scholarly journals Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study

2021 ◽  
pp. 1-9
Author(s):  
Catarina Frias-Gomes ◽  
Ana Carla Sousa ◽  
Inês Rolim ◽  
Ana Raquel Henriques ◽  
Francisco Branco ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Early Stage ◽  
Small Sample Size ◽  
Real Life ◽  
Disease Free Survival ◽  
Small Sample ◽  
Stage I ◽  
Curative Surgery ◽  
Genetic Characteristics

<b><i>Background and Aims:</i></b> Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. <b><i>Methods:</i></b> Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. <i>RAS</i> and <i>BRAF</i> mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. <b><i>Results:</i></b> Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). <i>RAS</i>-mutated tumours were associated with reduced DFS (<i>p</i> = 0.02) and OS (<i>p</i> = 0.045) in stage I–III CRC. <i>BRAF</i>-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I–III disease. However, after relapse, length of survival was 3.5 months in <i>BRAF</i>-mutated tumours in contrast to 18.6 months in <i>BRAF</i> wild-type tumours (<i>p</i> = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (<i>RAS, BRAF</i> and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. <b><i>Conclusion:</i></b> In our cohort, <i>RAS</i>-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.

scholarly journals Loss of survival advantage for deficient mismatch repair in patients with advanced colorectal cancer may be caused by changes in prognostic value of CD8+T cell

2020 ◽  
Author(s):  
Bingyan Wang ◽  
Fei Li ◽  
Limei Guo ◽  
Siyi Lu ◽  
Junren Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Prognostic Value ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Stage I ◽  
Stage Iii ◽  
Functional Changes ◽  
Deficient Mismatch Repair

Abstract Background: Patients with stage II deficient mismatch repair (dMMR) show a better prognosis than patients with colorectal cancer with proficient mismatch repair (pMMR). However, this beneficial effect is decreased in advanced stages of the disease. This study was conducted to investigate the prognostic value of dMMR and alterations in the tumour microenvironment.Methods: This was a matched retrospective cohort study. Thirty-two patients with stage III&IV dMMR matched with 32 patients with stage I&II dMMR and 64 patients with pMMR were evaluated. Immunohistochemistry analysis was performed for the 64 patients with dMMR to explore the expression and prognostic effect of CD3, CD4, CD8, and PD-L1.Results: Patients with stage III-IV dMMR showed no advantage in overall survival (OS) and disease-free survival (DFS) compared to patients with pMMR (P = 0.244, P = 0.667). No expression differences in CD3, CD4, CD8, and PD-L1 at the centre of the tumour (CT) or invasive margin (IM) were found between patients with stage I&II and stage III&IV dMMR. High CD3 expression at the CT and high CD3 an CD4 expression at the IM improved both OS and DFS. High CD8 expression showed opposite prognostic value in patients with stage I&II and III&IV dMMR. A similar tendency was observed for PD-L1 expression.Conclusion: Patients with stage III-IV dMMR showed no prognostic advantage over patients with pMMR. Expression of CD3, CD4, CD8, and PD-L1 was similar between stage I&II and III&IV dMMR CRC. High CD3 expression at the CT and high CD3 and CD4 expression at the IM can significantly improve patient prognosis. The opposite prognostic tendency of CD8 and PD-L1 for patients with stage I&II and III&IV dMMR may be relevant to CD8+T cell exhaustion and functional changes at inhibitory immune checkpoints.

scholarly journals Loss of survival advantage for deficient mismatch repair in patients with advanced colorectal cancer may be caused by changes in prognostic value of CD8+T cell expression

2020 ◽  
Author(s):  
Bingyan Wang ◽  
Fei Li ◽  
Limei Guo ◽  
Siyi Lu ◽  
Junren Ma ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Mismatch Repair ◽  
Prognostic Value ◽  
Disease Free Survival ◽  
Cd8 T Cell ◽  
Stage I ◽  
Stage Iii ◽  
Keywords Colorectal Cancer ◽  
Deficient Mismatch Repair

