Decoding microbe-diet-host synergy in colorectal cancer.

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

Guidelines on genetic evaluation and management of Lynch syndrome: A consensus statement by the U.S. Multi-Society Task Force on Colorectal Cancer

UK Fifth National Colorectal Cancer Consensus Meeting 2010

Colorectal Cancer Genetics Screening in the Community: Are We Ready? Can We Do It?

Rates of New or Missed Colorectal Cancers After Colonoscopy and Their Risk Factors: A Population-Based Analysis

BNC101 is a monoclonal antibody (mAb) targeting LGR5 currently undergoing IND-enabling studies in preparation for Phase I clinical studies in 2014. LGR5 is a validated cancer stem cell (CSC) receptor overexpressed in colorectal cancer (CRC), pancreatic cancer and most other solid tumors. Loss and gain-of-function studies indicate that LGR5 is a functional cancer receptor involved in the growth and survival of colon cancer cells in vitro and in vivo. Sorted LGR5+ primary CRC are highly tumorigenic compared to LGR5- cells in limiting dilution in vivo xenograft studies. Using Bionomics' CSC Rx Discovery™ platform, a panel of high affinity LGR5 mAbs were generated and screened for in vitro and in vivo activity against CSCs from patient-derived CRC tumors. LGR5 mAb therapeutic drug candidates were first screened and identified based on their ability to inhibit the formation of CRC CSC colonies in vitro. Top LGR5 mAb candidates were then tested as single agents and in combination with standard of care (SOC) chemotherapy in primary xenograft efficacy studies. Tumors from these studies were also harvested and re-implanted in limiting dilution assays (LDA) to assess in vivo anti-CSC activity of anti-LGR5 mAbs. A number of functional LGR5 mAbs with significant anti-tumor and anti-CSC activity were identified through this process. A lead BNC101 mAb clone was selected for clinical development based on its ability to inhibit CSC growth and key signaling pathways from multiple patient tumors both in vitro and in vivo. In LDA studies using two different CRC patient tumors, 5/8 (63%) and 6/8 (75%) mice implanted with serially diluted cells from BNC101 treated tumors remained tumor free, compared to 1/8 (13%) and 2/8 (25%) in the control groups. Combination with SOC chemotherapy was shown to further improve BNC101 activity in one CRC model, where 8/8 mice re-implanted for LDA remained tumor-free in a 6 month follow-up. BNC101 was also found to be highly active as a single agent and in combination with SOC in multiple pancreatic models and the MDA-MB-231 triple-negative breast cancer (TNBC) xenograft model. In one primary pancreatic model, BNC101 combined with SOC completely eradicated 3/7 established tumors, compared to 0/7 tumors eradicated with control SOC alone. Additional translational data in CRC, pancreatic and TNBC supporting our hypothesis that BNC101 targeting of CSCs will significantly improve survival and increase duration of response in cancer patients will be presented. Citation Format: Peter Chu, Kristen Smith, John Norton, Colin Walsh, Farbod Shojaei, Jose Iglesias, Christopher Reyes. Targeting colorectal and pancreatic cancer stem cells with the LGR5 monoclonal antibody BNC101. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3894. doi:10.1158/1538-7445.AM2014-3894

<div>Abstract<p><b>Purpose:</b> If immune cells are involved in tumor surveillance and have a prognostic impact in most primary tumors, little is known about their significance in metastases. Because patients' survival is heterogeneous, even at metastatic stages, we hypothesized that immune cells may be involved in the control of metastases. We therefore characterized the tumor immune microenvironment and its prognostic value in colorectal and renal cell carcinoma (RCC) metastases, and compared it to primary tumors.</p><p><b>Experimental Design:</b> We analyzed by immunohistochemistry (<i>n</i> = 192) and qPCR (<i>n</i> = 32) the immune environments of colorectal carcinoma and RCC lung metastases.</p><p><b>Results:</b> Metastases from colorectal carcinoma and RCC have different immune infiltrates. Higher densities of DC-LAMP<sup>+</sup> mature dendritic cells (<i>P</i> < 0.0001) and lower densities of NKp46<sup>+</sup> NK cells (<i>P</i> < 0.0001) were observed in colorectal carcinoma as compared to RCC metastases, whereas densities of T cells were similar. High densities of CD8<sup>+</sup> and DC-LAMP<sup>+</sup> cells correlated with longer overall survival (OS) in colorectal carcinoma (<i>P</i> = 0.008) and shorter OS in RCC (<i>P</i> < 0.0001). High NK-cell densities were associated with improved survival in RCC (<i>P</i> = 0.002) but not in colorectal carcinoma. Densities of immune cells correlated significantly from primary to relapsing metastases for the same patient. A T<sub>H</sub>1 orientation was found in colorectal carcinoma metastases, whereas a heterogeneous immune gene expression was found in RCC metastases.</p><p><b>Conclusions:</b> Our results show a major prognostic value of the immune pattern (CD8<sup>+</sup>/DC-LAMP<sup>+</sup> cell densities) in colorectal carcinoma and RCC, reproducible from primary to metastatic tumors, although with opposite clinical impacts, and highlight the role of the tumor cell in shaping its immune environment. <i>Clin Cancer Res; 19(15); 4079–91. ©2013 AACR</i>.</p></div>

