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Weixing Dai,1,2,* Yaqi Li,1,2,* Zhenyu Wu,3,* Yang Feng,1,2 Sanjun Cai,1,2 Ye Xu,1,2 Qingguo Li,1,2 Guoxiang Cai1,2 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; 3Department of Biostatistics, School of Public Health Safety, Ministry of Education, Fudan University, Shanghai 200032, China *These authors contributed equally to this work Background: Lymph node status can predict the prognosis of patients with rectal cancer treated with surgery. Thus, we sought to establish a standard for the minimum number of lymph nodes (LNs) examined in patients with rectal cancer by evaluating the probability that pathologically negative LNs prove positive during surgery. Patients and methods: We extracted information of 31,853 patients with stage I–III rectal carcinoma registered between 2004 and 2013 from the Surveillance, Epidemiology, and End Results database and divided them into two groups: the first group was SURG, including patients receiving surgery directly and the other group was NEO, encompassing those underwent neoadjuvant therapy. Using a beta-binomial model, we developed nodal staging score (NSS) based on pT/ypT stage and the number of LNs retrieved. Results: In both cohorts, the false-negative rate was estimated to be 16% when 12 LNs were examined, but it dropped to 10% when 20 LNs were evaluated. In the SURG cohort, to rule out 90% possibility of false staging, 3, 7, 28, and 32 LNs would be necessarily examined in patients with pT1–4 disease, respectively. While in the NEO cohort, 4, 7, 12, and 16 LNs would be included for examination in patients with ypT1–4 disease to guarantee an NSS of 90%. Conclusion: By determining whether a rectal cancer patient with negative LNs was appropriately staged, the NSS model we developed in this study may assist in tailoring postoperative management. Keywords: nodal staging score, rectal cancer, lymph node, neoadjuvant therapy, beta-binomial model

Figure S1. The peak map of DNA sequencing about the constructions of wild-type and mutant BIRC3 promoters. (PDF 712 kb)

Ectopic expression of lncRNA-MALAT1 has been discovered in recurrent colorectal cancer (CRC) and metastatic sites in postsurgical patients, however, its biological mechanism remained unelucidated. Our study first revealed the novel roles of MALAT1 in promoting CRC metastasis through two mechanisms: first, MALAT1 binds miR-15 family members, to “de-inhibit” their effect on LRP6 expression, enhances β-catenin signaling, leading to elevated transcriptional levels of downstream target genes RUNX2. Second, MALAT1 binds SFPQ, and dissociates SFPQ/PTBP2 dimer to release free PTBP2, which elevates translational levels of RUNX2, through interacting with IRES domain in the 5′UTR of the corresponding RUNX2 mRNAs. Moreover, increased RUNX2 expression levels were detected in recurrent CRC tumors, which were closely associated with TMN stages, metastasis, as well as CRC patients’ survival. Our study demonstrated that MALAT1 and RUNX2 may serve as two biomarkers for predicting the recurrence and metastasis of CRC patients.

Objectives We aimed to elucidate the role and molecular mechanisms of FOXM1 in regulating metastasis in oesophageal squamous cell carcinoma (ESCC) as well as its clinical implications. Materials and methods The expression levels of four isoforms of FOXM1 were analysed by real-time PCR. Next, genetically modification using overexpression and RNAi systems and transwell were employed to examine FOXM1c function in invasion and migration. Dual luciferase and ChIP assays were performed to decipher the underlying mechanism for transcriptional regulation. The expression levels of FOXM1 and IRF1 were determined by immunohistochemistry staining in ESCC specimens. Results The FOXM1c was predominantly overexpressed in ESCC cell lines compared to the other FOXM1 isoforms. Ectopic expression of FOXM1c promoted invasion and migration of ESCC cells lines, whereas downregulation of FOXM1c inhibited these processes. Moreover, FOXM1c expression was positively correlated with IRF1 expression in ESCC cell lines and tumour specimens. IRF1 is, at least in part, responsible for FOXM1c-mediated invasion and migration. Mechanistically, we identified IRF1 as a transcriptional target of FOXM1c and found a FOXM1c-binding site in the IRF1 promoter region. Furthermore, high expression levels of both FOXM1c and IRF1 were positively associated with low survival rate and predicted a poor prognosis of oesophageal cancer patients. Conclusion FOXM1c promotes the metastasis by transcriptionally targeting IRF1 and may serve as a potential prognostic predictor for oesophageal cancer.

We postulated that expression differences of autophagy-related genes are instrumental in stratifying the risk of early relapse after surgery and evaluating the prognosis of patients with stages I–III colon cancer. Therefore, propensity score matching analysis was performed between patients in early relapse group and long-term survival group from GSE39582 test series and internal validation series. Using Cox regression model, a nine-autophagy-related signature (CAPN2, ATG16L2, TP63, SIRT1, RPS6KB1, PEX3, ATG5, UVRAG, NAF1) was established to classify patients into those at high risk of early relapse (high-risk group), and those at low risk of early relapse (low-risk group). Relapse-free survival (RFS) was significantly different between the two groups in test [hazard ratio (HR): 2.019, 95% confidence interval (CI): 1.362–2.992, P < 0.001], internal validation (HR: 2.464, 95% CI: 1.196–5.079, P < 0.001) and another two external validation series (GSE14333—HR: 2.250, 95% CI: 1.227–4.126, P = 0.007; GSE33113—HR: 5.552, 95% CI: 2.098–14.693, P < 0.001). Then, based on RFS, we developed a nomogram, integrating the nine-autophagy-related classifier and four clinicopathological risk factors to evaluate prognosis of stages I–III colon cancer patients. Time-dependent receiver operating curve at 2 years showed that the integrated signature (area under curve = 0.758) had better prognostic accuracy than American Joint Committee on Cancer TNM stage (area under curve = 0.620). In conclusion, we identified and built a nine-autophagy-related signature, a credible approach to early relapse prediction in stages I–III colon cancer patients, which can assist physicians in devising more efficient therapeutic strategies.

