Prognostic significance of tumor stromal and epithelial claudin 2 in metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3597-3597
Author(s):  
Artur Mezheyeuski ◽  
Tormod Kyrre Guren ◽  
Bengt Glimelius ◽  
Per Pfeiffer ◽  
Elin Kure ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Alkaline Phosphatase ◽  
Cancer Cells ◽  
Tumor Tissue ◽  
Primary Cultures ◽  
Prognostic Significance ◽  
Tumor Stroma ◽  
Phase Iii ◽  
Rank Test ◽  
Worse Prognosis

3597 Background: Tight junctions (TJ) are the most apical epithelial cell–cell adhesions. Claudin super-family trans-membrane proteins, including claudin 2 (cl2), are important components of TJs. Expression of cl2 has been reported to be elevated in colorectal cancer (CRC) and its up-regulation increases tumorigenicity of CRC cells in vitro. The aim of this study was to analyze the prognostic significance of cl2 in CRC. Methods: A tissue microarray (TMA) from the stage IV CRC patients of the phase III NORDIC-VII study was used. Cl2 IHC staining was evaluated in a semi-quantitative manner in cancer cells (cl2-C) and in the tumor stroma (cl2-S). Primary fibroblasts were established from human CRC tumor tissue and non-tumor colon tissue, and evaluated by immunoblotting. Results: Analyses of the TMA derived from the NORDIC-VII cohort revealed that cancer cell expression and tumor stroma expression of cl2 was associated with shorter OS in a Log-Rank test for trend (cl2-C, n=315, p=0.018; cl2-S, n=319, p=0.020). Expression of cl2-S, but not cl2-C was prognostic in multivariate analysis including WHO performance status, alkaline phosphatase level and BRAF mutation status (HR=1.30; 95% CI 1.08-1.56; p=0.006). When cl2-C and cl2-S expression was combined the prognostic significance was increased. The group with high cl2-C and high cl2-S (N=182), when compared with the rest of the cases (n=129), displayed a worse prognosis in terms of OS (19.1 mo vs 27.2 mo; p=0.003) in univariate analyses (HR=1.55, 95% CI 1.16-2.08, p=0.003) and in multivariate analyses (HR=1.52, 95% CI 1.13-2.05, p=0.006). Immunoblotting analysis of primary cultures of fibroblasts confirmed cl2 expression in fibroblasts from CRC tissue and from non-tumor tissue, with higher expression observed in the tumor fibroblasts. Conclusions: CRC display a previously un-reported stromal expression of cl2 of prognostic significance. High cl2-S is associated with worse prognosis in patients with metastatic CRC, in a manner independent of WHO status, alkaline phosphatase levels and BRAF status. Furthermore, high expression of cl2 in both cancer cells and the tumor stroma is also associated with poor prognosis.

Tumor perivascular PDGFBR as an independent prognostic factor in metastatic colorectal cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3571-3571
Author(s):  
Maja Bradic Lindh ◽  
Artur Mezheyeuski ◽  
Bengt Glimelius ◽  
Per Pfeiffer ◽  
Elin Kure ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Alkaline Phosphatase ◽  
Prognostic Factor ◽  
Normal Tissue ◽  
Performance Status ◽  
Prognostic Significance ◽  
Growth Factor Receptor ◽  
Independent Prognostic Factor ◽  
Phase Iii ◽  
Double Staining

3571 Background: New vessel formation is an essential factor for tumor growth and metastasis. Tumor vessels show reduced and variable pericyte coverage. Several pericyte markers have been identified, including platelet-derived growth factor receptor beta (PDGFbR), smooth muscle α-actin (ASMA) and desmin. Variability in pericyte status and its prognostic significance remains largely uncharacterized in colorectal cancer (CRC). The aim of the present study was to perform a preliminary analysis of the variability in expression of the three pericyte markers and to investigate the potential prognostic significance of perivascular PDGFbR (PV-PDGFbR). Methods: A population-based cohort was used for double-staining, performed on 100 tumors with CD34 and above-named pericyte markers. For the rest of the study a metastatic CRC (mCRC) collection from the phase III NORDIC-VII study was used. Analyses were performed on a tissue microarray with tumor material from 328 out of the 566 patients in the intention to treat population. All tumors and corresponding normal tissue were scored by immunohistochemistry (IHC) with regard to PV-PDGFbR. 255 and 97 cases were analyzed by IHC with regard to perivascular ASMA and microvessel density (MVD), respectively. Results: Analyses of the double-staining revealed independent and variable expressions of all three pericyte markers. Analyses of the NORDIC-VII cohort revealed two prognostic groups with low and high PV-PDGFbR expression. Median OS was 14.3 mo for PV-PDGFbR-low tumors (N=22) vs. 22.9 mo for PV-PDGFbR-high (N=306) tumors (HR=1.95; 95% CI 1.20-3.16; log-rank p=0.007). Multivariate analysis, including WHO performance status, alkaline phosphatase level and BRAF mutation status confirmed PV-PDGFbR as an independent prognostic factor of OS (HR=1.75; 95% CI 1.07-2.84; p=0.025). PV-PDGFbR was not significantly linked to perivascular ASMA or MVD. PV-PDGFbR in normal tissue was not associated with survival. Conclusions: CRC display a previously un-recognized variability in pericyte characteristics. Low tumor PV-PDGFbR level is associated with worse prognosis in patients with mCRC, in a manner independent of performance status, alkaline phosphatase levels and BRAF status.