At present, the global incidence of colorectal cancer is increasing, with numerous individuals succumbing to the disease. The standard treatment strategy for colorectal cancer is curative resection. However, a cure is rarely achieved for metastatic colorectal cancer. Currently, chemotherapy is the main treatment for metastatic and recurrent colorectal cancer. The majority of metastases or recurrences have been found to respond well to chemotherapy. The present study evaluated the response rates of recurrent or metastatic colorectal cancer patients treated with a combination chemotherapy of irinotecan and oral uracil-tegafur (UFUR). In the pilot study, 33 patients with metastatic or recurrent colorectal cancer were treated with different regimens of irinotecan and UFUR with or without leucovorin; however, irinotecan (150 mg/m2 every two weeks) with continuous UFUR and leucovorin without interruption resulted in improved survival compared with the other regimens evaluated and, thus, was employed for the present study of 113 patients. The patients that received irinotecan with UFUR and leucovorin without interruption exhibited similar efficacy in terms of overall survival and response rate to that of the pilot study. In addition, the incidences of diarrhea, alopecia and hematologic toxicity were acceptable, which was in agreement with the results of the pilot study. Therefore, combination chemotherapy with irinotecan, oral UFUR and leucovorin appears to be a satisfactory treatment strategy for recurrent or metastatic colorectal cancer.

This research extracted patient-reported symptoms from free-text EHR notes of colorectal and breast cancer patients and studied the correlation of the symptoms with comorbid type 2 diabetes, race, and smoking status. An NLP framework was developed first to use UMLS MetaMap to extract all symptom terms from the 366,398 EHR clinical notes of 1694 colorectal cancer (CRC) patients and 3458 breast cancer (BC) patients. Semantic analysis and clustering algorithms were then developed to categorize all the relevant symptoms into eight symptom clusters defined by seed terms. After all the relevant symptoms were extracted from the EHR clinical notes, the frequency of the symptoms reported from colorectal cancer (CRC) and breast cancer (BC) patients over three time-periods post-chemotherapy was calculated. Logistic regression (LR) was performed with each symptom cluster as the response variable while controlling for diabetes, race, and smoking status. The results show that the CRC and BC patients with Type 2 Diabetes (T2D) were more likely to report symptoms than CRC and BC without T2D over three time-periods in the cancer trajectory. We also found that current smokers were more likely to report anxiety (CRC, BC), neuropathic symptoms (CRC, BC), anxiety (BC), and depression (BC) than non-smokers.

667 Background: The prognostic role of CpG Island Methylator Phenotype (CIMP) in colorectal cancer (CRC) is still controversial, especially in metastatic CRC. Methods: We retrospectively analyzed the CpG island methylator phenotype (CIMP) in stage I to IV CRC specimens, which were diagnosed during 2005-2013. CIMP status was determined using a 5- gene MethyLight-based assay ( p16, MINT1, MINT2, MINT31, and MLH1). Tumors were designated as CIMP if 3 or more of 5 genes gave percent of methylated reference value ≧ 10. The clinicopatholoical characteristics, anti-cancer therapies, and the overall survival outcome were reviewed. Overall survival (OS) was compared between patients with CIMP CRC and those with non-CIMP CRC. Results: Among 450 patients with successfully determined CIMP status, 259 (57.56%) were male, 312 (70.31%) were stages I-III, 316 (70.69%) were left-sided CRC. In the survival analyses in stages I-IV patients, there was no significant difference in OS between those with or without CIMP (long rank test, p = 0.4526). Importantly, patients with metastatic CIMP CRC had poor OS than those with metastatic non-CIMP CRC (median survival, CIMP vs. non-CIMP: 1.36 vs. 3.11 years, log rank test, p = 0.0047). In a multivariate analysis, which adjusted prognostic variables such as: KRAS and BRAF mutations, microsatellite instability status, age, sex, grade, primary site, metastatic site number, chemotherapies and targeted therapies, CIMP remained an independent poor prognostic factor for OS (HR = 6.213, 95% confidence interval: 2.443 to 15.799, p = 0.0001) in metastatic CRC. In an exploratory analysis, there were more tumors with liver metastases at diagnosis in CIMP CRC than in non-CIMP CRC (94.4% vs. 71.3%, p = 0.0416). Conclusions: Our data demonstrated CIMP might independently predict poor survival in metastatic CRC in a large East Asian cohort.