Hyperthermia enhances the anticancer effects of thymidylate synthase (TYMS) inhibitors (raltitrexed, RTX) and improves the precise biochemical mechanisms partially through enhancement of intracellular drug absorption. Recent research focuses on the potential anticancer drug target Heat Shock Protein 90 (HSP90), which could increase the sensitivity of cancer cells to TYMS inhibitors; however, with different HSP90 inhibitors, several research studies finally showed a poor efficacy in preclinical or clinical research. Here, we showed that 17-allylamino-17-demethoxygeldanamycin (17-AAG, HSP90 inhibitor) affects the efficacy of chemotherapy through antioxidant activation-induced resistance. In this study, we found that RTX, alone or in combination with hyperthermia, triggers reactive oxygen species (ROS) exposure and thus induces cell death. Also, the addition of hyperthermia showed more ROS exposure and function. The pharmacologic inhibition of HSP90 reversed the effects of chemotherapeutical treatments, while the overexpression of HSP90 showed no relation with these effects, which demonstrated that dysregulation of HSP90 might have a significant impact on chemotherapeutic treatments. The addition of 17-AAG increased the activation of antioxidant with increased antioxidant enzymes, thus affecting the RTX efficacy.

Background The objective of this study was to summarize the clinicopathological and molecular features of synchronous colorectal peritoneal metastases (CPM). We then combined clinical and pathological variables associated with synchronous CPM into a nomogram and confirmed its utilities using decision curve analysis. Materials and Methods Synchronous metastatic colorectal cancer (mCRC) patients who received primary tumor resection and underwent KRAS, NRAS, and BRAF gene mutation detection at our center from January 2014 to September 2015 were included in this retrospective study. An analysis was performed to investigate the clinicopathological and molecular features for independent risk factors of synchronous CPM and to subsequently develop a nomogram for synchronous CPM based on multivariate logistic regression. Model performance was quantified in terms of calibration and discrimination. We studied the utility of the nomogram using decision curve analysis. Results In total, 226 patients were diagnosed with synchronous mCRC, of whom 50 patients (22.1%) presented with CPM. After uni- and multivariate analysis, a nomogram was built based on tumor site, histological type, age, and T4 status. The model had good discrimination with an area under the curve (AUC) at 0.777 (95% CI 0.703–0.850) and adequate calibration. By decision curve analysis, the model was shown to be relevant between thresholds of 0.10 and 0.66. Conclusion Synchronous CPM is more likely to happen to patients with age ≤60, right-sided primary lesions, signet ring cell cancer or T4 stage. This is the first nomogram to predict synchronous CPM. To ensure generalizability, this model needs to be externally validated.

e15561 Background: Heart exposure to irradiation can cause cardiac events (CEs). The impact of radiation heart dosimetric parameters (RHDPs) on overall survival (OS) in esophageal cancer is not known. The aim of this study was to determine the association between heart dosimetric parameters and CEs and OS in patients with stage III esophageal cancer. Methods: 346 patients with esophageal cancer treated with definitive radiotherapy (RT) from 2011 to 2013 were enrolled retrospectively. We mainly observed three types of CEs: ischemic diseases (myocardial infarction and unstable angina), pericardial diseases (symptomatic effusion and pericarditis), and arrhythmia. We performed logistic regression or Cox proportional hazards models to evaluate the relationship between RHDPs, CEs and OS. Results: Median follow-up was 28 months and median prescribed doses was 60 Gy. Three and five-year OS was 43.9% and 16.8%, respectively. The number of patients who had ischemic diseases, pericardial diseases and arrhythmia in five years since they received treatment was 19, 12 and 26, respectively. Ischemic diseases was associated with pre-existing heart disease (P = .0016) and percentage of heart volume receiving ≥5 Gy (heart V5) (P = .0037), arrhythmia was associated with pre-existing heart disease (P = .0020), heart V5 (P = .0003) and mean heart dose (MHD) (P = .0021), but pericardial diseases was not correlated with RHDPs. In univariate analysis, smoking status, performance status, tumor location, lung V5, mean lung dose (MLD), heart V30, MHD and gross tumor volume (GTV) were significantly associated with three-year OS, and performance status, tumor location, concurrent or sequential chemotherapy, lung V5, heart V5, heart V30, MHD and GTV were correlated with five-year OS. In multivariate analysis, only poor performance status (hazard ratio (HR) 1.56; 95% confidence interval (CI), 1.16-2.10; P = .003 and HR 1.80; 95% CI, 1.15-2.82; P = .010) and larger GTV (HR 1.53; 95% CI, 1.14-2.05; P = .004 and HR 1.64; 95% CI, 1.07-2.49; P = 0.023) independently indicate worse three and five-year OS, and smoking status (HR 1.37; 95% CI, 1.03-1.82; P = 0.032) predict three-year OS only. Conclusions: Heart dose is associated with the occurrence of CEs, but it could not independently predict OS for patients with stage III esophageal cancer treated with definitive radiotherapy.

This study was retrospectively performed to analyze correlations between clinicopathological features of colorectal cancer (CRC) and mutations in KRAS, NRAS, and BRAF in Chinese patients, and to assess the importance of detecting additional mutations in KRAS exons 3 and 4 and NRAS in patients with CRC. RAS (KRAS and NRAS) and BRAF mutations were detected in 715 and 655 patients respectively. The mutation rate of RAS (KRAS or NRAS) was 45.6% (326/715). KRAS exon 2 mutations were evaluated in 36.6% of patients (262/715). Additional mutations in RAS exons occurred in 9.0% of patients (64/715), including KRAS exons 3 and 4 in 5.6% (40/715) and NRAS exons 2, 3, or 4 in 3.4% (24/715). Among 453 patients with wild-type KRAS exon 2, 14.1% (64/453) had other mutations in RAS exons. The most frequent sites of mutations were codons 12, 13, 61, and 146 in KRAS and codons 12 and 61 in NRAS. The mutation rate of BRAF (exon 15) was 4.0% (26/655), and the most frequent mutation site was codon 600. Among 440 patients with CRC who had a primary tumor resection at our center, those with mucinous or signet ring cell CRC were more likely to harbor KRAS mutations than those with adenocarcinoma (62.7% vs. 43.6%, P=0.006 and 59.3% vs. 39.6%, P=0.004, respectively). Female patients had a higher BRAF (exon 15) mutation rate than male patients (5.1% vs. 1.1%, P=0.017). Detection of both KRAS and NRAS mutations is useful for selecting patients who will benefit from anti-EGFR monoclonal antibody therapy. KRAS mutations were more frequent in patients with mucinous adenocarcinoma/signet ring cell CRC, whereas BRAF mutations were more common in female patients with CRC.