Prognostic role of microRNA-34a expression in colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 472-472
Author(s):  
Albert Y. Lin ◽  
Natalia B. Kouzminova ◽  
Jonathan Pollack ◽  
Gerard Nuovo
Keyword(s):  
Colorectal Cancer ◽  
Cancer Cells ◽  
Cell Fate ◽  
Cox Regression ◽  
Early Stage ◽  
Prognostic Significance ◽  
Rank Correlation ◽  
Suppressor Gene ◽  
Stage Ii ◽  
Rank Test

472 Background: Colorectal Cancer (CRC) is one of the leading causes of death worldwide. MicroRNA-34a (miR-34a), a tumor suppressor gene, is known to be down-regulated in CRC cell lines and recently shown to be a cell-fate determinant in early-stage dividing colon cancer stem cells. However, its prognostic significance is unclear. Methods: MiR-34a detection was performed by in situ hybridization on a CRC tissue microarray (n=127; stage I, 21 patients; II: 42; III: 33; IV: 31). Its expression was graded as negative (no signal), low (expression in 1-19% of cancer cells), moderate (20-49% of cancer cells), and strong (50-100% of cancer cells). The correlations between miR-34a expression and EGFR, osteopontin (OPN), p53, Ki67, LEF1, VEGF, COX2, MMR, stage and grade were evaluated by chi-squared test and Spearman's rank correlation coefficient. Kaplan-Meier survival analysis, log-rank test and Cox regression model were used to assess the association of miR-34a expression with recurrence-free survival (RFS) and disease specific survival (DSS). Results: MiR-34a expression had moderate positive correlation with genes associated with tissue proliferation and invasion, including Ki67 (Spearman's r=0.28, p=0.002), and weak correlation with EGFR (r=0.2, p=0.02) and LEF1 (r=0.18, p=0.039). In the subgroup of patients (n=75; stage II/III) with negative OPN expression (n=25), weak or negative miR-34a expression was associated with worse RFS (HR=4.1; 95%CI=1.1-15.9; p=0.036) and DSS (HR=10.5; 95%CI=1.2-94.5; p=0.036). Conclusions: Our results suggest that down-regulated or absent expression of miR-34a correlates with worse RFS and DSS in stage II - III CRC patients with negative OPN expression. Further investigation of miR34a in prospective randomized studies is warranted to establish its role as a prognostic factor for CRC outcome.

Tumor-Infiltrating FOXP3+ T Regulatory Cells Show Strong Prognostic Significance in Colorectal Cancer

2009 ◽  
Vol 27 (2) ◽  
pp. 186-192 ◽  
Author(s):  
Paul Salama ◽  
Michael Phillips ◽  
Fabienne Grieu ◽  
Melinda Morris ◽  
Nik Zeps ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colonic Mucosa ◽  
Tumor Tissue ◽  
Early Stage ◽  
Prognostic Significance ◽  
High Density ◽  
Prognostic Indicators ◽  
Normal Colonic Mucosa ◽  
Solid Cancer ◽  
Histopathologic Features

