Survival Of CRC Patients Research Articles

CK1\u03b1 overexpression correlates with poor survival in colorectal cancer

BackgroundColorectal cancer (CRC) is the fourth leading cause of cancer related deaths worldwide and prognosis in advanced tumor stage still remains poor. Since CK1 isoforms have been reported to be deregulated in several tumor entities CK1 has emerged as a novel drug target in cancer therapy. In this study we set out to investigate whether CK1α might have the potential to serve as prognostic marker.MethodsCK1α RNA and protein expression levels in healthy and tumor tissue of CRC patients were analyzed using quantitative real-time PCR and Western Blot analysis, respectively. Prognostic relevance was investigated by correlating obtained CK1α expression levels with patients’ survival rate generating Kaplan-Meier survival plots.ResultsIt could be shown that CK1α is overexpressed in colorectal tumor tissue compared to normal tissue and CK1α overexpression in tumor tissue correlates with poor survival in CRC patients. Results become more significant when only considering patients with high-grade tumors, as well as patients assigned to UICC II and UICC III stage. Furthermore, Cox regression analysis revealed that CK1α is an independent prognostic factor. In addition, tumors expressing decreased levels of the kinase reveal positive effects on overall survival when localized in the right colon compared to those in the left side.ConclusionIn summary, this study provides evidence for the first time that CK1α RNA levels might serve as prognostic marker for CRC.

Tumor deposit is an independent prognostic indicator in patients who underwent radical resection for colorectal cancer.

Background: Tumor deposits are one of the promising factors among the different edition of Tumor, Node, Metastasis classification. Despite improvement in the treatment of various types of metastatic disease the source and prognostic significance of tumor deposits in staging has not been deliberating the agreeable opinion. We investigated the possibility of tumor deposit as independent prognostic factor and evaluating its prognostic value in colorectal carcinoma patients.Methods: Author studied 313 colorectal cancer patients clinocopathological data and outcome who underwent radical resection. Data between 2011-2015 were retrospectively collected from Shanghai East Hospital, affiliated with Tongji University data information centre. The analysis was used to calculate 2 years disease free survival(DFS) and relation of tumor deposit with number of lymph node positive. Cox-regression analysis was performed to assess the prognostic factor.Results: Out of 313 colorectal patients included in the study, tumor deposits were detected in 17%. Tumor deposits (TDs) are relevantly associated with significant poor outcomes. The tumor deposit were significantly correlated with T-stage(P=<0.001), N-stage(P=<0.001), PLNC(P=<0.001), venous invasion(P=<0.001), TNM staging(P=<0.001), CEA(P=0.021) and CA19-9(P=0.042) of primary tumor. The Kaplan-Meier analysis revealed that disease-free survival of CRC patients with positive tumor deposit were significantly poorer that those with negative tumor deposit cohort(P=<0.001) And with multivariate analysis in different model, we found that positive tumor deposit were significantly associated with shorter DSF which is totally independent with lymph node status (P=0.001 and P=0.023 respectively). Subgroup analysis found that of 179 CRC patients with negative lymph node status, the DFS of patients with positive tumor deposit were significantly shorter that those with negative tumor deposit(P=,0.001). Of 134patients with positive lymph node status, the DFS of patients shows similar result. (P=<0.001).Conclusion: We have shown that TDs are not equal to lymph node metastasis with respect to biology and outcome. Tumor deposits are an independent adverse prognostic factor in CRC patient who have undergone radical resection.

Prognostic impact of changes in base excision repair machinery in sporadic colorectal cancer

Objectiveto evaluate the prognostic value of base excision repair proteins in sporadic colorectal cancer. MethodsPre-treatment tumor samples from 72 patients with sporadic colorectal adenocarcinoma were assessed for APC, MPG, Polβ, XRCC1 and Fen1 expression by immunohistochemistry. The associations of molecular data were analyzed in relation to clinical features and TNM staging as a prognosis predictor and disease-free survival. ResultsHigher levels of MPG, Polβ and XRCC1, but not Fen1, were associated with unfavorable pathological outcomes, such as poor cellular differentiation, advanced TNM stages, presence of lymphatic and perineural invasions and metastatic lymph nodes. MPG and Polβ overexpression were associated with right-sided CRC. However, only MPG high expression is associated with shorter disease-free survival in CRC patients. ConclusionsOur results suggest that increased expression of MPG, Polβ and XRCC1 are more likely to evolve to poor pathological outcomes, but only the elevated expression of MPG protein predicts recurrence. The BER proteins appear to be suitable candidates to refine the TNM current staging of colorectal cancer.