Incidental pulmonary lesions are frequently found during the preoperative evaluation of patients considered for resection of colorectal liver metastases (CRLM), and their presence can confound management decisions. This study investigates the role of clinical and radiologic factors, including response to preoperative systemic chemotherapy, in determining the malignant probability of these lesions.Computed tomography (CT) scans of 33 patients with small (≤1 cm) lung lesions undergoing resection for CRLM after preoperative chemotherapy were reviewed. Radiological features were recorded from three sequential CT scans (baseline, postchemotherapy, and follow-up). Malignancy was diagnosed either by resection or serial imaging. Chemotherapy response comparing lung lesions and CRLM was categorized as: (1) concordant or (2) discordant. Chemotherapy response, imaging features, and other clinical factors were evaluated in multivariate analyses as predictors of malignancy.Among the 86 indeterminate lung lesions identified, 23 % (20/86) were found to be metastases on follow-up. Lesions 6-10 mm were more likely to be metastases (odds ratio [OR] = 3.14, p = 0.045), as were lesions located in the lower lobes (OR = 4.50, p = 0.018). Concordant chemotherapy response was found in 13 of 86 (15 %) and was independently associated with metastatic disease (OR = 19.87, p0.001), with 11 of 13 (85 %) lesions determined to be metastases. In contrast, only 9 of 73 lesions (12 %) with discordant response were found to be metastases.Lesion size, location, and chemotherapy response pattern were independent predictors of malignancy for patients with resectable CRLM and small indeterminate lung lesions. Utilization of preoperative chemotherapy can be a useful method of ruling out pulmonary metastases in these patients.

Few previous studies have taken the growth pattern into consideration when analyzing the prognostic value of tumor size in colorectal cancer (CRC).We sought to reveal the prognostic role of tumor size in different macroscopic growth patterns of CRC.Using Cancer Center datasets, we identified 4057 cases with colorectal adenocarcinoma treated with curative resection. Macroscopic growth patterns of tumors were classified into three types: infiltrative, ulcerative and expansive types based on tumor gross appearance. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic factors for overall survival (OS) and disease-free survival (DFS).In whole cohort, tumor size was an independent factor for OS (HR 1.10, 95%CI 1.04-1.16, p 0.001). Subgroup analysis based on macroscopic growth pattern suggested that tumor size was an independent factor for OS both in the infiltrative (HR 1.37, 95%CI 1.12-1.66, p = 0.002) group and ulcerative group (HR 1.08, 95%CI 1.00-1.16, p = 0.044) and tumor size (HR 1.22, 95%CI 1.06-1.40, p = 0.004) was found as an independent factor for DFS only in infiltrative group.Tumor size is an independent factor for OS and DFS in patients with colorectal adenocarcinoma of infiltrative type, while only for OS in patients of ulcerative type.

Distant metastasis impaired the value of neoadjunctive chemoradiation therapy (NCRT) for patients who were not pathological completed response. The objective of this study was to evaluate whether the absolute counts of preoperative neutrophils (pN) could predict survival outcomes of patients treated with NCRT. In this study, 289 locally advanced rectal cancer patients receiving NCRT and radical surgery were recruited between January 2006 and December 2012 at the Fudan University Shanghai Cancer Center. The absolute counts of pN were gathered and analyzed. Survival analysis was used to evaluate the prognostic value of pN. As results, a pN 3.00 was elected as the optimal cutoff points in term of survival by X-tile program. There were 112 patients (38.8%) in high-pN group and 177 patients (61.2%) in low pN group. The 4-year rectal cancer-specific survival (RCSS) and disease free survival (DFS) rate was 48.5% and 80.6%, 50.9% and 76.7% in high and low pN group, respectively. Univariate and multivariate analysis revealed that high-pN predicted poor RCSS and DFS. In conclusion, an elevated pN level was a significantly risk factor for locally advanced rectal cancer patient treated with NCRT, which may serve as a valuable marker to predict the outcomes of those patients.

The purpose of this study was to analyze the impact of tumor size on cancer-specific survival (CSS) in patients with mucinous adenocarcinoma (MAC) of the colon, showing heavy intestinal wall invasion without distant metastasis (T4 N0-2 M0).Patients with T4N0-2M0 MAC of colon were analyzed based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method, and the log-rank test was used to identify differences. Risk factors were analyzed using the Cox proportional hazard model. A preliminary analysis of T4N0-2M0 adenocarcinoma of colon patients from the SEER database is also presented.A total of 585 patients from the SEER database were included in the analysis. The cutoff value (5.0 cm) was determined using the X-tile program. Kaplan-Meier analysis showed that tumors ≤5.0 cm had a poorer CSS compared to tumors5.0 cm (p=0.034). Multivariate analysis indicated that tumor size is an independent prognostic factor for these patients, and compared to tumors ≤5.0 cm, tumors5.0 cm were more likely to have better CSS (HR 0.658, 95% CI 0.506-0.854, p=0.002). Tumor size was also analyzed as a continuous variable in multivariate analysis, and CSS decreased with decreasing tumor size (HR 0.919, 95% CI 0.873-0.968, p0.001). No significant association between tumor size and CSS was observed in patients with T4N0- 2M0 MAC of the colon.Smaller tumor size is associated with poorer CSS in patients with T4N0-2M0 MAC of the colon.

Purpose: Metabolic phenotyping has provided important biomarker findings, which, unfortunately, are rarely replicated across different sample sets due to the variations from different analytical and clinical protocols used in the studies. To date, very few metabolic hallmarks in a given cancer type have been confirmed and validated by use of a metabolomic approach and other clinical modalities. Here, we report a metabolomics study to identify potential metabolite biomarkers of colorectal cancer with potential theranostic value. Experimental Design: Gas chromatography–time-of-flight mass spectrometry (GC–TOFMS)–based metabolomics was used to analyze 376 surgical specimens, which were collected from four independent cohorts of patients with colorectal cancer at three hospitals located in China and City of Hope Comprehensive Cancer Center in the United States. Differential metabolites were identified and evaluated as potential prognostic markers. A targeted transcriptomic analysis of 29 colorectal cancer and 27 adjacent nontumor tissues was applied to analyze the gene expression levels for key enzymes associated with these shared metabolites. Results: A panel of 15 significantly altered metabolites was identified, which demonstrates the ability to predict the rate of recurrence and survival for patients after surgery and chemotherapy. The targeted transcriptomic analysis suggests that the differential expression of these metabolites is due to robust metabolic adaptations in cancer cells to increased oxidative stress as well as demand for energy, and macromolecular substrates for cell growth and proliferation. Conclusions: These patients with colorectal cancer, despite their varied genetic background, mutations, pathologic stages, and geographic locations, shared a metabolic signature that is of great prognostic and therapeutic potential. Clin Cancer Res; 20(8); 2136–46. ©2014 AACR.