Purpose To determine the prognostic significance of FOXP3+ lymphocyte (Treg) density in colorectal cancer compared with conventional histopathologic features and with CD8+ and CD45RO+ lymphocyte densities. Patients and Methods Tissue microarrays and immunohistochemistry were used to assess the densities of CD8+, CD45RO+, and FOXP3+ lymphocytes in tumor tissue and normal colonic mucosa from 967 stage II and stage III colorectal cancers. These were evaluated for associations with histopathologic features and patient survival. Results FOXP3+ Treg density was higher in tumor tissue compared with normal colonic mucosa, whereas CD8+ and CD45RO+ cell densities were lower. FOXP3+ Tregs were not associated with any histopathologic features, with the exception of tumor stage. Multivariate analysis showed that stage, vascular invasion, and FOXP3+ Treg density in normal and tumor tissue were independent prognostic indicators, but not CD8+ and CD45RO+. High FOXP3+ Treg density in normal mucosa was associated with worse prognosis (hazard ratio [HR] = 1.51; 95% CI, 1.07 to 2.13; P = .019). In contrast, a high density of FOXP3+ Tregs in tumor tissue was associated with improved survival (HR = 0.54; 95% CI, 0.38 to 0.77; P = .001). Conclusion FOXP3+ Treg density in normal and tumor tissue had stronger prognostic significance in colorectal cancer compared with CD8+ and CD45RO+ lymphocytes. The finding of improved survival associated with a high density of tumor-infiltrating FOXP3+ Tregs in colorectal cancer contrasts with several other solid cancer types. The inclusion of FOXP3+ Treg density may help to improve the prognostication of early-stage colorectal cancer.

Analysis of RGS2 expression and prognostic significance in stage II and III colorectal cancer

2010 ◽  
Vol 30 (6) ◽  
pp. 383-390 ◽  
Author(s):  
Zheng Jiang ◽  
Zhimin Wang ◽  
Ye Xu ◽  
Beilan Wang ◽  
Wei Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mrna Expression ◽  
Survival Time ◽  
Cell Lines ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Stage Ii ◽  
Rank Test ◽  
Clinicopathological Factors ◽  
Real Time Quantitative Pcr

The role of RGS2 (regulator of G-protein signalling 2) has been studied in several tumours. The purpose of the present study is to investigate the correlations between clinicopathological factors and patients' survival time and RGS2 expression in stage II and III CRC (colorectal cancer) patients. Real-time quantitative PCR was performed in 36 CRC tissues with recurrence and 28 without recurrence, and in three CRC-metastasis-derived cell lines (SW620, LoVo and Colo205) and 3 primary-CRC-derived ones (SW480, Caco-2 and HCT116) to examine RGS2 mRNA expression. In addition, to provide visualized evidence for RGS2 mRNA expression, random CRC samples were also performed with RT–PCR (reverse transcription–PCR). RGS2 protein was detected by immunostaining in 118 paraffin-embedded specimens, and the correlations between clinicopathological factors and survival time and RGS2 expression were analysed. We found that RGS2 mRNA was down-regulated both in CRC tissues with recurrence and metastasis-derived cell lines, and the expression level of RGS2 was unrelated to gender, age, tumour grade, or lymphovascular or perineural invasion. However, it was positively related to disease-free survival time (P<0.05). Furthermore, low RGS2 expression indicated a poorer survival rate (P<0.05, log-rank test). Multivariate analysis also showed that weak RGS2 protein expression was an independent adverse prognosticator in CRC (P<0.05). Taken together, we suggested that down-regulation of RGS2 might play an important role in CRC metastasis and predict poor prognosis in stage II and III CRC patients.

scholarly journals Prognostic significance of MUC2, CDX2 and SOX2 in stage II colorectal cancer patients

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Sara Ribeirinho-Soares ◽  
Diana Pádua ◽  
Ana Luísa Amaral ◽  
Elvia Valentini ◽  
Daniela Azevedo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Prognostic Significance ◽  
Tumor Resection ◽  
Disease Free Survival ◽  
Predictive Biomarkers ◽  
Stage Ii ◽  
Health Concern ◽  
Rank Test ◽  
Low Expression

Abstract Background Colorectal cancer (CRC) remains a serious health concern worldwide. Despite advances in diagnosis and treatment, about 15 to 30% of stage II CRC patients subjected to tumor resection with curative intent, develop disease relapse. Moreover, the therapeutic strategy adopted after surgery is not consensual for these patients. This supports the imperative need to find new prognostic and predictive biomarkers for stage II CRC. Methods For this purpose, we used a one-hospital series of 227 stage II CRC patient samples to assess the biomarker potential of the immunohistochemical expression of MUC2 mucin and CDX2 and SOX2 transcription factors. The Kaplan-Meier method was used to generate disease-free survival curves that were compared using the log-rank test, in order to determine prognosis of cases with different expression of these proteins, different mismatch repair (MMR) status and administration or not of adjuvant chemotherapy. Results In this stage II CRC series, none of the studied biomarkers showed prognostic value for patient outcome. However low expression of MUC2, in cases with high expression of CDX2, absence of SOX2 or MMR-proficiency, conferred a significantly worst prognosis. Moreover, cases with low expression of MUC2 showed a significantly clear benefit from treatment with adjuvant chemotherapy. Conclusion In conclusion, we observe that patients with stage II CRC with low expression of MUC2 in the tumor respond better when treated with adjuvant chemotherapy. This observation supports that MUC2 is involved in resistance to fluorouracil-based adjuvant chemotherapy and might be a promising future predictive biomarker in stage II CRC patients.