High HSF4 expression is an independent indicator of poor overall survival and recurrence free survival in patients with primary colorectal cancer.

Heat shock factor 4 (HSF4) is a member of the HSF family. In this study, by using data from the Cancer Genome Atlas-Colorectal Cancer (TCGA-CRC), we investigated the expression profile and the prognostic value of the HSF4 in terms of overall survival (OS) and recurrence free survival (RFS) in CRC patients. RNA-Seq data showed that HSF4 RNA expression was significantly higher in CRC tissues (N = 380) than in the corresponding normal tissues (N = 51) (mean ± SD: 3.56 ± 1.28 vs. 1.85 ± 0.87, P < 0.0001). High HSF4 expression group had significantly higher ratio of stages III/IV patients (52/86, 60.5%) than low HSF4 expression group (110/264, 41.7%; P = 0.0024). Besides, the high HSF4 expression group also had significantly increased expression of CEA (CEA ≥ 5, 26/51, 51.0% vs. 64/186, 34.4%), higher proportion of recurrence (32/86, 37.2% vs. 48/254, 18.9%, P = 0.0005) and death (36/90, 40.0% vs. 49/277, 17.7%, P < 0.0001) compared with the low HSF4 expression group. Multivariate analysis confirmed that high HSF4 expression was an independent prognostic factor of poor OS (HR = 2.111, 95%CI: 1.350-3.302, P = 0.001) and RFS (HR = 1.958, 95%CI: 1.224-3.131, P = 0.005). Bioinformatic analysis showed that HSF4 can directly interact with DUSP26, ZBED8, and MAPK14. It is also coexpressed with PTGER1, COL11A2, CLPS, and ARSA and colocalized with PTGER1, ADRB1, PEX12, CLPS, PSEN2, KCNJ5, CPA1, ARSA, PNLIP, IRX4, CPA2, IDUA, BCKDHA, and CTRL. We hypothesized that HSF4 might exert its oncogenic effects in CRC via some of these genes. © 2017 IUBMB Life, 69(12):956-961, 2017.

Abstract 3888: DCLK1 is part of an EMT feedback loop and promotes colorectal cancer cell invasion and drug resistance

Abstract Colorectal cancer (CRC) is the third leading cause of cancer death in the U.S., with only a 6% 5-yr survival rate for stage IV disease. Its spread and acquisition of resistance to chemotherapy, which are fueled by the epithelial-mesenchymal transition (EMT) process and supported by tumor stem cells (TSCs), are major challenges to improving patient outcomes. New therapies that target stemness and EMT are desperately needed to prevent or delay metastasis and improve patient survival. Recently doublecortin-like kinase 1 (DCLK1) has been definitively proven to mark TSCs in CRC by two independent groups. Previous studies have demonstrated that DCLK1 is a prognostic factor in CRC and that targeted downregulation or inhibition of DCLK1 results in decreased CRC proliferation, migration, invasion, and other anti-oncogenic effects. However, the effect of overexpression of DCLK1 and its kinase active mutant on CRC has not been assessed. In this study, we investigate the correlative role of EMT and DCLK1 expression in CRC progress. Human colon cancer cells (HCT116) were infected with Lentivirus containing wild type DCLK1 or mutant DCLK1R326C cDNA sequences to overexpress DCLK1, DCLK1R326C or green fluorescent protein (GFP) cDNA sequence as control. The expressing levels of DCLK1 and EMT factors were analyzed by western blotting. The proliferative and invasive potential of these cells were compared using a MTT assay for proliferation, wound healing assay for migration, and Matrigel coated transwell assay for invasion. Knockdown of either ZEB1 or DCLK1 by specific siRNA in HCT116 cells was performed. The effects of siDCLK1 on 5-FU were performed in both HCT116 and SW480 cells using a Caspase 3/7 activity assay. Analysis of human CRC was performed using TCGA COADREAD dataset. Here we report that compared to GFP control cells, HCT116-DCLK1 and HCT116-DCLK1R326C cells exhibited a more than 20% increase in proliferation, approximately 30% increase in migration, and a 2-fold increase (p &amp;lt; 0.05) in invasion. DCLK1 expression level is decreased more than 30% by knocking down ZEB1 in HCT116 cells. In addition, knockdown DCLK1 increased 5-FU induced cell apoptosis more than 50% (P&amp;lt;0.05). Evidence from TCGA COADREAD demonstrated that EMT predicts survival in CRC patients, and increased expression level of DCLK1 in CRC patients correlate to EMT and mesenchymal phenotype. These data suggest that DCLK1 is a part of an EMT feedback-loop and may be exploited with DCLK1-targeted therapeutics for CRC. Citation Format: Dongfeng Qu, Nathaniel Weygant, William L. Berry, Randal May, Parthasarathy Chandrakesan, James J. Tomasek, Sripathi M. Sureban, Courtney Houchen, Yang Ge, Jiannan Yao, Guangyu An, Edwin Bannerman-Menson. DCLK1 is part of an EMT feedback loop and promotes colorectal cancer cell invasion and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3888. doi:10.1158/1538-7445.AM2017-3888

Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway.

Emerging studies indicated that cancer stem cells represent a subpopulation of cells within the tumor that is responsible for chemotherapeutic resistance. However, the underlying mechanism is still not clarified yet. Here we report that miR-196b-5p is dramatically upregulated in CRC tissues and high expression of miR-196b-5p correlates with poor survival in CRC patients. Moreover, recurrent gains (amplification) contribute to the miR-196b-5p overexpression in CRC tissues. Silencing miR-196b-5p suppresses spheroids formation ability, the fraction of SP cells, expression of stem cell factors and the mitochondrial potential, and enhances the apoptosis induced by 5-fluorouracil in CRC cells; while ectopic expression of miR-196b-5p yields an opposite effect. In addition, downregulation of miR-196b-5p resensitizes CRC cells to 5-fluorouracil in vivo. Our results further demonstrate that miR-196b-5p promotes stemness and chemoresistance of CRC cells to 5-fluorouracil via targeting negative regulators SOCS1 and SOCS3 of STAT3 signaling pathway, giving rise to activation of STAT3 signaling. Interestingly, miR-196b-5p is highly enriched in the serum exosomes of patients with CRC compared to the healthy control subjects. Thus, our results unravel a novel mechanism of miR-196b-5p implicating in the maintenance of stem cell property and chemotherapeutic resistance in CRC, offering a potential rational registry of anti-miR-196b-5p combining with conventional chemotherapy against CRC.

PD-L2 expression in colorectal cancer: Independent prognostic effect and targetability by deglycosylation

ABSTRACTColorectal cancer (CRC) is the second leading cause of cancer death worldwide, and immune checkpoint blockade therapy provides an opportunity for improving the outcome of CRC patients. Recent studies suggest that programmed death ligand-1 (PD-L1) is only expressed in 12% of CRCs. Here, we demonstrate that PD-L2 is expressed in approximately 40% CRCs, and its expression independently associates with poor survival of CRC patients. By detection of PD-L2 expression by immunofluorescence in 124 CRC cases with 10-y survival data, we found significant association between PD-L2 overexpression in cancer cells and worse overall survival (46.3 vs 69.1 mo; p = 0.0004). The association remained significant in multivariate COX regression analysis (hazard ratio = 2.778, 95% confidence interval [CI] = 1.668–4.627; p < 0.0001). In the validation CRC data set, significant association between PD-L2 overexpression and poor survival was supported by the univariate analysis (27.1 vs. 88.9 mo; p = 0.0002) and multivariate model (hazard ratio = 7.09, 95%CI 1.78–28.16; p = 0.005). Western Blot revealed strong induction of PD-L2 expression by interferon-γ (IFNγ) in CRC cells, and the mRNA levels of both genes were significantly correlated in CRC tissue samples. Suppression of glycosylation with tunicamycin caused a shift in molecular weight and significant decrease in the expression of PD-L2 protein. In conclusion, PD-L2 overexpression in CRC cells, under the regulation by IFNγ and glycosylation, associates with poor survival of patients with colorectal cancer. These findings highlight PD-L2 as a promising therapeutic target in CRC and suggest potential routes to control PD-L2 expression in CRC cells.

Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model

BackgroundColorectal cancer (CRC) is among one of the top common cancers worldwide. Developing novel comprehensive treatment strategies is critical for improving survival of late stage CRC patients. Recent advances in immune checkpoint blockades provided a novel strategy for treating cancers via stimulating the antitumor immune response. However, the effects of immune checkpoint blockades were limited in CRC due to intrinsic resistance. Oxaliplatin (OXA) based chemotherapy was the foundation of CRC adjuvant chemotherapy. Here, we investigated the potential roles of OXA in inducing immunogenicity and synergizing with immune checkpoints in CRC. MethodImmunogenicity of OXA was tested in CRC cell lines. Immune checkpoint blockades sensitive and resistant CRC models were used to study the potential synergistic roles of OXA with immune checkpoint blockades. ResultsWe found CT26 mouse model was sensitive to immune checkpoint blockades, while MC38 mouse model was resistant. OXA could induce immunogenic cell death in several human and mouse CRC cell lines. Short term OXA treatment increased immune cell infiltration in MC38 mouse model and therefore enhanced the efficacy of immune checkpoint in MC38 mouse model. As a response to the OXA and immune checkpoint blockades combination, inhibitory immune checkpoints were down-regulated in MC38 tumors, while immune enhancing cytokines were up-regulated. Short term OXA treatment induced antitumor immune response in an immune checkpoint blockades resistant mouse model, therefore synergized with immune checkpoint blockades.

Age-related systemic treatment and survival of patients with metachronous metastases from colorectal cancer

Background: Although the spectrum of systemic treatment for metastatic colorectal cancer (mCRC) has widened, there is a paucity of evidence for the feasibility and optimal use of these systemic agents in elderly patients. The present study provides real world data on the age-related systemic treatment and survival of CRC patients with non-resectable metachronous metastases.Methods: All consecutive patients with non-resectable metastases from primary resected CRC were extracted from the Eindhoven area of the Netherlands Cancer Registry (NCR). Patients receiving palliative systemic therapy were enrolled (n = 385). Systemic treatment and survival were analyzed according to age at diagnosis of metastases.Results: Patients aged ≥75 years more often received first-line single-agent chemotherapy than their younger counterparts (63% vs. 32%, p < .0001). First-line single-agent chemotherapy was often prescribed without additional targeted therapy (78%). Advanced age (≥75 years) was associated with a lower probability of receiving all active cytotoxic agents compared to patients aged <60 years at time of diagnosis of metastases (odds ratio (OR) 0.2, 95% CI 0.10–0.77). In a multivariable Cox regression analysis with adjustment for age and other relevant prognostic factors, the total number of received systemic agents was the only predictor of death (hazard ratio (HR) 0.7, 95% CI 0.61–0.81).Conclusion: The beneficial effect of treatment with all active systemic agents on survival (simultaneously or sequentially prescribed) should be taken into account when considering systemic therapy in patients with mCRC. In light of our results, future studies are warranted to clarify the role of potential targeted therapy in elderly mCRC patients, who are often not candidates for combination chemotherapy and treatment with all active cytotoxic agents.

MiR-449a inhibits colorectal cancer progression by targeting SATB2.

miR-449a has been reported to act as a tumor suppressor in several cancers, however, it is controversial whether it inhibits tumor growth in colorectal cancer. The mechanisms underlying its expression and functions in colorectal cancers are still largely unknown. SATB2 is a sensitive and specific marker for CRC diagnosis. However, the mechanisms by which the expression and functions of SATB2 are regulated still remain to be clarified. We investigated the expression and functional significance of miR-449a and SATB2 and the mechanisms of their dysregulation in human CRC cells. miR-449a overexpression or SATB2 depletion inhibited tumor growth and promoted apoptosis in colorectal tumor cells in vitro and in xenograft mouse model, partially by downregulating SATB2. Expression of miR-449a was increased epigenetically via knocking down their targets, particularly SATB2. miR-449a was downregulated and STAB2 expression was upregulated in human CRCs. Their expressions were significantly associated with overall survival of CRC patients. Our findings demonstrate the existence of a miR-449a-SATB2 negative feedback loop that maintains low levels of miR-449a as well as high level of SATB2, thereby promoting CRC development.