Ectopic expression of lncRNA-MALAT1 has been discovered in recurrent colorectal cancer (CRC) and metastatic sites in post-surgical patients, however, its biological mechanism remained un-elucidated. Our study firstly revealed the novel mechanisms of MALAT1 in promoting CRC metastasis through at least the following two mechanisms: First of all, MALAT1 binds miR-15 family members, to “de-inhibit” their effect on LRP6 expression, enhances beta-catenin signaling, leading to elevated transcriptional levels of downstream target genes RUNX2. Secondly, MALAT1 binds SFPQ, dissociate SFPQ/PTBP2 dimer to release free PTBP2, which elevates translational levels of RUNX2, through interacting with IRES domain in the 5’UTR of the corresponding RUNX2 mRNAs. Moreover, elevated RUNX2 expression levels were detected in recurrent CRC tumors, which were closely associated with TMN stages and CRC patients’ survival. Our data demonstrated that, MALAT1 and RUNX2 may serve as two biomarkers for predicting the recurrence of CRC patients. Note: This abstract was not presented at the meeting. Citation Format: Qing Ji, Guoxiang Cai, Xuan Liu, Yi Zhang, Yan Wang, Lihong Zhou, Hua Sui, Qi Li. MALAT1 regulates the transcriptional and translational levels of proto-oncogene RUNX2 and promotes colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 164.

Rectal gastrointestinal stromal tumor (GIST) was a rare disease. This study sought to summarize clinicopathological features and prognostic factors of rectal GISTs. Clinicopathological characteristics and prognostic factors of rectal GISTs were investigated by reviewing patients undergoing curative resection at the Fudan University Shanghai Cancer Center between 1986 and 2010. Twenty-one patients, 15 male and 6 female, were included. The mean age of onset was 51 years. The most common initial presentation was hematochezia (7 cases). Eleven patients underwent radical resection, and the other 10 received local resection. No lymph node metastases were identified. All cases were positive for CD117. Seventeen patients were classified as high National Institutes of Health (NIH) risk category. The 5-year disease-free survival (DFS) and overall survival were 33 and 46 %, respectively. Fifteen cases had recurrence postoperatively. Both univariate and multivariate analyses demonstrated the NIH risk category (p = 0.028) and hematochezia symptom (p = 0.014) were independent prognostic factors of the DFS of patients. Hematochezia was the most common initial symptom. Over 50 % of patients received radical surgery. More than 80 % of patients were at high NIH risk of recurrence. Hematochezia symptom and high NIH risk category indicated poor prognosis of rectal GISTs.

Long non-coding RNAs (lncRNAs) play critical roles in tumor development and progression. This study was undertaken to examine the expression and biological functions of a novel lncRNA SBDSP1 in colorectal cancer (CRC). Quantitative real-time PCR analysis was used to measure the expression of SBDSP1 in CRC tissues and cell lines. Knockdown of SBDSP1 via short hairpin RNA technology was performed to determine the roles of SBDSP1 in CRC cell growth, colony formation, cell cycle progression, migration, and invasion. The effect of SBDSP1 knockdown on tumorigenesis of CRC cells was investigated in a subcutaneous tumor mouse model. Western blot analysis was done to examine the involvement of signaling pathways in the action of SBDSP1. Notably, SBDSP1 was overexpressed in CRC tissues and cells relative to corresponding normal controls. Moreover, SBDSP1 expression was significantly greater in CRCs with nodal metastasis than in primary tumors (P=0.0259). Downregulation of SBDSP1 significantly inhibited cell proliferation, colony formation, migration, and invasion in SW480 and HCT116 cells, which was accompanied by suppression of Akt, ERK1/2, and STAT3 phosphorylation. SBDSP1-depleted cells showed a G0/G1 cell cycle arrest and deregulation of p21 and cyclin D1. In vivo studies confirmed that SBDSP1 downregulation retarded the growth of HCT116 xenogaft tumors. Altogether, SBDSP1 plays an essential role in CRC cell growth, invasion, and tumorigenesis, largely through inactivation of multiple signaling pathways. Therefore, targeting SBDSP1 may have therapeutic benefits in the treatment of CRC.

Purpose Yielding pathologic-lymph node ratio (yp-LNR) was considered to be a better staging system than yp-N stage in rectal cancer patients treated with preoperative radiotherapy (pre-RT). We aimed to compare the predictive ability of yielding pathologic log odds of positive lymph nodes (yp-LODDS) with that of yp-LNR for cancer-specific survival (CSS) in stage III rectal cancer patients treated with pre-RT. Methods We analyzed stage III rectal cancer patients treated with pre-RT in the Surveillance, Epidemiology and End Results (SEER) database. Patients were classified into 4 groups, yp-LNR1 to 4, based on the LNR cutoff points 0.25, 0.50, and 0.75. Subjects were categorized into 5 groups, yp-LODDS1 to yp-LODDS5, based on the LODDS cutoff points −1, 0, 1, and 2. Univariate and multivariate Cox proportional hazards models were performed to analyze the risk factors for survival outcome. Results A total of 4,612 patients were included from the SEER database. Patients in the yp-LNR4 group could be further divided into yp-LODDS4 and yp-LODDS5 groups with 5-year CSS of 47.6% and 31.5%, respectively (pConclusions The prognostic value of yp-LNR can be confounded by yp-LODDS. In stage III rectal cancer patients treated with pre-RT, yp-LODDS has superior discrimination power over yp-LNR and can more accurately evaluate CSS.