scholarly journals Resampling the N9741 Trial to Compare Tumor Dynamic Versus Conventional End Points in Randomized Phase II Trials

2015 ◽  
Vol 33 (1) ◽  
pp. 36-41 ◽  
Author(s):  
Manish R. Sharma ◽  
Elizabeth Gray ◽  
Richard M. Goldberg ◽  
Daniel J. Sargent ◽  
Theodore G. Karrison
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Phase Iii ◽  
Rank Test ◽  
Phase Ii Trials ◽  
End Points ◽  
End Point ◽  
Randomized Phase Ii ◽  
Log Ratio

Purpose The optimal end point for randomized phase II trials of anticancer therapies remains controversial. We simulated phase II trials by resampling patients from N9741, a randomized phase III trial of chemotherapy regimens for metastatic colorectal cancer, and compared the power of various end points to detect the superior therapy (FOLFOX [infusional fluorouracil, leucovorin, and oxaliplatin] had longer overall survival than both IROX [irinotecan plus oxaliplatin] and IFL [irinotecan and bolus fluorouracil plus leucovorin]). Methods Tumor measurements and progression-free survival (PFS) data were obtained for 1,471 patients; 1,002 had consistently measured tumors and were resampled (5,000 replicates) to simulate two-arm, randomized phase II trials with α = 0.10 (one sided) and 20 to 80 patients per arm. End points included log ratio of tumor size at 6, 12, and 18 weeks relative to baseline; time to tumor growth (TTG), estimated using a nonlinear mixed-effects model; and PFS. Arms were compared using rank sum tests for log ratio and TTG and a log-rank test for PFS. Results For FOLFOX versus IFL, TTG and PFS had similar power, with both exceeding the power of log ratio at 18 weeks; for FOLFOX versus IROX, TTG and log ratio at 18 weeks had similar power, with both exceeding the power of PFS. The best end points exhibited > 80% power with 60 to 80 patients per arm. Conclusion TTG is a powerful end point for randomized phase II trials of cytotoxic therapies in metastatic colorectal cancer; it was either comparable or superior to PFS and log ratio at 18 weeks. Additional studies will be needed to clarify the potential of TTG as a phase II end point.

scholarly journals Prognostic significance of S100A4 expression in stage II and III colorectal cancer: results from a population‐based series and a randomized phase III study on adjuvant chemotherapy

2016 ◽  
Vol 5 (8) ◽  
pp. 1840-1849 ◽  
Author(s):  
Kjetil Boye ◽  
Havjin Jacob ◽  
Kari‐Anne M. Frikstad ◽  
Jahn M. Nesland ◽  
Gunhild M. Mælandsmo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Prognostic Significance ◽  
Population Based ◽  
Stage Ii ◽  
Phase Iii ◽  
S100a4 Expression ◽  
Phase Iii Study

scholarly journals Correlation of Clinicopathological Features and IL6 Expression in Tumor Budding of Colon Adenocarcinoma

2020 ◽  
Author(s):  
Koichi Sato ◽  
Takeshi Uehara ◽  
Mai Iwaya ◽  
Tomoyuki Nakajima ◽  
Yosuke Tobe ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Prognostic Significance ◽  
Colon Adenocarcinoma ◽  
Tumor Budding ◽  
Rank Test ◽  
Negative Group ◽  
Positive Group ◽  
Significant Difference ◽  
Cox Proportional Hazard Regression

Abstract Background: Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts (CAFs). IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in tumor budding (TB) and its association with TB in colon adenocarcinoma (CA). Methods: The clinicopathological and prognostic significance of IL6 in TB was examined using a tissue microarray consisting of 36 patient samples of TB in CA. IL6 mRNA was detected by RNAscope kit. Patients were stratified into negative and positive IL6 expression groups.Results: IL6 expression was overwhelmingly observed in CAFs but was negligible in cancer cells. In the IL6-positive group in CAFs, TB grade was higher than in the IL6-negative group (P=0.0161). There was a significant difference in overall survival (OS) between CA cases in the IL6-positive group and the IL6-negative group (log rank test, P=0.0367). Cox proportional hazard regression model revealed that the IL6-negative group (OR = 0.25; 95% CI: 0.05–0.96; P=0.0440) had better OS for CA than the IL6-positive group. Conclusions: TB may be affected by IL6 expression, and IL6 expression in CAFs at TB may make IL6 an important prognostic marker.