Abstract LB-354: Investigating potential molecular biomarkers for cetuximab response in metastatic colorectal cancer tissue using reverse phase protein array

Abstract Colorectal cancer (CRC) is the third and second most commonly diagnosed cancer in males and females, and the second most common cause of cancer-related deaths in the developed world. Identifying the importance of epidermal growth factor (EGF) signalling pathways for the survival of CRC cells (Van Cutsem, Kohne et al. 2011) resulted in development of therapies that target EGF-receptors (EGFR). Late stage CRC patients are mainly treated with monoclonal anti-EGFR antibodies such as cetuximab. Although anti-EGFR therapies have significantly improved survival in CRC patients (Van Cutsem, Kohne et al. 2009), they are not effective in patients with activating KRAS, BRAF, NRAS and PI3KCA mutations (De Roock, Claes et al. 2010). Nevertheless, between 50-60% of patients will not benefit from the additional anti-EGFR treatment, even when these have a quadruple wild-type status (De Roock, De Vriendt et al. 2011), suggesting that novel biomarkers and targeted therapies are required. In this study, we investigate potential biomarkers for cetuximab response in a panel of 93 quadruple wild-type, liver metastatic CRC samples from patient derived xenografts (PDX) with known responses to cetuximab. Matching PDXs were used to measure changes in tumour volumes post cetuximab treatment (Bertotti, Papp et al. 2015) and were later categorised as regressing, progressing or stabilised. Protein expression levels were measured in matched PDXs, using a reverse phase protein array (RPPA) with a panel of 72 antibodies targeting key cancer related proteins as previously described). Statistical analysis of measured values showed significant correlation between high protein expression levels, such as Chk-1, PARP, HIAP-2 (cIAP-1), and PDX progression post cetuximab treatment. These proteins were significantly expressed lower in both regressing and stable PDXs. Interestingly, we found a high cross correlation between expression levels of these proteins across all the samples, giving them a great potential to act as predictive biomarkers for cetuximab response. Bioinformatics pathway enrichment of these proteins showed a significant enrichment of intrinsic apoptotic and cell cycle signalling pathways. These results have also been investigated in publically available patient data with cetuximab response and together will be used to construct a deterministic mathematical cell cycle model that will help to predict the outcome of cetuximab therapy in future. Citation Format: Naser Monsefi, Robert O’Byrne, Steven Carberry, Eugenia R. Zanella, Ana Barat, Mattia Cremona, Clare Morgan, Bryan T. Hennessy, Andrea Bertotti, Livio Trusolino, Jochen H.M. Prehn. Investigating potential molecular biomarkers for cetuximab response in metastatic colorectal cancer tissue using reverse phase protein array. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-354.

The Preoperative Peripheral Blood Monocyte Count Is Associated with Liver Metastasis and Overall Survival in Colorectal Cancer Patients.

BackgroundColorectal cancer (CRC) is the third most common malignancy in males and the second most common in females worldwide. Distant metastases have a strong negative impact on the prognosis of CRC patients. The most common site of CRC metastases is the liver. Both disease progression and metastasis have been related to the patient’s peripheral blood monocyte count. We therefore performed a case-control study to assess the relationship between the preoperative peripheral blood monocyte count and colorectal liver metastases (CRLM).MethodsClinical data from 117 patients with colon cancer and 93 with rectal cancer who were admitted to the Chinese People’s Liberation Army General Hospital (Beijing, China) between December 2003 and May 2015 were analysed retrospectively, with the permission of both the patients and the hospital.ResultsPreoperative peripheral blood monocyte counts, the T and N classifications of the primary tumour and its primary site differed significantly between the two groups (P < 0.001, P < 0.001, P = 0.002, P < 0.001), whereas there were no differences in the sex, age, degree of tumour differentiation or largest tumour diameter. Lymph node metastasis and a high preoperative peripheral blood monocyte count were independent risk factors for liver metastasis (OR: 2.178, 95%CI: 1.148~4.134, P = 0.017; OR: 12.422, 95%CI: 5.076~30.398, P < 0.001), although the risk was lower in patients with rectal versus colon cancer (OR: 0.078, 95%CI: 0.020~0.309, P < 0.001). Primary tumour site (P<0.001), degree of tumour differentiation (P = 0.009), T, N and M classifications, TNM staging and preoperative monocyte counts (P<0.001) were associated with the 5-year overall survival (OS) of CRC patients. A preoperative peripheral blood monocyte count > 0.505 × 109 cells/L, high T classification and liver metastasis were independent risk factors for 5-year OS (RR: 2.737, 95% CI: 1.573~ 4.764, P <0.001; RR: 2.687, 95%CI: 1.498~4.820, P = 0.001; RR: 4.928, 95%CI: 2.871~8.457, P < 0.001).ConclusionsThe demonstrated association between preoperative peripheral blood monocyte count and liver metastasis in patients with CRC recommends the former as a useful predictor of postoperative prognosis in CRC patients.