Background Colorectal cancer (CRC) is 3rd most commonly diagnosed cancer in males and the second in females. PD-1/PD-L1 axis, as an immune checkpoint, is up-regulated in many tumors and their microenvironment. However, the prognostic value of PD-1/PD-L1 in CRC remains unclear. Methods The Cancer Genome Atlas (TCGA) database (N = 356) and Fudan University Shanghai Cancer Center (FUSCC) cohort of patients (N = 276) were adopted to analyze the prognostic value of PD-L1 in colorectal tumor cells (TCs) and of PD-1 in tumor infiltrating cells (TILs) for CRC. Subgroup analyses were conducted in FUSCC cohort according to patients’ status of mismatch repair. Results In TCGA cohort, the cut-off values of PD-1 and PD-L1 expression were determined by X-tile program, which were 4.40 and 2.92, respectively. Kaplan-Meier analysis indicated that higher PD-1 and PD-L1 expressions correlated with better OS (P = 0.032 and P = 0.002, respectively). In FUSCC cohort, expressions of PD-1 on TILs and PD-L1 on TCs were analyzed separately by immunohistochemistry (IHC) staining based on a TMA sample (N = 276) and revealed that both TILs-PD-1 and TCs-PD-L1 were associated with OS (P = 0.006 and P = 0.002, respectively) and DFS (P = 0.025 and P = 0.004, respectively) of CRC patients. Multivariate Cox regression analysis indicated TILs-PD-1 was an independent prognostic factor both for OS and DFS of CRC patients (P 0.05). Conclusions Higher expressions of PD-1 and PD-L1 correlates with better prognosis of CRC patients. TILs-PD-1 is an independent prognostic factor for OS and DFS of CRC patients, especially for MMR-proficient subgroup. Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0539-x) contains supplementary material, which is available to authorized users.

Multi-disciplinary treatment (MDT) is an effective pattern to implement the standardized and individualized treatment for cancer. Under the pattern of MDT which integrates the surgery, chemotherapy, radiotherapy, interventional therapy, targeted therapy and immune therapy, there has been a landmark progress in the diagnosis and treatment of colorectal cancer. Curative resection followed by adjuvant chemotherapy has been established as a standard treatment for stage III( colon cancer, but it is still controversial about whether patients with stage II( colon cancer should receive adjuvant chemotherapy and which regimen is preferred. Decision making regarding the use of adjuvant therapy for stage II( patients should not only depend upon the clinicopathological features but also individualized discussion between patients and physicians about the biological behavior of the disease, evidence supporting the efficacy, and possible toxicity. Radical operation following neoadjuvant chemoradiotherapy is currently the standard modality for locally advanced rectal cancer, but the strategy of 'Wait and See' is proposed by some researchers for those achieving complete response after chemoradiotherapy, although there is no sufficient supportive data yet. Patients with metastatic colorectal cancer should undergo an upfront evaluation and discussion by a multidisciplinary team before the initial treatment. Achieving a negative surgical margin with adequate remanent liver reserve is the criteria for determining the resectability of liver metastasis. Both adjuvant and neoadjuvant chemotherapy are two alternatives for initially resectable liver metastasis. Concomitant with the progress of medicine, the MDT is moving toward a precise treatment system oriented by genes and being able to predict the prognosis, efficacy and side effects exactly.

We hypothesized that in patients with colon cancer showing heavy intestinal wall invasion without lymph node metastasis (stage II), small tumor size would correlate with more aggressive tumor behaviors and thus poorer cancer-specific survival (CSS).We analyzed Caucasian patients with stage II colon cancer based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival was analyzed using the Kaplan-Meier method, and the log-rank test was used to identify differences. Risk factors were analyzed using the Cox proportional hazard model.A total of 7719 stage II colon cancer patients from the SEER database were included in the analysis. The cutoff value (5.0 cm) was determined using the X-tile program. The Kaplan-Meier analysis showed that tumors5.0 cm had a poorer CSS compared to tumors ≥5.0 cm (p = 0.006). Multivariate analysis indicated that tumor size is an independent prognostic factor for stage II patients, and compared to tumors5.0 cm, tumors ≥5.0 cm were more likely to result in a better CSS (HR 0.775, 95% CI 0.691-0.870, p 0.001). Tumor size was also analyzed as a continuous variable in the multivariate analysis, and the CSS decreased with decreasing tumor size (HR 0.958, 95% CI 0.936-0.981, p 0.001). Subgroup analyses suggested that tumor size is also an independent prognostic factor for stage IIA (p = 0.002) and IIC (p 0.001) patients.Smaller tumor size is associated with poor CSS in the stage II colon cancer and particularly in the stage IIA and IIC subgroups.

We aim to compare the prognosis between patients with stage IIA and stage IIIA colon cancer.We analysed patients with stage IIA or stage IIIA colon cancer based on data from the US Surveillance, Epidemiology, and End Results (SEER) database. Survival data were generated as Kaplan-Meier curves and were compared by log-rank tests. A multivariate Cox proportional hazards model was used to analyze the risk factors.In total, 43 379 patients (38 784 stage IIA and 4595 stage IIIA) were included from the SEER database. A Kaplan-Meier analysis showed no significant difference between patients with stage IIA and IIIA colon cancer (P = 0.547). In the subgroup of patients with number of lymph nodes harvested (LNH) ≥12, a multivariate analysis showed that compared with stage IIA patients, stage IIIA patients were more likely to have a poorer cancer-specific survival (CSS) (hazard ratio (HR) 1.252, 95% confidence interval (CI) 1.095-1.431, P = 0.001). In the subgroup of patients with LNH12, a multivariate analysis showed that compared with stage IIA patients, stage IIIA patients were more likely to have a better CSS (HR 0.820, 95% CI 0.731-0.919, P = 0.001).Patients with stage IIA colon cancer had a CSS comparable with that of patients with stage IIIA disease. When adequate lymph nodes were retrieved (LNH ≥12), stage IIA patients had a greater CSS than stage IIIA patients. On the contrary, when inadequate lymph nodes were retrieved (LNH12), stage IIA patients had a poorer CSS than stage IIIA patients.

MicroRNAs (miRNAs) are important regulators involved in various cancers, including colorectal cancer (CRC). The functions and mechanisms of the miRNAs involved in CRC progress and metastasis are largely unknown. In this study, miRNA microarray analysis was performed to screen crucial miRNAs involved in CRC progress and miR-139-5p was chosen for further study. The functional roles of miR-139-5p in colon cancer were demonstrated by CCK-8 proliferation assay, cell invasion and migration, cell apoptosis and in a KO mouse study. miR-139-5p expression was significantly decreased in cancer tissues compared to normal tissues. The miR-139-5p expression level was associated with tumour stage (P in vitro. The patient samples and KO mice model showed that BCL2 expression was inversely correlated with the expression of miR-139-5p. In conclusion, we found that miR-139-5p targeted the BCL2 pathway to reduce tumour metastasis and drug sensitivity in CRC. This axis provided insight into the mechanism underlying miRNA regulation of CRC metastasis and a novel therapeutic target for CRC therapy.