scholarly journals Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

2021 ◽  
Author(s):  
Elham Kalantari ◽  
Roya Ghods ◽  
Leili Saeednejad Zanjani ◽  
Mandana Rahimi ◽  
Leila Eini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Polyclonal Antibody ◽  
Prognostic Significance ◽  
Rank Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Disease Specific Survival ◽  
Cytoplasmic Expression ◽  
Advanced Tumor ◽  
Disease Specific

Abstract Background: Oncogenic role of doublecortin-like kinase 1 (DCLK1) as a putative cancer stem cell (CSC) marker has been clarified in colorectal cancer (CRC). Isoform-specific function of DCLK1 has highlighted key role of the DCLK1-S (short isoform) in tumor maintenance, progression, and invasion. Considering the lack of commercial anti-DCLK1-S antibody suitable for immunohistochemical (IHC) application, this study was conducted to produce and validate an anti-DCLK1-S polyclonal antibody in order to specifically evaluate expression pattern and clinical significance of short isoform of DCLK1 in colorectal cancer tissues.Methods: Rabbit immunization was performed against a synthetic peptide corresponding to the published six specific amino acid sequences of DCLK1-S, and production of antibody was evaluated by enzyme-linked immunosorbent assay (ELISA). After IHC assessment of the purified anti-DCLK1-S polyclonal antibody, it was used to undertake a definitive study for determining prognostic significance of DCLK1-S expression in a well-defined tissue microarray (TMA) series including 348 CRC and 51 adjacent normal tissues with a follow-up period of 108 months. Results: Positive immunoreactivity of DCLK1-S was found in 84.2% of CRC samples. Cytoplasmic expression was the main localization of DCLK1-S compared to nuclear and membranous area of tumor cells. Expression of DCLK1-S in CRC samples was significantly higher compared to adjacent normal samples (P <0.001). A positive significant association was found between high cytoplasmic expression of DCLK1-S and advanced tumor, nodes, and metastases (TNM) stage (P<0.001) as well as the increased tumor differentiation (P= 0.02). Moreover, the patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rate (P= 0.01). Additionally, the improved prognostic value was seen in the patients with CRC with high DCLK1-S expression versus moderate expression (HR: 2.70, 95% CI: 0.98-7.38; p =0.04) by multivariate analysis.Conclusions: Our findings strongly supported that DCLK1-S isoform may play a crucial role in invasion, tumor aggressive behavior, and worsened DSS of the patients with CRC. Importantly, high cytoplasmic expression of DCLK1-S compared to moderate expression could be considered as an independent prognostic factor influencing DSS. Taken together, DCLK1-S can be a candidate as a promising prognostic and targeted-therapeutic indicator for effective treatment of CRC.

scholarly journals Efficacy of Panitumumab and Cetuximab in Patients with Colorectal Cancer Previously Treated with Bevacizumab; a Combined Analysis of Individual Patient Data from ASPECCT and WJOG6510G

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1715
Author(s):  
Hiroya Taniguchi ◽  
Takeharu Yamanaka ◽  
Daisuke Sakai ◽  
Kei Muro ◽  
Kentaro Yamazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Rank Test ◽  
Clinical Trial Registration ◽  
Cox Models ◽  
Exon 2 ◽  
Free Survival ◽  
Previously Treated

Background: Phase-III ASPECCT and randomised phase-II WJOG6510G trials demonstrated the noninferiority of panitumumab, when compared with cetuximab, for overall survival in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. Methods: The subgroup that received bevacizumab either prior to panitumumab or cetuximab monotherapy (ASPECCT) or in combination with irinotecan (WJOG6510G) was included. Multivariate Cox models were created, including the treatment arms as covariates together with patient, disease and treatment characteristics. Results: We included 185 and 189 patients in the panitumumab and cetuximab arms, respectively. The median overall survival was 12.8 and 10.1 months [p = 0.0031; log-rank test, stratified by trial; hazard ratio (HR), 0.72; 95% confidence interval (CI), 0.58–0.90], and the median progression-free survival was 4.7 and 4.1 months, in the panitumumab and cetuximab arms, respectively (p = 0.0207; HR, 0.79; 95% CI, 0.64–0.97). The treatment regimen was an independent prognostic factor of overall survival (adjusted HR, 0.69; 95% CI, 0.54–0.87; p = 0.0013). Conclusions: Panitumumab significantly prolonged the overall survival and progression-free survival, when compared with cetuximab in the cohort that previously received bevacizumab in the included studies. Clinical Trial Registration: ASPECCT trial registered with ClinicalTrials.gov (NCT01001377) and WJOG6510G trial registered with UMIN-CTR (UMIN000006643).

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