Background:Colorectal cancer (CRC) is one of the most common cancers worldwide, with the highest incidence rates western countriesThe 5-year survival rate for a patient diagnosed with stage I or II colorectal cancer, is up to 90%. However, the 5-year survival rate for patients diagnosed with stage IV disease, once the cancer has metastasized to other organs, is only 12%. Aim of the work :is todetect levels of Visfatin,Nitric oxide,Lipid peroxide and Superoxide dismutase in serum of patients with colorectal cancer and compare results with patients with benign colorectal tumor and with control group and detect the relation of each of them to the clinic-pathological criteria colorectal cancer. Patients and methods:This study was performed at Sohag University Hospital from December 2015 to June 2016, eighty-five persons were enrolled the study and divided into three groups. 60 patients with colorectal cancer, 10 patients with begin colorectal tumors all of them were selected from SohagCancer Institute and Sohag University Hospital and 15 healthy persons of matched age and sex without evidence of any cancer (controls). All were matched for age and sex, for each participantcomplete medical history, physical examination, and routine investigations were done.Nicotinamidephosphoribosyltransferase (NAMPT) was measured by Eliza kitsNitric oxide and Superoxide dismutase (SOD) activities level were measured by colorimetry.. Results:The serum levels of visfatinNAMPT,NO and lipid peroxidation products as MDAin patients with benign tumor were significantly higher than healthy controls ,in patients with colorectal cancer the levels is significantly higher than healthy controls and patients with benign tumor (p-value < 0.001), and there is significant relations between levels of NAMPT and the clinicopathologicalcritiria of the cancer ,In contrast the levels of antioxidant enzyme (superoxide dismutase) where altereddecreased in colorectal cancer group , benign lesions group comparing to healthy control group . Conculsion:our study relieved that there is positive relation between level of visfatin and colorectal caneroccurance and cancer clinicopathological criteria . Also our study relievedColorectal carcinogenesis is associated with serious oxidative stress and confirms that gradual advancement of oxidative-antioxidative disorders is followed by progression of colorectal cancer.

Colon Cancer Screening Models: Lessons and Challenges

One of the most effective means of reducing cancer-specific mortality is early detection via cancer screening; however, Hispanic men continue to have lower colorectal, prostate and skin cancer screening rates than White non-Hispanic men. To combat this disparity and educate men and women aged 50 and older about the importance of regular colorectal cancer (CRC) screening, the Screen for Life campaign, which included directed intervention materials in Spanish as well as in English, was launched by the Center for Disease Control and Prevention (CDC) in 1999. We hypothesized that CRC screening rates would increase overtime among Hispanics and non-Hispanics as a result of this campaign and that prostate and skin cancer screening would also increase due to screening recommendations and raised awareness and necessity of cancer screening. The objective of this study was to assess whether CRC, as well as prostate and skin cancer screening rates among Hispanic and White non-Hispanic men changed between 2000 and 2005 using the National Health Interview Survey (NHIS) data. Our results showed that Hispanic men were less likely to comply with cancer screening guidelines for these three common malignancies than White non-Hispanic men. However, significant increases in CRC endoscopic screening were observed in both ethnic groups. It increased 2.1-fold and 2.4-fold for Hispanic and White non-Hispanic men, respectively (P&amp;lt;0.05). In contrast, the use of home fecal occult blood tests remained stable among Hispanics and decreased significantly among White non-Hispanics. PSA screening remained stable, while the use of skin cancer screening tended to increase among both ethnic groups. Our study suggests that a targeted public education program that is culturally sensitive and linguistically appropriate may be effective in increasing CRC screening rates. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-434.

Aspirin could reduce the risk of cancer metastasis. Circulating tumor cells (CTCs) are a key factor of cancer metastasis, but no evidence has revealed how aspirin affects CTCs and its epithelial-mesenchymal transition (EMT). Here, we conducted a clinical trial to investigate how aspirin affects CTCs in metastatic colorectal cancer (MCC) and breast cancer patients (MBC). The trial is retrospective registered at clinicaltrials.gov (NCT02602938). The eligible patients are given 100mg aspirin q.d. for 8weeks, and CTCs are evaluated at baseline, 4 and 8weeks for absolute number, phenotype (epithelial type, E+, mesenchymal type, M+, and biophenotypic type, B+), and vimentin expression. Data on 21 MCC and 19 MBC patients are analyzed, and it revealed that the CTC numbers decreased with aspirin treatment in MCC (p<0.001) but not MBC (p=0.0532); besides, ratio of E+ CTCs increased (p=0.037) and M+ CTCs decreased at 2months in MCC (p=0.013), but neither the ratio of E+ or M+ CTCs changes significantly in MBC; vimentin expression of M+ CTCs is higher than E+ and B+ CTCs either in MBC or MCC patients at baseline (p<0.01); and aspirin suppresses the vimentin expression in M+ (p=0.002)and B+ (p=0.006) CTCs of MCC and M+ CTCs of MBC (p=0.004); besides it find vimentin expression in B+ (p=0.004) or M+ (p<0.001), CTCs are markedly decreased in patients with total CTC numbers declined. Aspirin could decrease CTCs numbers and block EMT transition in MCC patients and part of MBC patients.

Dietary fiber intake and risk of colorectal cancer and incident and recurrent adenoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial