Dukes Stage Research Articles

Expressions of octamer-binding transcription factor 4 and phosphorylated-protein kinase B in colorectal cancer and their clinical significances

Objective To investigate the expressions of octamer-binding transcription factor 4 (Oct4) and phosphorylated-protein kinase B (p-Akt) proteins in colorectal cancer and their clinical significances, in order to explore the roles of Oct4 and p-Akt in the staging and grading of colorectal cancer. Methods Immunohistochemical technique was used to examine the expression of Oct4 and p-Akt proteins in 78 cases of colorectal cancer in Wuxi Second Hospital of Traditional Chinese Medicine and Wuxi First People's Hospital from January 2011 to December 2016. Relationship between expressions of Oct4 and p-Akt proteins and clinicopathological parameters were analyzed. Results The positive rate of Oct4 in tumors was 74.36 % (58/78), which was obviously higher than that in normal tissues [35.90 % (20/78), χ2 = 23.32, P < 0.01]; and the positive rate of p-Akt in tumors was 67.95 % (53/78), which was obviously higher than that in normal tissues[28.21 % (25/78), χ2 = 24.68, P < 0.01]. The double positive and negative expression rate of these two proteins accounted for 80.8 % (63/78), with a linear positive correlation (r = 0.455, P < 0.000 1). In 78 cases of colorectal cancer, the expression of Oct4 protein was correlated with histological grade, lymph node metastasis, and Duke staging (all P < 0.05), and the expression of p-Akt protein was correlated with histological grade and lymph node metastasis (both P < 0.05). The multivariate logistic regression analysis showed that the expression of Oct4 protein was related to histological grade and Duke staging (both P < 0.05), and the expression of p-Akt protein was only related to lymph node metastasis (P < 0.05). Conclusion The combined detection of Oct4 protein and p-Akt protein has reliable and important clinical significance for judging the histological grade, lymph node metastasis and Duke staging of colorectal cancer. Key words: Colorectal neoplasms; Octamer-binding transcription factor 4; Phosphorylated-protein kinase B

High Oct4 predicted worse prognosis of right-sided colon cancer patients.

This present study was aimed to compare the role of Oct4 in left-sided colon cancer (LCC) with right-sided colon cancer (RCC). One hundred and fifty one pathology specimens, 68 frozen-thawed tumors and cell lines were used to evaluate the role of Oct4 in LCC and RCC through immunohistochemistry, western blot and real-time quantitative PCR. In LCC, positive expression of Oct4 was positively related to differentiation and Dukes stage (p<0.01). Only in RCC, Oct4 expression was also positively related to lymphatic invasion and survival rates of 'negative group' were significantly higher. In summary, Oct4 was related to tumor differentiation and later Dukes stage in colon cancer, and was correlated with invasion of lymphatic only in RCC. In addition, Oct4 was a potential prognostic indicator in RCC.

CD10 inhibits cell motility but expression is associated with advanced stage disease in colorectal cancer

IntroductionCD10 is a cell membrane-bound endopeptidase which is expressed in normal small bowel but not in normal colon. It is aberrantly expressed in a small proportion of colorectal cancers (CRC) and this has been associated with liver metastasis and poor prognosis. We sought to investigate the mechanism of CD10 activity and its association with clinicopathological features. Material and methodsCD10 was stably knocked down by lentiviral shRNA transduction in the CRC cell lines SW480 and SW620 which are derived from a primary tumour and its corresponding metastasis respectively. Expression of epithelial – mesenchymal transition (EMT) markers was tested as well as the effect of knockdown on cell viability, migration and invasion assays. In addition, immunohistochemical expression of CD10 in primary colorectal tumours (N = 84) in a tissue microarray was digitally quantified and analysed for associations with clinicopathological variables. ResultsKnockdown of CD10 did not alter cell viability in SW480, but migration and invasion levels increased (P < 0.001 for each) and this was associated with a cadherin switch. In SW620, CD10 knockdown caused a reduction in cell viability after 72 h (P = 0.0018) but it had no effect on cell migration and invasion. Expression of epithelial CD10 in primary tumours was associated with presence of lymph node invasion (P = 0.001) and advanced Duke's stage (P = 0.001). ConclusionsOur results suggest that the function of CD10 may change during tumour evolution. It may inhibit cell motility in early-stage disease whilst promoting cell viability in late-stage disease. It has a complex role and further studies are needed to elucidate the suitability of CD10 as a prognostic marker or therapeutic target.

Prognostic and clinicopathological value of p16 protein aberrant expression in colorectal cancer: A PRISMA-compliant Meta-analysis.

Purpose:Several studies have examined the potential role of p16 protein expression as a diagnostic and prognostic biomarker in various cancers. However, it remains unclear whether p16 protein expression is a prognostic and diagnostic factor for colorectal cancer. Therefore, this meta-analysis is conducted to evaluate the associations of p16 protein expression with overall survival (OS) and clinicopathological characteristics of colorectal cancer.Methods:According to PRISMA guideline, relevant literatures were identified by searching Medicine, Web of Science, WanFang, and CNKI databases. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from included studies to assess the association between p16 protein expression and OS of patients with colorectal cancer. Other relevant data were extracted to evaluate the correlations of p16 protein expression with risk and clinicopathological characteristics of colorectal cancer. Stata 12.0 software was applied to calculate the strength of association between p16 protein expression and colorectal cancer.Results:Forty-one studies were included to evaluate the association between p16 protein expression and colorectal cancer. Nine studies involving 1731 patients with colorectal cancer found that there was no association between p16 protein expression and OS of colorectal cancer in the overall analysis (HR = 0.78, 95% CI: 0.55–1.10). However, p16 protein overexpression was significantly associated with a better prognosis in patients with colorectal cancer when cut-off value of p16 protein expression was <10% (HR = 0.23, 95% CI: 0.08–0.66). The results of subgroup analysis based on ethnicity indicated that p16 protein overexpression was a risk factor for the occurrence of colorectal cancer in Caucasians (odds ratio = 28.95, 95% CI: 6.08–137.89), but not in Asians. Furthermore, p16 protein overexpression was significantly associated with the Dukes stage, lymph node metastasis, tumor location, and Tumor Lymph Node Metastasis-stage of colorectal cancer.Conclusions:p16 protein overexpression might be a useful biomarker to predict the clinicopathological progress and prognosis of colorectal cancer.

Changes of serum and peritoneal inflammatory mediators in laparoscopic radical resection for right colon carcinoma.

Objective:The objective of this study is to investigate the effects of laparoscopic and open operation on serum and peritoneal inflammatory mediators in patients with right colon carcinoma.Patients and Methods:A total of 100 patients were randomly divided into laparoscopic group (n = 50) and open group (n = 50). The age, sex, operation time, operation blood loss, post-operative Dukes stage, time to first passage of flatus and post-operative hospital stay were recorded. The levels of hypersensitive C reactive protein (hsCRP) and tumour necrosis factor-α (TNF-α) in serum and abdominal exudate were measured by ELISA at the time of pre-operative 2 h and post-operative 6 h and 24 h.Results:There was no significant difference in age, sex, Dukes stage and pre-operative inflammatory mediators between the two groups (P > 0.05). The operation time, intraoperative blood loss, time to first passage of flatus and post-operative hospital stay were significantly better in laparoscopic group than those in open operation group. At 6 h and 24 h after operation, the levels of hsCRP and TNF-α in serum and abdominal exudate in laparoscopic group were significantly lower than those in open operation group.Conclusions:Laparoscopic surgery for the treatment of right colon carcinoma has the advantages of fewer traumas, less systemic and local inflammatory response, rapider post-operative recovery and shorter hospital stay. It is worthy of clinical application.

High expression of estrogen-related receptor α is significantly associated with poor prognosis in patients with colorectal cancer.

Colorectal cancer (CRC) is one of the most common types of malignancy with high morbidity and mortality rates worldwide. This biologically heterogeneous disease results in diverse therapeutic responses, thus, novel prognostic biomarkers are required to improve CRC treatment. Estrogen-related receptor α (ERRα) is a nuclear orphan receptor, which is associated with estrogen receptor α. The present study aimed to investigate the expression of ERRα in patients with CRC, and explore the association between ERRα expression and clinicopathological factors, local recurrence and prognosis. In the present study, ERRα expression was detected in 15 fresh CRC tissues using quantitative real-time polymerase chain reaction (RT-qPCR) and in 128 paraffin-embedded CRC tissues using immunohistochemistry. The associations between ERRα expression and prognosis of CRC patients were evaluated by univariate, and multivariate (Cox proportional hazards model) analysis. RT-qPCR demonstrated that the mRNA expression of ERRα in CRC tissues was significantly higher compared with that in matched normal tissues. Immunohistochemistry revealed that ERRα high expression was detected in the nuclei of cancer cells from 39.1% (50/128) of CRC tissues. ERRα expression based on immunohistochemical staining was significantly associated with tumor differentiation, tumor invasion, lymph node status and Dukes stage (all P<0.05). Furthermore, patients with high ERRα expression were significantly associated with an increased risk of recurrence and poor prognosis, compared with patients with low ERRα expression. ERRα expression was identified as an independent prognostic factor for patients with CRC. In conclusion, ERRα serves important roles in the progression of CRC and is a potential prognostic factor for patients with CRC.

Expressions and clinical significances of Eag1 and VEGF in colorectal cancer tissues

Objective To study the expressions of Eag1 and vascular endothelial growth factor (VEGF) in colorectal cancer, and to explore the relationships between Eag1 and VEGF expressions and clinicopathologic features of colorectal cancer. The correlation between Eag1 and VEGF and their clinical significance in colorectal cancer were explored. Methods A total of 73 cases of colorectal cancer tissues, 25 cases of colorectal adenoma and 10 cases of normal colorectal mucosa from January 2015 to December 2016 in Hunan Provincial People′s Hospital were collected. The expressions of Eag1, VEGF protein and mRNA in 73 cases of colorectal cancer tissues, 25 cases of colorectal adenoma and 10 cases of normal colorectal mucosa were detected by immunohistochemistry and real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The relationships between the two factors and the clinical pathological features of patients with colorectal cancer were analyzed. Results Immunohistochemistry showed that the positive rate of Eag1 in colorectal cancer group was 86.30% (63/73), which was significantly higher than that in colorectal adenoma group (20.00%, 5/25) and normal colorectal mucosa group (10.00%, 1/10), with significant differences (χ2=38.539, P<0.001; χ2=24.874, P<0.001). The positive rate of VEGF in colorectal cancer group was 89.04% (65/73), which was significantly higher than that in colorectal adenoma group (56.00%, 14/25) and normal colorectal mucosa group (30.00%, 3/10), with significant differences (χ2=10.980, P<0.001; χ2=16.911, P<0.001). There was a significant positive correlation between Eag1 and VEGF in colorectal cancer and colorectal adenoma tissues (c=0.580, P=0.010; c=0.669, P<0.001). The results of RT-qPCR showed that the expressions of Eag1 and VEGF mRNA in colorectal cancer group, colorectal adenoma group and normal colorectal mucosa group were 4.50±0.34, 3.14±0.44; 1.42±0.22, 1.61±0.15 and 1.00±0.16, 1.00±0.53, respectively, and the differences were statistically significant (F=15.546, P=0.014; F=5.363, P=0.025). The relative expression levels of Eag1 and VEGF mRNA in colorectal cancer group was about 4.50 times (t=31.851, P=0.003) and 3.14 times (t=6.870, P=0.014) than those in normal colorectal mucosa group. The mRNA expression levels of Eag1 and VEGF in colorectal cancer were correlated with degree of differentiation (F=840.725, P<0.001; F=102.950, P<0.001), depth of invasion (t=4.754, P<0.001; t=8.557, P<0.001), Duke staging (F=179.902, P<0.001; F=55.911, P<0.001) and lymph node metastasis (t=20.337, P<0.001; t=25.218, P<0.001). But they were not related to age (t=0.196, P=0.845; t=0.534, P=0.595) and sex (t=0.409, P=0.684; t=1.078, P=0.285). Conclusion Eag1 and VEGF are highly expressed in colorectal cancer tissues with positive correlation, and are closely related to the degree of differentiation, depth of invasion, Duke staging and lymph node metastasis of colorectal cancer. Both of them play important roles in the occurrence and development of colorectal cancer, which is expected to provide favorable research directions to the early diagnosis, treatment and prognosis of colorectal cancer. Key words: Colorectal neoplasms; Vascular endothelial growth factors; Eag1

Analysis of correlation between RASSF2A gene methylation and colorectal cancer

Objective To investigate the methylation status of RASSF2A gene promoter in colorectal cancer tissues and its correlation with the occurrence of colorectal. Methods From February 2007 to March 2013, a total of 111 cases of sporadic colorectal cancer patients were selected. The methylation status of RASSF2A gene in tumor tissue and normal mucosa were detected by using combined bisulfite restriction endonuclease method (COBRA). The correlations between the methylation of RASSF2A gene and the clinicopathologic features of colorectal cancer were analyzed. Results Methylation of RASSF2A gene was found in 83.78% (93/111) and 7.21% (8/111) of colorectal cancer tissues and normal tissues, with statistically significant difference (χ2=131.245, P<0.001). The methylation of RASFF2A gene was not correlated with histology type (χ2=3.554, P=0.314), Duke staging (χ2=3.217, P=0.359) and location of tumor (χ2=1.060, P=0.303). Conclusion The presence of RASSF2A hypermethylation in colorectal cancer may be associated with the occurrence of colorectal cancer. Key words: Colorectal neoplasms; DNA methylation; RASSF2A gene

B Subunit of Human Chorionic Gonadotropin Promotes Tumor Invasion and Predicts Poor Prognosis of Early-Stage Colorectal Cancer

Background/Aims: It is well established that many non-trophoblastic tumors secrete HCG (human chorionic gonadotropin) and that such secretion is correlated with the poor prognosis of tumor patients. This study aims to analyze the correlation between β-HCG expression and outcome of colorectal cancer (CRC) and understand its role in CRC pathology Methods: We detected the mRNA and protein expression of β-HCG in human CRC tissues with RT-qPCR and immunohistochemistry, and we compared the clinical-pathological characteristics, prognosis and progression between the β-HCG positive and negative groups. We also generated CRC cell lines with β-HCG over-expression as well as β-HCG stable knockout, and evaluated cell function and mechanism in vitro and in vivo. Results: Fifty out of 136 CRC patients (37%) expressed β-HCG at the invasive front. Clinical-pathological data showed that β-HCG was positively correlated with Dukes staging (P=0.031) and lymph node metastasis (P=0.012). Survival analysis suggested that the patients with high expression of β-HCG had poorer prognosis than those with low β-HCG expression (P=0.0289). β-HCG expression level was also positively correlated with tumor invasion in early-stage CRC patient tissues (P=0.0227). Additionally β-HCG promoted the migration and invasion of CRC in vitro and in vivo but had no effect on the proliferation of tumor cells. Conclusion: Our study demonstrated that β-HCG was ectopically expressed in the CRC patients and its high expression correlated with poor prognosis of early-stage CRC. Additionally it worked as an oncogene that promotes the migration and invasion of CRC by epithelial-mesenchymal transition (EMT).

Histopathological report of colorectal carcinoma resections: A 5-year audit in Lagos.

Complete and accurate pathology reporting of colorectal carcinoma (CRC) resection specimen is critical to clinical management of individual patients. The study aims to audit colorectal cancer histopathology reporting in Lagos between 2011 and 2015 before the adoption of the Society for Gastroenterology and Hepatology in Nigeria pro forma in 2016. All resected CRC cases were identified from the Histopathology record of our Department and that of a private Laboratory in Lagos over a 5-year from 2011 to 2015. The dataset as contained in the pro forma was extracted from the reports and analysed using SPSS version 16 software. A total of 92 colorectal resections were received during the 5-year period consisting of 90 colonic and 2 rectal tumours. Data inclusiveness on tumour differentiation, extent of primary tumour, total lymph node and lymph node involvement were 96.7%, 91.3%, 83.7% and 92.4%, respectively. Tumour perforation, level of venous involvement and distant metastasis were reported in 73.9%, 21.7% and 96.7% respectively. The circumferential resection margin (CRM) in the 2 rectal tumours had 100% inclusiveness. Tumour node metastasis staging was complete in 87% of cases while Dukes staging was documented in 8.7% of the reports. None of the data items was 100% complete except the CRM for rectal carcinoma. Free text reporting results in incomplete data resulting in improper staging, especially the lymph node status. This highlights the need for pro forma reporting to ensure and maintain consistent reporting of important parameters required for proper staging and management of patients with colorectal cancer.

Prognostic value of SPARCL1 in patients with colorectal cancer.

Secreted protein acidic and rich in cysteine-like 1 (SPARCL1), a member of extracelluar matrix glycoprotein, has been reported to be associated with various tumor types. The present study aimed to evaluate the prognostic value of SPARCL1 in patients with colorectal cancer. Tissue microarray blocks were constructed based on 79 patients who underwent radical surgery at the Kunshan First People's Hospital between 2008 and 2010. Thirty pairs of fresh-frozen tissues were also obtained for total protein extraction. The expression of SPARCL1 protein was analyzed using immunohistochemistry and western blotting analyses, and the association between overexpressed SPARCL1 and clinicopathological factors was evaluated. Survival analysis with Kaplan Meier curves and Cox regression analysis was used to analyze the prognostic value of SPARCL1. According to western blot analyses, SPARCL1 protein expression in colorectal tumors was significantly lower compared with corresponding normal tissues. The expression of SPARCL1 was markedly decreased from differentiation I to III, and the negative rate of SPARCL1 was higher at Duke's stage C compared with B. Though without any difference between ‘positive’ and ‘negative’ in overall survival, significantly higher survival in patients with positive SPARCL1 expression at Duke's stage B was detected in the present study. These results indicated that SPARCL1 may be a potential tumor suppressor gene and associated with good prognosis.

LRP6 promotes invasion and metastasis of colorectal cancer through cytoskeleton dynamics.

Low density lipoprotein (LDL) receptor-related protein-6 (LRP6) is an important co-receptor of Wnt pathway, which plays a predominant role in development and progression of colorectal cancer. Recently, dysregulation of LRP6 has proved to be involved in the progression of cancers, but its biological role and clinical significance in colorectal cancer remain unclear. In present study, we revealed that phosphorylation of LRP6 was aberrantly upregulated in colorectal carcinoma correlating with TNM or Dukes staging and worse prognosis. In addition, phosphorylated LRP6 was positively correlated with nuclear accumulation of β-catenin. Overexpression or activation of LRP6 could activate Wnt signaling and promote tumor cell migration in vitro. The activation of LRP6 could induce microtubule dynamics and actin remodeling, probably through regulation of microtubule-associated protein 1B (MAP1B), microtubule actin cross-linking factor 1 (MACF1) and Rho GTPase--RhoA and Rac1. The investigation suggests that LRP6 may be a potential prognostic marker and therapeutic target in the progression of colorectal cancers.

Revisiting Dukes' paradigm; some node positive colon cancer patients have better prognosis than some node negative patients.

The current study tried to evaluate the prognostic value of a modified staging system compared to the American Joint Committee on Cancer (AJCC) staging system for patients with colon cancer. Surveillance, epidemiology and end results (SEER) database (2004-2014) was queried through SEER*Stat program and AJCC 7th stages were constructed. Through recursive partitioning analysis and subsequent decision tree formation, suggested new stages were formulated based on T and N descriptors. Overall survival analyses were performed through Kaplan-Meier analysis. The cancer-specific Cox regression hazard (adjusted for age, gender, sub-site, grade, race and surgery) was calculated and pair wise comparisons of hazard ratios were conducted. A total of 159,683 non-metastatic patients with colon cancer were recruited in the analysis. Pair wise hazard ratio comparisons among different AJCC 7th stages were conducted and all comparisons were significant (P<0.0001). However, it should be noted that the adjusted risk of death among stage IIC patients was higher than stage IIIA and IIIB. Pair wise hazard ratio comparisons among different modified system stages were also conducted and all comparisons were significant (P<0.0001). The outcomes of survival analysis were the same regardless of the number of examined lymph nodes (<12 vs.≥12). Concordance index (using death from colon cancer as the dependent variable) for AJCC 6th staging system was 0.704 (SE 0.002; 95% CI 0.701-0.708); for AJCC 7th staging system was 0.708 (SE 0.002; 95% CI 0.704-0.711); for Dukes staging system was 0.670 (SE 0.002; 95% CI 0.666-0.674); and for modified staging system was 0.712 (SE 0.002; 95% CI 0.709-0.716). The proposed modified staging system provided an improved prognostication for colon cancer patients (particularly for stage II/III disease) compared to AJCC staging system. Further external validation of the proposed staging system is needed before adoption into routine practice.

Strategies for detecting colon cancer in patients with inflammatory bowel disease.

Patients with longstanding ulcerative colitis and colonic Crohn's disease have an increased risk of colorectal cancer (CRC) compared with the general population. This review assessed the evidence that endoscopic surveillance may prolong life by allowing earlier detection of CRC or its pre-cursor lesion, dysplasia, in patients with inflammatory bowel disease (IBD). To assess the effectiveness of cancer surveillance programs for diagnosis of IBD-associated colorectal cancer and in reducing the mortality rate from colorectal cancer in patients with IBD. We searched MEDLINE, EMBASE, CENTRAL and clinical clinicaltrials.gov from inception to 19 September 2016. We also searched conference abstracts and reference lists to identify additional studies. Potentially relevant articles were reviewed independently and unblinded by two authors to determine eligibility. Randomised controlled trials (RCTs) or observational studies (cohort or case control) assessing any form of endoscopic surveillance aimed at early detection of CRC were considered for inclusion. Studies had to have a no surveillance comparison group to be eligible for inclusion. Eligible studies were reviewed in duplicate and the results of the primary research trials were independently extracted by two authors. The primary outcome was detection of CRC. Secondary outcomes included death from CRC, time to cancer detection, time to death and adverse events. Deaths from CRC were derived from life tables, survival curves or where possible, by calculating life tables from the data provided. The presence of significant heterogeneity among studies was tested by the chi-square test. Because this is a relatively insensitive test, a P value of less than 0.1 was considered statistically significant. Provided statistical heterogeneity was not present, the fixed effects model was used for the pooling of data. The 2x2 tables were combined into a summary test statistic using the pooled odds ratio (OR) and 95% confidence intervals as described by Cochrane and Mantel and Haenszel. The methodological quality of the included studies was assessed using the Newcastle-Ottawa scale for non-randomised studies The overall quality of the evidence supporting the primary and selected secondary outcomes was assessed using the GRADE criteria. No RCTs were identified. Five observational studies (N = 7199) met the inclusion criteria. The studies scored well on the Newcastle-Ottawa scale, but due to the nature of observational studies, a high risk of bias was assigned to all the studies. Three studies were pooled to assess the rate of cancer detected in the surveillance group compared to the non-surveillance group. The studies found a significantly higher rate of cancer detection in the non surveillance group compared to the surveillance group. CRC was detected in 1.83% (53/2895) of patients in the surveillance group compared to 3.17% (135/4256) of patients in the non-surveillance group (OR 0.58, 95% CI 0.42 to 0.80; P = 0.0009). Four studies were pooled to assess the death rate associated with CRC in patients who underwent surveillance compared to patients who did not undergo surveillance. There was a significantly lower death rate associated with CRC in the surveillance group compared to the non-surveillance group. Eight per cent (15/176) of patients in the surveillance group died from CRC compared to 22% (79/354) of patients in the non-surveillance group (OR 0.36, 95% CI 0.19 to 0.69, P=0.002). Data were pooled from two studies to examine the rate of early stage versus late stage colorectal cancer (Duke stages A & B compared to Duke stages C & D) in patients who underwent surveillance compared to patients who do not undergo surveillance. A significantly higher rate of early stage CRC (Duke A & B) was detected in the surveillance group compared to the non-surveillance group. Sixteen per cent (17/110) of patients in the surveillance group had early stage CRC compared to 8% (9/117) of patients in the non-surveillance group (OR 5.40, 95% CI 1.51 to 19.30; P = 0.009). A higher rate of late stage CRC (Duke C & D) was observed in the non-surveillance group compared to the surveillance group. Nine per cent (10/110) of patients in the surveillance group had late stage CRC compared to 16% (19/117) of patients in the non-surveillance group (OR 0.46, 95% CI 0.08 to 2.51; P = 0.37). A GRADE analysis indicated that the quality of the data was very low for all of these outcomes. The included studies did not report on the other pre-specified outcomes including time to cancer detection, time to death and adverse events. The current data suggest that colonoscopic surveillance in IBD may reduce the development of both CRC and the rate of CRC-associated death through early detection, although the quality of the evidence is very low. The detection of earlier stage CRC in the surveillance group may explain some of the survival benefit observed. RCTs assessing the efficacy of endoscopic surveillance in people with IBD are unlikely to be undertaken due to ethical considerations.

Overexpression of Rictor protein in colorectal cancer is correlated with tumor progression and prognosis.