Abstract Background: Patients with stage II deficient mismatch repair (dMMR) show a better prognosis than patients with colorectal cancer with proficient mismatch repair (pMMR). However, this beneficial effect is decreased in advanced stages of the disease. This study was conducted to investigate the prognostic value of dMMR and alterations in the tumour microenvironment. Methods: This was a matched retrospective cohort study. Thirty-two patients with stage III&IV dMMR matched with 32 patients with stage I&II dMMR and 64 patients with pMMR were evaluated. Immunohistochemistry analysis was performed for the 64 patients with dMMR to explore the expression and prognostic effect of CD3, CD4, CD8, and PD-L1. Results: Patients with stage III-IV dMMR showed no advantage in overall survival (OS) and disease-free survival (DFS) compared to patients with pMMR (P = 0.244, P = 0.667). No expression differences in CD3, CD4, CD8, and PD-L1 at the centre of the tumour (CT) or invasive margin (IM) were found between patients with stage I&II and stage III&IV dMMR. High CD3 expression at the CT and high CD3 an CD4 expression at the IM improved both OS and DFS. High CD8 expression showed opposite prognostic value in patients with stage I&II and III&IV dMMR. A similar tendency was observed for PD-L1 expression. Conclusion: Patients with stage III-IV dMMR showed no prognostic advantage over patients with pMMR. Expression of CD3, CD4, CD8, and PD-L1 was similar between stage I&II and III&IV dMMR CRC. High CD3 expression at the CT and high CD3 and CD4 expression at the IM can significantly improve patient prognosis. The opposite prognostic tendency of CD8 and PD-L1 for patients with stage I&II and III&IV dMMR may be relevant to CD8+T cell exhaustion and functional changes at inhibitory immune checkpoints. Keywords: colorectal cancer, deficient mismatch repair, tumour-infiltrating lymphocyte, PD-L1, prognosis

scholarly journals A signature of hypoxia-related factors reveals functional dysregulation and robustly predicts clinical outcomes in stage I/II colorectal cancer patients

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi-feng Zou ◽  
Yu-ming Rong ◽  
Ying-xin Tan ◽  
Jian Xiao ◽  
Zhao-liang Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Validation Cohort ◽  
Risk Group ◽  
Early Stage ◽  
Disease Free Survival ◽  
Gene Signature ◽  
Low Risk ◽  
Stage I ◽  
Related Factors ◽  
Training Cohort

Abstract Background The hypoxic tumor microenvironment accelerates the invasion and migration of colorectal cancer (CRC) cells. The aim of this study was to develop and validate a hypoxia gene signature for predicting the outcome in stage I/II CRC patients that have limited therapeutic options. Methods The hypoxic gene signature (HGS) was constructed using transcriptomic data of 309 CRC patients with complete clinical information from the CIT microarray dataset. A total of 1877 CRC patients with complete prognostic information in six independent datasets were divided into a training cohort and two validation cohorts. Univariate and multivariate analyses were conducted to evaluate the prognostic value of HGS. Results The HGS consisted of 14 genes, and demarcated the CRC patients into the high- and low-risk groups. In all three cohorts, patients in the high-risk group had significantly worse disease free survival (DFS) compared with those in the low risk group (training cohort—HR = 4.35, 95% CI 2.30–8.23, P < 0.001; TCGA cohort—HR = 2.14, 95% CI 1.09–4.21, P = 0.024; meta-validation cohort—HR = 1.91, 95% CI 1.08–3.39, P = 0.024). Compared to Oncotype DX, HGS showed superior predictive outcome in the training cohort (C-index, 0.80 vs 0.65) and the validation cohort (C-index, 0.70 vs 0.61). Pathway analysis of the high- and low-HGS groups showed significant differences in the expression of genes involved in mTROC1, G2-M, mitosis, oxidative phosphorylation, MYC and PI3K–AKT–mTOR pathways (P < 0.005). Conclusion Hypoxic gene signature is a satisfactory prognostic model for early stage CRC patients, and the exact biological mechanism needs to be validated further.

An Integrated Feature Selection Algorithm for Cancer Classification using Gene Expression Data

2019 ◽  
Vol 21 (9) ◽  
pp. 631-645 ◽  
Author(s):  
Saeed Ahmed ◽  
Muhammad Kabir ◽  
Zakir Ali ◽  
Muhammad Arif ◽  
Farman Ali ◽  
...  
Keyword(s):  
Gene Expression ◽  
Feature Selection ◽  
Gene Expression Data ◽  
Classification Accuracy ◽  
Early Stage ◽  
Small Sample Size ◽  
Feature Selection Method ◽  
Small Sample ◽  
Expression Data ◽  
Base Function