Aim In this study we explored the prognostic impact of synchronous bilateral prophylactic oophorectomy in female patients with primary colorectal cancer undergoing radical surgery. Method From 1991 to 2000, 267 female patients with stage II or stage III colorectal cancer, who had undergone curative resection, were retrospectively reviewed. In 224 patients, the ovaries were preserved. The other 43 patients underwent synchronous bilateral prophylactic oophorectomy. Univariate and multivariate analyses (Kaplan–Meier and Cox regression, respectively) were used to evaluate the effect of prophylactic oophorectomy and other clinical factors on the prognosis of patients. Results Both univariate and multivariate analyses showed that tumor stage and adjuvant chemotherapy were the only two significant clinical factors that affected the 5-year overall survival of patients (P 0.05). In the subgroup analysis by adjuvant chemotherapy, the 5-year overall survival in patients receiving adjuvant chemotherapy was similar between nonoophorectomy and oophorectomy groups. However, in patients without adjuvant chemotherapy, the oophorectomy group was shown to have a significantly better 5-year overall survival than the nonoophorectomy group (76%vs 51%, P = 0.047). Conclusion Prophylactic oophorectomy may improve the overall survival of female patients with locally advanced colorectal cancer without adjuvant chemotherapy, but its survival benefit vanished in patients receiving adjuvant chemotherapy. The role of prophylactic oophorectomy may be substituted by adjuvant chemotherapy, which makes prophylactic oophorectomy unnecessary during surgery for locally advanced colorectal cancer.

Objectives: To explore the long-term outcome and prognostic factors for early stage rectal cancer patients undergoing standard resection (SR) or local excision (LE). Patients and Methods This study included 350 patients with stage I rectal cancer, in which 283 cases (80.9%) received SR, and 67 cases (19.1%) received LE. Survival analyses were performed to compare outcomes of different surgeries. Results The 5-year local recurrence (LR) rate was 14.1% in LE group versus 3.3% in SR group (P = .0004), and the 10-year overall survival (OS) rate was not significantly different between the 2 groups. Multivariate analysis suggested that LE was an independent risk factor for 5-year LR rate and 10-year OS rate. Tumor grade was found related to 5-year LR, and T stage was found related to 10-year OS. Tumor size of 2.5 cm is found as a possible cut-off for predicting 5-year LR rate in LE group, with a sensitivity of 77.8% and a specificity of 75.9%. In patients with LE, the 5-year LR rate for tumors ≥ 2.5 cm was 40%, compared with 4.3% for tumors Conclusion Local excision in early-stage rectal cancer may result in high local recurrence rate. The procedure is only recommended in highly selective groups of patients. A tumor size of 2.5 cm is a useful criterion for choosing LE rather than SR.

Aim We studied the outcome and prognostic factors for T1 rectal cancer patients undergoing standard resection or transanal excision. Method One hundred and twenty-four patients with T1 rectal cancer were included in the study, of whom 66 (53.2%) underwent standard resection and 58 (46.8%) underwent transanal excision. Survival analysis was performed to compare the outcome. Results The 5-year local recurrence rate was 11.0% in the transanal excision group versus 1.6% in the standard resection group (P = 0.031) but the 5-year disease-free survival and overall survival rates were not significantly different between the two groups. Multivariate analysis suggested that a high tumour grade and perineural or lymphovascular invasion were independent risk factors for local recurrence and recurrence-free survival. For high-risk patients (with at least one of the above risk factors), the 5-year local recurrence and 10-year recurrence-free survival rates were 21.2% and 74.5%, versus 1.2% and 92.0% in low-risk patients (P = 0.00003 and P = 0.003). In patients undergoing transanal excision, none in the low-risk group had local recurrence during follow up, while 40% (6 of 15) of patients in the high-risk group developed local recurrence within 5 years after surgery. The 5-year local recurrence rate was 45.0%. Conclusion Transanal excision in T1 rectal cancer may result in a high rate of local failure for patients with a high-grade tumour, or perineural or lymphovascular invasion. Local excision should be avoided as a curative treatment in high-risk patients.

Chromosomal instability (CIN) and microsatellite instability (MSI) are two major causes of colorectal cancers. Recently, a percentage of colorectal cancers were found to be neither CIN nor MSI. This study was performed to explore whether microsatellite- and chromosomal-stable (MACS) colorectal cancers comprise a substantially distinct subtype.Sixty-nine sporadic colorectal cancers were classified into three subsets according to ploidy and microsatellite instability status: CIN+, MSI+, and MACS. Clinicopathologic, genetic, and epigenetic differences among these three groups were investigated by immunohistochemical analysis of p53, APC, hMLH1, and BAX and methylation study of pl4ARF, hMLH1, p161NK4a MGMT, and MINT1 with methylation-specific polymerase chain reaction.The 69 cases included 49 CIN+, 7 MSI+, and 13 MACS. MACS were found to differ from CIN+ and MSI+ in three aspects. The clinicopathologic features of MACS were similar to MSI+ but distinguished from CIN+. Comparatively, MACS preferred proximal location and poor differentiation (p0.05). An immunohistochemical study demonstrated that MACS had a lower rate of loss of hMLH1 or BAX protein than MSI+ and less loss of APC protein than CIN+. In an epigenetic aspect, both MACS and MSI+ had a high rate of CpG island methylator phenotype (46.2 and 42.9%). However, they differed in the presence of hMLH1 methylation (7.7 vs 57.1%, p0.05). Otherwise, compared with CIN+, MACS had a more frequent CpG island methylator phenotype and MINT1 methylation (p0.05) and relatively more common p161IK4a methylation with marginal significance (p= 0 .056).MACS sporadic colorectal cancers may compose a unique phenotype with distinct clinicopathologic and molecular characteristics.