In order to understand the clinical significance of rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) in colorectal cancer (CRC), 62 CRC tissue samples excised during operations were evaluated by immunohistochemistry. Analysis of the association between the expression level of Rictor protein and clinicopathological parameters demonstrated that the expression level of Rictor in CRC tissues was significantly higher than that in paracarcinoma tissues (P<0.0001). In cellular experiments, this result was further confirmed by comparing differences in Rictor expression between the CRC cell lines HCT116, SW480 and LoVo, and the human normal liver cell line HL-7702. It was also noticed that the expression of Rictor was associated with Dukes stage, lymphatic metastasis and prognosis, as determined by χ2 test, Kaplan-Meier analysis and log-rank test. These results suggest that Rictor may be a novel target for the treatment and prognostic assessment of CRC patients in the future.

New use of low-dose aspirin and risk of colorectal cancer by stage at diagnosis: a nested case\u2013control study in UK general practice

BackgroundEvidence from clinical trial populations suggests low-dose aspirin reduces the risk of colorectal cancer (CRC). Part of this reduction in risk might be due to protection against metastatic disease.MethodsWe investigated the risk of CRC among new-users of low-dose aspirin (75–300 mg), including risk by stage at diagnosis. Using The Health Improvement Network, we conducted a cohort study with nested case–control analysis. Two cohorts (N = 170,336 each) aged 40–89 years from 2000 to 2009 and free of cancer were identified: i) new-users of low-dose aspirin, ii) non-users of low-dose aspirin, at start of follow-up, matched by age, sex and previous primary care practitioner visits. Patients were followed for up to 12 years to identify incident CRC. 10,000 frequency-matched controls were selected by incidence density sampling where the odds ratio is an unbiased estimator of the incidence rate ratio (RR). RRs with 95% confidence intervals were calculated. Low-dose aspirin use was classified ‘as-treated’ independent from baseline exposure status to account for changes in exposure during follow-up.ResultsCurrent users of low-dose aspirin (use on the index date or in the previous 90 days) had a significantly reduced risk of CRC, RR 0.66 (95% CI 0.60–0.74). The reduction in risk was apparent across all age groups, and was unrelated to dose, indication, gender, CRC location or case-fatality status. Reduced risks occurred throughout treatment duration and with all low-dose aspirin doses. RRs by aspirin indication were 0.71 (0·63–0·79) and 0.60 (0.53–0.68) for primary and secondary cardiovascular protection, respectively. Among cases with staging information (n = 1421), RRs for current use of low-dose aspirin were 0.94 (0.66–1.33) for Dukes Stage A CRC, 0.54 (0.42–0.68) for Dukes B, 0.71 (0.56–0.91) for Dukes C, and 0.60 (0.48–0.74) for Dukes D. After 5 years’ therapy, the RR for Dukes Stage A CRC was 0.53 (0.24–1.19).ConclusionsPatients starting low-dose aspirin therapy have a reduced risk of Stages B–D CRC, suggesting a role for low-dose aspirin in the progression of established CRC; a substantial reduction in the risk of Dukes A CRC may occur after 5 years’ therapy.

The Association Between HSP90/topoisomerase I Immunophenotype and the Clinical Features of Colorectal Cancers in Respect to KRAS Gene Status.

The aim of this study was to investigate heat shock protein 90 (HSP90) and topoisomerase I (Topo I) expression and the association between both proteins and clinicopathological parameters of colorectal cancer (CRC), in order to describe their role in tumor biology regarding to Kirsten Ras (KRAS) - positive/negative cases. Expression of HSP90 and Topo I, and KRAS gene mutations were estimated in primary CRCs. HSP90/Topo I immunophenotype correlated with gender, Duke staging, tumor grade and lymph node metastasis (p<0.01). Positive correlation was found between KRAS mutation and HSP90 expression (p=0.02). HSP90, Topo I expression, and co-expression of HSP90/Topo I correlated with unfavorable parameters of CRCs in respect to KRAS gene status (p<0.001). Our results revealed that cooperation between HSP90 and Topo I expression exists in CRCs, independently of KRAS gene status, suggesting that co-expression of both proteins might be considered as a double target on individual tumor cells.