Aim and Objective: Cancer is a dangerous disease worldwide, caused by somatic mutations in the genome. Diagnosis of this deadly disease at an early stage is exceptionally new clinical application of microarray data. In DNA microarray technology, gene expression data have a high dimension with small sample size. Therefore, the development of efficient and robust feature selection methods is indispensable that identify a small set of genes to achieve better classification performance. Materials and Methods: In this study, we developed a hybrid feature selection method that integrates correlation-based feature selection (CFS) and Multi-Objective Evolutionary Algorithm (MOEA) approaches which select the highly informative genes. The hybrid model with Redial base function neural network (RBFNN) classifier has been evaluated on 11 benchmark gene expression datasets by employing a 10-fold cross-validation test. Results: The experimental results are compared with seven conventional-based feature selection and other methods in the literature, which shows that our approach owned the obvious merits in the aspect of classification accuracy ratio and some genes selected by extensive comparing with other methods. Conclusion: Our proposed CFS-MOEA algorithm attained up to 100% classification accuracy for six out of eleven datasets with a minimal sized predictive gene subset.

scholarly journals Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma

2021 ◽  
Author(s):  
Ignacio Ruz-Caracuel ◽  
Álvaro López-Janeiro ◽  
Victoria Heredia-Soto ◽  
Jorge L. Ramón-Patino ◽  
Laura Yébenes ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Mismatch Repair ◽  
Predictive Value ◽  
Early Stage ◽  
Disease Free Survival ◽  
Low Grade ◽  
Beta Catenin ◽  
Free Survival ◽  
Disease Free ◽  
Risk Of Relapse

AbstractLow-grade and early-stage endometrioid endometrial carcinomas (EECs) have an overall good prognosis but biomarkers identifying patients at risk of relapse are still lacking. Recently, CTNNB1 exon 3 mutation has been identified as a potential risk factor of recurrence in these patients. We evaluate the prognostic value of CTNNB1 mutation in a single-centre cohort of 218 low-grade, early-stage EECs, and the correlation with beta-catenin and LEF1 immunohistochemistry as candidate surrogate markers. CTNNB1 exon 3 hotspot mutations were evaluated by Sanger sequencing. Immunohistochemical staining of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), p53, beta-catenin, and LEF1 was performed in representative tissue microarrays. Tumours were also reviewed for mucinous and squamous differentiation, and MELF pattern. Nineteen (8.7%) tumours harboured a mutation in CTNNB1 exon 3. Nuclear beta-catenin and LEF1 were significantly associated with CTNNB1 mutation, showing nuclear beta-catenin a better specificity and positive predictive value for CTNNB1 mutation. Tumours with CTNNB1 exon 3 mutation were associated with reduced disease-free survival (p = 0.010), but no impact on overall survival was found (p = 0.807). The risk of relapse in tumours with CTNNB1 exon 3 mutation was independent of FIGO stage, tumour grade, mismatch repair protein expression, or the presence of lymphovascular space invasion. CTNNB1 exon 3 mutation has a negative impact on disease-free survival in low-grade, early-stage EECs. Nuclear beta-catenin shows a higher positive predictive value than LEF1 for CTNNB1 exon 3 mutation in these tumours. Graphical abstract

scholarly journals Epithelial-Mesenchymal Transition Phenotype, Metformin, and Survival for Colorectal Cancer Patients with Diabetes Mellitus II

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Yaodu Wang ◽  
Zhiyang Wu ◽  
Likuan Hu
Keyword(s):  
Diabetes Mellitus ◽  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Disease Free Survival ◽  
Multivariate Regression Analysis ◽  
Stage I ◽  
Clinicopathological Parameters ◽  
Mesenchymal Transition ◽  
Patients With Diabetes ◽  
E Cadherin