Univariate and multivariate Cox proportional hazards analysis of OS and DFS for patients with CRC in MMR-proficient subgroup of the FUSCC cohort. (DOCX 18Â kb)

Univariate and multivariate Cox proportional hazards analysis of OS and DFS for patients with CRC in MMR-deficient subgroup of the FUSCC cohort. (DOCX 17Â kb)

Epigenetic markers based on differential methylation of DNA sequences are used in cancer screening and diagnostics. Detection of abnormal methylation at specific loci by real-time quantitative polymerase chain reaction (RT-qPCR) has been developed to enable high-throughput cancer screening. For tests that combine the results of multiple PCR replicates into a single reportable result, both individual PCR cutoff and weighting of the individual PCR result are essential to test outcome. In this opportunistic screening study, we tested samples from 1133 patients using the triplicate Epi proColon assay with various algorithms and compared it with the newly developed single replicate SensiColon assay that measures methylation status of the same SEPT9 gene sequence. The Epi proColon test approved by the US FDA (1/3 algorithm) showed the highest sensitivity (82.4%) at a lower specificity (82.0%) compared with the Epi proColon 2.0 CE version with 2/3 algorithm (75.1% sensitivity, 97.1% specificity) or 1/1 algorithm (71.3% sensitivity, 92.7% specificity). No significant difference in performance was found between the Epi proColon 2.0 CE and the SensiColon assays. The choice of algorithm must depend on specific test usage, including screening and early detection. These considerations allow one to choose the optimal algorithm to maximize the test performance. We hope this study can help to optimize the methylation detection in cancer screening and early detection.

Background The study was to investigate whether 18F-fluorodeoxyglucose (18F-FDG) uptake, analyzed by positron emission tomography (PET), can be used preoperatively to predict survival in Chinese patients with colorectal carcinoma. Methods A prospectively maintained colorectal cancer database was retrospectively reviewed between June 2009 and December 2011. All included patients had been newly diagnosed with colorectal cancer (of various stages) and evaluated by 18F-FDG-PET/computed tomography (CT) within the 2 weeks preceding surgery. Univariate and multivariate analyses were used to determine whether the maximal standardized uptake value (SUVmax) and various clinicopathological and immunohistochemical factors were correlated with survival. Receiver operating characteristics (ROC) curve and Kaplan-Meier survival curve analyses were used to explore whether SUVmax could predict survival in these patients. Results A total of 107 patients were enrolled in the study (mean age, 59.26 ± 12.66 years; 66.35 % males), with 77 surviving to the end of follow-up (average 60 months). Univariate analysis indicated that tumor size, TNM stage, nodal metastasis, the ratio of metastasized nodes to retrieved nodes, cyclin D1 immunostaining and SUVmax correlated with survival (P

Lymph node (LN) status after surgery for rectal cancer is affected by preoperative radiotherapy. The purpose of this study was to perform a population-based evaluation of the impact of pathologic LN status after neoadjuvant radiotherapy on survival. A total of 1,650 patients receiving neoadjuvant chemotherapy in Surveillance, Epidemiology and End Results Program (SEER)-registered ypIII stage rectal cancer was analyzed. We identified the optimal cutoff for retrieved LNs as 10 (χ2 = 14.006, P 0.001), which was validated as an independent prognosis factors in a Cox regression model. Further analysis showed that the LN count was only a prognosis factor with the number from 8 to 16(except for 13).After the number 16, the 5-year survival rate decreased gradually. Collectively, our results confirmed that the number of LNs in yp III stage rectal patients was a prognosis factor only with the numbers from 8 to 16(except for 13). Using the total mesorectal excision technique with an adequate pathologic examination, a large number of LNs retrieved (≥17) might indicate worse tumor response grade and poorer survival.

// Lin Zhou 1, * , Xin Liang 2, * , Lingling Zhang 2 , Liyan Yang 2 , Norio Nagao 3 , Hongkun Wu 1 , Chang Liu 1 , Shengchao Lin 2 , Guoxiang Cai 4 , Jianwen Liu 2 1 Department of Laboratory Medicine, Changzhen Hospital, Second Military Medical University, Shanghai 200003, China 2 State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China 3 Department of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, 727-0023 Japan 4 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032,China * Authorship note: Lin Zhou and Xin Liang contributed equally to this work as co-first authors Correspondence to: Lin Zhou, email: lynnzhou36@163.com Guoxiang Cai, email: gxcai@fudan.edu.cn Jianwen Liu, email: liujian@ecust.edu.cn Keywords: miR-27a-3p, apoptosis, BTG2, gastric cancer, cell proliferation Abbreviations: miRNA, microRNA; GC, Gastric cancer; BTG2, B-cell translocation gene2; UTR, untranslated region Received: October 22, 2015 Accepted: June 17, 2016 Published: July 07, 2016 ABSTRACT microRNA-27a (miR-27a) is frequently dysregulated in human carcinoma, including gastric cancer. The B-cell translocation gene 2 (BTG2) has been implicated in gastric carcinogenesis. However, till now, the link between miR-27a and BTG2 in gastric cancer has not been reported. Here, we found that two isoforms of mature miR-27a, miR-27a-5p and miR-27-3p, were both frequently overexpressed in gastric cancer tissues and cell lines, whereas the expression level of miR-27-3p in gastric cancer was significantly higher than that of miR-27a-5p. And overexpression of miR-27a-3p, but not miR-27a-5p, markedly promoted gastric cancer cell proliferation in vitro as well as tumor growth in vivo. Further experiments revealed that BTG2 was a direct and functional target of miR-27a-3p in gastric cancer and miR-27a-3p inhibition obviously up-regulated the expression of BTG2. In turn, overexpression of BTG2 triggered G1/S cell cycle arrest, induced subsequent apoptosis, and inhibited C-myc activation following Ras/MEK/ERK signaling pathway, which involved in the biological effects of miR-27a-3p/BTG2 axis on gastric carcinogenesis and cancer progression. Overall, these results suggested that the miR-27a-3p/BTG2 axis might represent a promising diagnostic biomarker for gastric cancer patients and could be a potential therapeutic target in the management of gastric cancer.

miR-139-5p, which has been reported to be underexpressed in several types of cancer, is associated with tumorigenesis by participating in various biological processes via the modulation of different target genes. In the present study, we analyzed mice deficient in miR-139-5p, aiming to investigate its role in intestinal inflammation and colitis-associated colorectal cancer. We show that miR-139-5p knockout (KO) mice are highly susceptible to colitis and colon cancer, accompanied by elevated proliferation and decreased apoptosis, as well as an increased production of inflammatory cytokines, chemokines and tumorigenic factors. Furthermore, enhanced colon inflammation and colorectal tumor development in miR-139-5p KO mice are a result of the regulatory effects of miR-139-5p on its target genes for Rap1b and nuclear factor-kappa B, thus affecting the activity of the mitogen-activated protein kinase, nuclear factor-kappa B and signal transducer and activator of transcription 3 signaling pathways. These results reveal a critical part for miR-139-5p in maintaining intestinal homeostasis and protecting against colitis and colorectal cancer in vivo, providing new insights into the function of miR-139-5p with respect to linking inflammation to carcinogenesis.