Improved survival of colorectal cancer in Denmark during 2001–2012 – The efforts of several national initiatives

Background The Danish Colorectal Cancer Group (DCCG) established a national clinical database in 2001 with the aim to monitor and improve outcome of colorectal cancer patients. Since 2000 several national initiatives have been taken to improve cancer outcome. In the present study we used DCCG data to evaluate mortality and survival of CRC patients with focus on comorbidity, stage, and perioperative treatment.Material and methods Patients notified to the DCCG database from 2001 to 2012 were included. Patients with primary cancer of the colon and rectum were analyzed separately. Analyses were stratified according to gender, comorbidity, Union for International Cancer Control (UICC) stage, and operative priority (elective/emergency/no surgery). Data were stratified into three time periods (2001–2004, 2005–2008, 2009–2012). Mortality and survival were age adjusted.Results In total 29 385 patients with colon cancer and 15 213 patients with rectal cancer were included. The stage distribution was almost stable over time. The mortality rate per 100 patient year within one year decreased from 32 to 26 in colon cancer and from 26 to 19 in rectal cancer with associated improvements in absolute survival from 73% to 78% in colon cancer and from 78% to 83% in rectal cancer. The five-year relative survival of colon cancer improved from 58% to 63% and in rectal cancer from 59% to 65%. Comorbidity had major negative impact on outcome. Irrespective of tumor location, outcome improved relatively more in patients with stage III and IV disease. The proportion of patients who were spared surgery increased from 8% to 15% in colon cancer and from 13% to 19% in rectal cancer, and these changes were associated with improved outcome for rectal cancer patients, whereas outcome worsened for colon cancer patients.Conclusion The Danish efforts to improve outcome of cancer have succeeded with improved outcomes in patients with colorectal cancer.

Clusterin expression (CLU) as a prognostic marker in colorectal carcinoma (CCR).

563 Background: Increased CLU is involved in malignant progression and anticlusterin treatment with antisense oligonucleotides enhances apoptosis induced by several citotoxics. However, clinical significance of CLU expression in human CRCs has been scarcely studied. We investigated whether changes in CLU could be related to carcinogenesis and survival (sv) of CRC patients (pts). Methods: Formalin-fixed and paraffin-embedded specimens were examined from 31 adenomas and 103 CRCs resected at Costa del Sol Hospital. The study was approved by Research Ethics Committee. Immunohistochemistry using monoclonal anti-α chain clusterin antibody (Upstate-Millipore, Watford, England) was performed, following standard staining procedure. CLU was scored as negative (CLU–) (no staining) or positive (CLU +) (&gt;10% of tumor cells with strong staining). Cytoplasmic CLU in tumors was evaluated for cancer cells only, and in normal mucosa for epithelial cells only. Sv curves were calculated and plotted according to Kaplan-Meier method. Predictors that were significant at p&lt;0.10 in univariate analysis, were entered into a Cox proportional hazards model for multivariate analysis, remaining significant at p&lt;0.05. Results: Median follow-up was 54 months. Median age was 70 years (45-91). TNM stage distribution was: I (13%), II (48%), III (25%) and IV (14%). Epithelial normal cells were always CLU-, but 16% (5/31) of adenomas was CLU+ and this percentage increased in CRCs (30%, 31/103). Positive staining always presented an apical cytoplasmic pattern. Recurrence was more frequent in CLU+ (61%,19/ 31) than in CLU- tumors (37%, 27/72) and CLU was significantly associated with lower disease-free survival (DFS) (p&lt;0.05). In multivariate analysis, CLU and stage remained significant independent prognostic factors for DFS (Table). Conclusions: CLU has a role in colon carcinogenesis and prognostic value. CLU is associated with decreased DFS among pts with CRCs. These findings have important implications for identifying CRC pts with more aggressive tumors who may benefit from targeted therapy against clusterin. [Table: see text]

The prognostic effect of PTEN expression status in colorectal cancer development and evaluation of factors affecting it: miR-21 and promoter methylation.

