of 7 hub FRGs in ccRCC.Conclusions: Collectively, we successfully constructed a novel ferroptosis-related risk signature that was significantly associated with the prognosis of ccRCC.

scholarly journals Clinical characteristics and outcome of patients with enterococcal liver abscess

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
K. Große ◽  
D. Ohm ◽  
S. Würstle ◽  
J. F. Brozat ◽  
R. M. Schmid ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Regression Analysis ◽  
Clinical Characteristics ◽  
Cox Regression ◽  
Binary Logistic Regression ◽  
Treatment Protocols ◽  
Cox Regression Analysis ◽  
Hepatobiliary Malignancies ◽  
Kaplan Meier ◽  
Increased Risk

AbstractEpidemiology of bacteria isolated from pyogenic liver abscesses change, and an increase in enterococci has been reported in European hospitals. The aim of this study was to investigate the clinical characteristics and outcome of enterococcal PLA. We performed a retrospective analysis of patients with microbiologically confirmed PLA at three German university centers. Indicators of enterococcal PLA were determined using binary logistic regression, and survival analysis was performed using Kaplan–Meier statistics and Cox regression analysis. Enterococci were isolated in 51/133 (38%) patients with PLA. Patients with enterococcal PLA had smaller abscess diameter (4.8 vs. 6.7 cm, p = 0.03) than patients with non-enterococcal PLA, but had more frequent polymicrobial culture results. In univariate logistic regression analysis, alcohol abuse (OR 3.94, 95% CI 1.24–12.49, p = 0.02), hepatobiliary malignancies (OR 3.90, 95% CI 1.86–8.18, p < 0.001) and cirrhosis (OR 6.36, 95% CI 1.27–31.96, p = 0.02) were associated with enterococcal PLA. Patients with enterococcal PLA had a higher mortality than patients with non-enterococcal PLA (hazard ratio 2.92; 95% confidence interval 1.09–7.80; p = 0.03), which remained elevated even after excluding patients with hepatobiliary malignancies, cirrhosis, and transplant recipients in a sensitivity analysis. The increased mortality was associated with non-fecal enterococci but not in patients with Enterococcus faecalis. In this retrospective, multicenter study, enterococcal PLA was common and indicated an increased risk of mortality, underscoring the need for close clinical monitoring and appropriate treatment protocols in these patients.

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