Immune evasion in colo-rectal cancer in a cohort of Sudanese patients: possible roles for MHC Class II antigens

Background: Colorectal cancer (CRC) is the third most common cancer world-wide. The majority of cases occur in the developed world. This prospective study aimed to correlate different human leukocyte antigens (HLA types; HLA DRB1 and DRB3) with the aggressiveness of CRC in Sudanese patients.Methods: Thirty-three patients with histopathologically confirmed CRC were included in the study. Demographic, clinical and laboratory data were recorded. Molecular typing for HLA DRB1 (DR1, 7 and 17), DRB3 and DRB4 were carried out using PCR-based Sequence-Specific Primers.Results: Forty percent of the patients were ≤ 50years; with a male to female ratio of 2.5:1. Rectal bleeding was the commonest presenting symptom. While moderately differentiated adenocarcinoma was the dominant histological type. Duke's stages B and C were reported in 54.6% and 42.4% of patients, respectively. No patients presented with Dukes stages A or D. HLA DRB3 was the most frequent allele detected followed by DRB4 and DR17. A higher frequency of the DRB3 allele was found in the peripheral blood when compared with the tumor and apparently normal tissues. HLA DRB3 and DR7 allele frequencies correlated with Duke's stages B and C but not with age, sex or degree of differentiation, while blood DR17 antigen correlated only with the degree of tumor differentiation.Conclusion: CRC was found to have a higher occurrence in younger patients. Tumors were aggressive with advance Duke's stage at presentation. This aggressive nature could possibly be related to either increased HLA DRB3 or DR7 or decreased HLA DR17 levels in the tumor tissue when compared with the blood. No differences between tumor and normal colon tissues were found, in concordance with the multifocally of colon cancer theory.

Galectin-3 Expression in Colorectal Cancer and its Correlation with Clinical Pathological Characteristics and Prognosis.

ObjectiveTo explore the expression levels of galectin-3 in colorectal cancer and the association between galectin-3 and its clinical pathological parameters, as well as the prognosis of colorectal cancer patients.MethodsAn immunohistochemistry assay was used to test the expression levels of galectin-3 in cancer tissues of 61 colorectal cancer cases and in normal intestinal tissues adjacent to the cancer tissues of 23 cases. The associations between protein expression levels of galectin-3 and the clinicopathological features, such as age, sex, pathology type, lymphatic metastasis, and prognosis were also analyzed.ResultsThe positive rate of galectin-3 in cancer tissues was significantly higher than that of cancer-adjacent tissues: 62.5% (38/61) versus 13.0% (3/23) (P<0.05), respectively. Correlation was found between the protein expression of galectin-3 and the tumor size (P<0.05), as well as between the tumor differentiation (P<0.05) and Duke staging (P<0.05). The median progression-free survival times of patients with galectin-3 positive and negative expression were 19.2 and 35.1 months, respectively, with significant statistical difference (P<0.05).ConclusionGalectin-3 expression was correlated with the genesis and development of colorectal cancer and which could be used a biological marker for the prognosis of colorectal cancer patients.

Abstract 5718: Outcome prediction in colorectal cancer using digitized tumor samples and machine learning

Abstract Additional prognostic stratification of colorectal cancer patients is needed to improve management of patients. Visual microscopic assessment of tumor samples remains the standard method for disease subtyping. However, visual analysis of samples is subjective and weakly reproducible due to inter- and intra-observer variations. Recent progress within machine learning, especially its novel branch called deep learning, enables accurate evaluation of complex patterns observed in microscopic tissue images. Here, we combined deep learning techniques to evaluate a set of digitized formalin fixed paraffin embedded hematoxylin-eosin stained tumor tissue microarray (TMA) samples from 420 randomly selected patients with colorectal cancer. For each patient a set of clinicopathological characteristics including histological grade, Dukes stage and age at diagnosis are available as well as outcome data. Using convolutional neural networks and Long Short-Term Memory networks we validated the predictive power of the colorectal TMAs with regards to patient outcome. Univariate Cox proportional hazard regression analysis demonstrated that the prognostic accuracy of the deep learning algorithm on TMAs (hazard ratio 2.3; CI 95% 1.79-3.03) outperforms visual histological grading performed by a certified pathologist on a whole slide level (hazard ratio 1.65; CI 95% 1.30-2.15). In multivariate Cox proportional hazard regression, the deep learning based model was a prognostic factor, independent of histological grade, Dukes stage and age at diagnosis (Wald p-value &amp;lt; 0.001). Thus, we demonstrate that novel deep learning models can serve as digital prognostic biomarkers in colorectal cancer. Citation Format: Dmitrii Bychkov, Riku Turkki, Caj Haglund, Nina Linder, Johan Lundin. Outcome prediction in colorectal cancer using digitized tumor samples and machine learning [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 5718. doi:10.1158/1538-7445.AM2017-5718