BackgroundPTEN is a tumor suppressor gene which is involved in cellular proliferation, differentiation, and apoptosis. Loss or down-regulation of PTEN plays an important role in human cancers development. In this study, we investigated the effect of miR-21 and promoter methylation on the PTEN expression status in CRC tissues and analyzed association of the PTEN expression status with clinicopathological features in patients with CRC.ResultsThe PTEN expression was positively detected in 67.2 % CRC tissues and all adjacent non-cancerous samples. PTEN mRNA level was negatively correlated with miR-21 level (r = −0.595, P < 0.001). PTEN expression was also correlated directly with the PTEN mRNA level (r = 0.583, P < 0.001) and conversely with miR-21 level (r = −0.632, P < 0.001). PTEN Promoter methylation was significantly associated with PTEN expression status (p = 0.013). PTEN expression was negatively associated with tumor size (p = 0.007) and advanced tumor stage (P = 0.011). Multivariate analysis indicated that tumor stage, tumor differentiation and PTEN expression status were independent prognostic factors for overall carcinoma in CRC patients (P < 0.05). The Kaplan-Meier curve indicated a negative correlation between PTEN expression levels and survival of CRC patients (P = 0.013).ConclusionsThis study suggests a high frequency of miR-21 overexpression and aberrant promoter methylation in down-regulation of PTEN expression in colorectal carcinoma. Loss of PTEN may be a prognostic factor for patients with CRC.

Familial risk and diagnosis of colorectal cancer in young individuals

The age standardized (world) incidence (per 100000) of large bowel cancer in Lithuania is increasing: in 1993-1997 it was 25.6 for males and 16.8 for females; in 1998-2002 it was 30.4 and 19.1 respectively. Meanwhile the age standardized (world) cancer mortality remains without change: in the same periods it was 18.0 for males and 11.5 for females; 18.6 and 10.6 respectively. These epidemiological aspects are basically for start CRC screening in national population. The age for population screening recommended by EC is 50-74 years and the optimal participation rate to get better survival of CRC patients is 45-60% of population. Numerous studies have shown the risk of getting CRC is higher if a first-degree family member had the disease, and shows that your chances of surviving the disease may be influenced in part by your family ties. It hypothesized that patients with a family history of CRC might be more likely to get screened for the disease, finding tumors earlier, and are more likely to have a better prognosis. In addition to collecting family tree information help for recognition of hereditary cancer syndrome such as HNPCC, Peutz-Jeghers Polyposis, and FAP. The familial risk for CRC and effective cancer prevention become more important in individuals aged below 50-55 years. The study in Lithuania was aimed to prove more knowledge on familial CRC risk and the surveillance of family members at risk for large bowel malignancy. This study indicates that a positive family history of CRC can be recognized as a prognostic factor for individuals aged 25-39 years. Results shows that a positive family history was not a clear indicator of early stage diagnosis in the groups studied compared to the population.

Extreme cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Outcomes from a single tertiary center

BackgroundMultivisceral resection as part of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) may be required in order to achieve optimal debulking. This study aimed to assess perioperative and long-term outcomes of the most extensive CRS/HIPEC procedures. MethodsAll patients who underwent CRS/HIPEC at our institution between March 2007 and July 2014 were retrospectively reviewed. Patients undergoing extreme cytoreduction (n = 50), defined as a resection of ≥5 organs or ≥3 bowel anastomoses, were compared with patients who underwent less extensive procedures (n = 219). ResultsComplete cytoreduction (CC score ≤1) was achieved in 76% of the extreme CRS/HIPEC group, which included patients with colorectal cancer (CRC, n = 17), appendiceal adenocarcinoma (n = 20), gastric cancer (n = 6), and low-grade appendiceal neoplasm (n = 3). When compared with other patients undergoing CRS/HIPEC, the extreme CRS/HIPEC group had higher median PCI score, increased intraoperative blood loss, longer duration of surgery and longer hospital stay (all p values < 0.001). Major 30-day morbidity was significantly higher among the extreme CRS/HIPEC group (34% vs. 17.4%, p = 0.008) and there was also a trend towards higher 90-day mortality (12% vs. 5.1%, p = 0.07). Median disease free survival and overall survival in CRC patients undergoing extreme CRS/HIPEC was poorer (4.1 vs. 14.3 months, p = 0.01 and 10.1 vs. 43.8 months, p < 0.001, respectively). Extreme CRS/HIPEC was found to independently predict decreased overall survival in CRC patients. ConclusionsExtreme multivisceral resection as part of CRS/HIPEC is associated with higher major morbidity and inferior oncologic outcomes; therefore CRS/HIPEC provides the best outcomes in patients with fewer organs involved.

Systematic review of the predictive effect of MSI status in colorectal cancer patients undergoing 5FU-based chemotherapy.

BackgroundWe systematically reviewed the evidence for the interaction of microsatellite instability status (MSI) and treatment with 5FU in colorectal cancer to determine how well MSI status predicts health outcomes in patients undergoing 5FU-based chemotherapy.MethodsWe conducted a search of four electronic databases through June 2013. We considered studies that included both colorectal cancer patients treated with 5FU-based chemotherapy and untreated patients with survival outcomes presented by MSI status.ResultsWe identified 16 studies for qualitative analysis (9,212 patients) with 14 studies eligible for meta-analysis. The microsatellite stable (MSS) group showed an effect of 5FU treatment on disease-free survival (HR of 0.62 [95% CI: 0.54, 0.71]) and overall survival (HR of 0.65 [95% CI: 0.54, 0.79]), indicating that MSS patients who received 5FU treatment had longer survival than MSS patients who were untreated. The effect of 5FU treatment was not statistically significant for microsatellite high (MSI-H) patients for disease-free survival (HR of 0.84 [95% CI: 0.53, 1.32]) or overall survival (HR 0.66 [95% CI: 0.43, 1.03]). However, the summarized point estimates of the effects of 5FU treatment for the MSS and MSI-H groups were not different at a statistically significant level.ConclusionsOur analyses indicate that treatment with 5FU-based chemotherapy improves disease-free and overall survival in CRC patients, but that there is no difference in the effect of treatment based on MSI status. Therefore, the use of MSI status to guide treatment decisions about the use of 5FU treatment for CRC has no significant benefits for patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1093-4) contains supplementary material, which is available to authorized users.

Epidermal growth factor receptor in CRC patients in the era of the RAS.

The aim of this study was to investigate EGFR expression patterns and the effect of EGFR expression on stage, prognosis and response to conventional chemotherapy agents other than monoclonal antibodies in CRC patients. This study included 59 metastatic CRC patients. The expression of EGFR was quantified by immunochemistry in biopsy specimens that were obtained before treatment was initiated. The cases were considered to be positive for EGFR if >1% of the tumor cells had complete circumferential membranous staining. The median age of the patients was 54.6 years, and 59% of the patients were male. Twenty-six patients presented with stage IV disease, and the remaining patients developed distant metastasis during follow-up. Fifty-one patients were treated with regimens containing irinotecan. The numbers of patients with EGFR expression in the primary tumors, the metastatic lymph nodes and the normal colonic tissue were 34 (65.4%), 10 (76.9%) and 34 (65.4%) respectively. The initial disease stage and lymph node stage were correlated with EGFR expression (p<0.05). Additionally, EGFR positivity was correlated with a statistically significant reduction in the response rate to chemotherapy, the overall survival (21 vs. 28 months) and the progression-free survival (15 vs. 22 months) in metastatic patiens treated with chemotherapy other than targeted therapies. In conclusion, EGFR expression in correlated with stage in all CRC patients and response to chemotherapy and survival in metastatic CRC patients.

ATAD2 Overexpression Identifies Colorectal Cancer Patients with Poor Prognosis and Drives Proliferation of Cancer Cells.

ATPase family AAA domain-containing 2 (ATAD2) has been identified as a critical modulator involved in cell proliferation and invasion. The purpose of this study was to explore the expression of ATAD2 in CRC tissues as well as its relationship with degree of malignancy. Data containing three independent investigations from Oncomine database demonstrated that ATAD2 is overexpressed in CRC compared with normal tissue, and similar result was also found in 32 pairs of CRC tissues by qPCR. The protein expression of ATAD2 was examined in six CRC cell lines and 300 CRC specimens. The results showed that high expression of ATAD2 was significantly correlated with tumor size (P < 0.001), serum CEA (P = 0.012), lymph node metastasis (P = 0.018), liver metastasis (P = 0.025), and clinical stage (P = 0.004). Kaplan-Meier method suggested that higher ATAD2 protein expression significantly associated with the overall survival (OS) of CRC patients (P < 0.001) and was an independent predictor of poor OS. Functional studies showed that suppression of ATAD2 expression with siRNA could significantly inhibit the growth in SW480 and HCT116 cells. These results indicated that ATAD2 could serve as a prognostic marker and a therapeutic target for CRC.