Objectives. We aimed to explore the association between metformin treatment and epithelial-mesenchymal transition (EMT) phenotype and further appraise the prognostic values of metformin and EMT markers E-cadherin and vimentin for colorectal cancer (CRC) in clinical practice. Methods. We collected specimens and evaluated clinicopathological parameters of 102 stage I to III CRC patients with prediagnosed type 2 diabetes mellitus (DM II). Expression of E-cadherin and vimentin in tumors was detected by immunohistochemistry (IHC), and statistical analysis was performed using SPSS 19.0. Results. In correlation tests, we found a lower tumor cell EMT degree (more E-cadherin (P=0.014) and less vimentin (P=0.011) expression in patients who used metformin, and the expression of E-cadherin and vimentin was associated with serum CA19-9 (P=0.048, P=0.009), tumor invasive depth (T) (P<0.001, P=0.045), and lymph invasion (N) (P=0.013, P=0.001). In Cox multivariate regression analysis, E-cadherin was identified as a prognostic factor for disease-free survival (DFS) (P=0.038) and metformin use (P=0.015P=0.044) and lymph invasion (P=0.016P=0.023) were considered as the prognostic factors for both DFS and overall survival (OS). Conclusion. Our study suggested that metformin may impede the EMT process and improve survival for stage I–III CRC patients with DM II.

scholarly journals Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting

2016 ◽  
Vol 23 (3) ◽  
pp. 171 ◽  
Author(s):  
A. Mamo ◽  
J. Easaw ◽  
F. Ibnshamsah ◽  
A. Baig ◽  
Y.S. Rho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dose Reduction ◽  
Real Life ◽  
Disease Free Survival ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Stage Iii ◽  
Cancer Centre ◽  
Peripheral Sensory ◽  
Disease Free

Background Despite lack of a true comparative study, the FOLFOX (5-fluorouracil–leucovorin–oxaliplatin) and CAPOX (capecitabine–oxaliplatin) regimens are believed to be similar in their efficacy and tolerability in the treatment of stage III colorectal cancer. However, that belief has been disputed, because real-life data suggest that the CAPOX regimen is more toxic, leading to more frequent reductions in the delivered dose intensity—thus raising questions about the effect of dose intensity on clinical outcomes.Methods A retrospective data review for two Canadian institutions, the Segal Cancer Centre and the Tom Baker Cancer Centre, considered patients diagnosed with stage III colorectal cancer during 2006–2013. Primary endpoints were dose intensity and toxicity, with a secondary endpoint of disease-free survival.Results The study enrolled 180 eligible patients (80 at the Segal Cancer Centre, 100 at the Tom Baker Cancer Centre). Of those 180 patients, 75 received CAPOX, and 105 received mFOLFOX6. In the CAPOX group, a significant dose reduction was identified for capecitabine compared with 5-fluorouracil in mFOLFOX6 group (p = 0.0014). Similarly, a significant dose reduction was observed for oxaliplatin in mFOLFOX6 compared with oxaliplatin in CAPOX (p = 0.0001). Compared with the patients receiving CAPOX, those receiving mFOLFOX6 were twice as likely to experience a treatment delay of more than 1 cycle-length (p = 0.03855). Toxicity was more frequent in patients receiving mFOLFOX6 (nausea: 30% vs. 18%; diarrhea: 47% vs. 24%; peripheral sensory neuropathy: 32% vs. 3%). At a median follow-up of 40 months, preliminary data showed no difference in disease-free survival (p = 0.598). Pooled data from both institutions were also separately analyzed, and no significant differences were found.Conclusions Our results support the use of CAPOX despite a lack of head-to-head randomized trial data.

scholarly journals HER2 and BRAF mutation in colorectal cancer patients: a retrospective study in Eastern China

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8602 ◽  
Author(s):  
Xiangyan Zhang ◽  
Jie Wu ◽  
Lili Wang ◽  
Han Zhao ◽  
Hong Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Eastern China ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Molecular Classification ◽  
Clinicopathological Characteristics ◽  
Stage I ◽  
Chinese Patients ◽  
Poor Differentiation ◽  
Colorectal Cancer Patients

Objective To investigate the frequency and prognostic role of the human epidermal growth factor receptor 2 gene (HER2) and BRAF V600E gene mutation in Chinese patients with colorectal cancer (CRC). Methods Clinicopathological and survival information from 480 patients with stage I–III CRC were reviewed and recorded. HER2 amplification was analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), BRAF V600E mutation was tested by IHC and Sanger sequencing. The relationship between HER2 and BRAF V600E mutation status and clinicopathological characteristics and outcomes were determined. Results The amplification of HER2 and BRAF V600E mutation were identified in 27 of 480 (5.63%) and 19 of 480 (3.96%) CRC patients, respectively. HER2 amplification significantly correlated with greater bowel wall invasion (P = 0.041) and more advanced TNM stage (I vs. II vs. III; 0 vs 5.78% vs. 7.41%, P = 0.013). Patients suffering from tumors with poor differentiation had a higher incidence rate of BRAF V600E mutation than those with moderate/well differentiation (7.77% vs 2.92%, P = 0.04). HER2 amplification was an independent prognostic factor for worse disease-free survival (DFS) (HR = 2.53, 95% CI: 1.21–5.30, P = 0.014). Conclusion The prevalence of HER2 amplification and BRAF V600E mutation in stage I–III CRC patients in Chinese was 6% and 4%, respectively, and HER2 amplification appeared to be associated with a worse DFS. More comprehensive molecular classification and survival analysis are needed to validate our findings.

scholarly journals Management of patients with early stage lung cancer – why do some patients not receive treatment with curative intent?

2020 ◽  
Author(s):  
Ross Lawrenson ◽  
Chunhuan Lao ◽  
Leonie Brown ◽  
Lucia Moosa ◽  
Lynne Chepulis ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Early Stage ◽  
Hazard Ratio ◽  
Stage I ◽  
Curative Treatment ◽  
Curative Surgery ◽  
Early Stage Lung Cancer ◽  
Curative Intent ◽  
Receive Treatment ◽  
Stage Lung Cancer

Abstract Backgrounds This study aims to understand the factors that influence whether patients receive potentially curative treatment for early stage lung cancer. Methods Patients included those diagnosed with early stage lung cancer in 2011-2018 and resident in the New Zealand Midland Cancer Network region. Logistic regression model was used to estimate the odds ratios of having curative surgery/ treatment. The Kaplan Meier method was used to examine the all-cause survival and Cox proportional hazard model was used to estimate the hazard ratio of death. Results In total 419/583 (71.9%) of patients with Stage I and II disease were treated with curative intent - 272 (46.7%) patients had curative surgery. Patients not receiving potentially curative treatment were older, were less likely to have non-small cell lung cancer (NSCLC), had poorer lung function and were more likely to have an ECOG performance status of 2+. Current smokers were less likely to be treated with surgery and more likely to receive treatment with radiotherapy and chemotherapy. Those who were treated with surgery had a 2-year survival of 87.8% (95% CI: 83.8%-91.8%) and 5-year survival of 69.6% (95% CI: 63.2%-76.0%). Stereotactic ablative body radiotherapy (SABR) has equivalent effect on survival compared to curative surgery (hazard ratio: 0.77, 95% CI: 0.37-1.61). Conclusions The majority of patients with stage I and II lung cancer are managed with potentially curative treatment – mainly surgery and increasingly with SABR. The outcomes of those being diagnosed with stage I and II disease and receiving treatment is positive with 70% surviving 5 years.

scholarly journals Über die Situation der Jungwissenschaftlerinnen und -wissenschaftler in der Psychologie in Österreich

2020 ◽  
Author(s):  
Jakob C. Bergmann ◽  
Hanna M. Mües ◽  
Jochen Mosbacher ◽  
Lisa V. Eckerstorfer ◽  
Ulrich Pomper ◽  
...  
Keyword(s):  
Working Conditions ◽  
Early Stage ◽  
Small Sample Size ◽  
Work Satisfaction ◽  
Young Scientist ◽  
Theoretical Background ◽  
Small Sample ◽  
Temporary Work ◽  
Work Done ◽  
High Work

Theoretical Background: Uncertainty with respect to professional prospects, a challenging work-life-balance and health problems as well as moderate to high work satisfaction are associated with being a young scientist. This paper aims to investigate the working conditions, job satisfaction, and strain of early stage researchers working in the field of psychology in Austria. To date, no systematic investigations have examined the working situations of these individuals.Methods: A total of 97 early stage researchers – 64 praedocs (66% female; M Age = 29.84 years, SD Age = 4.00 years), and 33 postdocs (55% female, M Age = 33.39 years, SD Age = 3.41 years) – participated in an online survey.Results: The results reveal that both groups report highly demanding working conditions (e.g. uncertain career paths due to temporary work contracts, high number of additional hours of work done outside the contractual work hours), moderate to high levels of work satisfaction and moderate to low strain.Conclusion: A considerable number of potential areas for improvement become apparent. However, due to the small sample size, the representativeness as well as generalizability of the results are limited. Based on the results of this survey, possible measures to improve the current situation are presented. This article provides guidance for potential future early stage researchers.

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