Objective: We investigated mechanisms of colorectal cancer (CRC) chemoresistance to first-line chemotherapy (capecitabine plus oxaliplatin (XELOX)) and identified two putative chemoresistant microRNAs, miR-1914* and -1915, that are downregulated in plasma samples from patients with chemoresistant CRC. Methods: A number of plasma samples from CRC patients were analyzed for the levels of miR-1914* and - 1915. Effects of stable and transient expression of 2 microRNAs in human chemoresistant CRC cell lines were analyzed. Tumor formation and chemoresistance in HCT116/5-Fu/OXA that did or did not express 2 microRNAs were analyzed in mice. Nuclear factor I/X (NFIX) was predicted to target the gene of 2 miRNAs and verified in vivo and in vitro. Results: Plasma levels of miR-1914* and -1915 in chemoresistant CRC patients were different than levels in responders, and associated with clinical response. Overexpression of miR-1914* and -1915 in chemoresistant CRC cells reduced resistance to 5-FU and Oxaliplatin in vitro. The microRNAs suppressed chemoresistance in CRC tumors in mice by affecting cell growth, invasion, apoptosis and tumor suppressor function. miR-1914* and -1915 interacted with the 3’-untranslated region of NFIX and reduced NFIX its level in chemoresistant CRC cells. Overexpression of NFIX did not inhibit chemoresistant CRC cell motility and chemoresistant proteins when miR-1914* and -1915 were transfected. Conclusion: Plasma miR-1914* and -1915 interact with NFIX RNA and reduce its level in chemoresistant CRC cells to first-line chemotherapy. Up-regulation of miR-1914* and -1915 decreased the chemoresistance abilities of chemoresistant CRC cells. The plasma miR-1914* and -1915 may play a role in colorectal cancer therapy and diagnosis.

// Changhua Zhuo 1, 2, * , Qingguo Li 1, * , Yuchen Wu 1 , Yiwei Li 1 , Jia Nie 3 , Dawei Li 1 , Junjie Peng 1 , Peng Lian 1 , Bin Li 3 , Guoxiang Cai 1 , Xinxiang Li 1 , Sanjun Cai 1 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China 2 Department of Surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou 350014, People’s Republic of China 3 Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Sanjun Cai, e-mail: caisanjun@gmail.com Xinxiang Li, e-mail: lxx1149@163.com Keywords: colon cancer, LINE-1, microsatellite instability, epigenetic modification, survival analysis Received: March 06, 2015 Accepted: June 19, 2015 Published: June 29, 2015 ABSTRACT Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients’ colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3–85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45–86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer.

Methylated SEPT9 is a novel circulating tumor DNA marker for colorectal cancer, while the effects of various colorectal cancer clinicopathological factors on its detection performance have not been fully evaluated. This study aims to investigate the significance of the clinicopathological factors on methylated SEPT9 performance in a symptomatic endoscopy cohort, with a specific focus on colorectal cancer.A total of 1160 participants were recruited in this study, including 300 patients with colorectal cancer, 122 patients with adenoma, 103 patients with hyperplastic polyps, 568 normal participants (no evidence of disease), and 67 patients with other gastrointestinal diseases. Peripheral blood samples of these participants were collected from 3 Chinese hospitals, and the methylated SEPT9 level was measured using the Epi proColon 2.0 assay.Cancer stage, size, and invasion depth were positively correlated with the detection sensitivity, while no difference in sensitivity was identified among cancers at various locations. Infiltrative colorectal cancer exhibited higher sensitivity than ulcerative and protrude colorectal cancer, while no difference in sensitivity was observed among assessed histological types. The colorectal cancer differentiation showed a clear correlation with the cancer stage, and moderate and poorly differentiated colorectal cancer exhibited higher sensitivity than well-differentiated colorectal cancer. Furthermore, colorectal cancer with distal metastasis (M1) showed higher sensitivity than those without any metastasis, while colorectal cancer with lymph node metastasis (N1 and N2) did not show statistical significance compared to those without it. Finally, local vessel or nerve invasion did not affect the sensitivity.Factors that reflect the colorectal cancer intrinsic properties, including cancer stage, size, invasion depth, classification, differentiation, and metastasis, exhibited significant effect on the mSEPT9 detection performance.

Background and Objective Inhibitors of apoptosis proteins (IAPs) have been well investigated in human cancers, where they are frequently overexpressed and associated with poor prognosis. Here we explored the role of baculoviral IAP repeat containing 6 (BIRC6), a member of IAPs, in human colorectal cancer (CRC). Methods We used Western blotting and immunohistochemistry to examine BIRC6 expression in 7 CRC cell lines and 126 CRC clinical samples. We determined the biological significance of BIRC6 in CRC cell lines by a lentivirus-mediated silencing method. Results We reported that BIRC6 was overexpressed in CRC cell lines and clinical CRC tissues. BIRC6 overexpression was correlated with tumor size and invasion depth of CRC. BIRC6 overexpression is associated with worse overall survival (OS) (P = 0.001) and shorter disease-free survival (DFS) (P = 0.010). BIRC6 knockdown inhibited cell proliferation, arrested cell cycle at S phase, downregulated cyclin A2, B1, D1 and E1 levels, and sensitized CRC cells to chemotherapy in vitro and in vivo. Conclusions Taken together, these data suggests that BIRC6 overexpression is a predictor of poor prognosis in colorectal cancer and BIRC6 could be a potential target of CRC therapy.

We sought to determine the prognostic role of tumor size on cause-specific survival (CSS) of patients with stage IIA colon cancer. Surveillance, Epidemiology and End Results (SEER) database was utilized to identify patients with stage IIA colorectal cancer (examined lymph nodes ≥12) diagnosed from 1988 to 2003. The prognostic effect of tumor size on CSS was evaluated by univariate and multivariate analyses. A total of 8775 patients were enrolled in the analysis. The median follow-up time was 109 months. As determined by minimal P value method, tumor sizes of 2.5 and 6.0 cm were used as optimal cutoff value to divide the cohort. The 8-year CSS of colon cancer with tumor sizes ≤2.5, 2.6–6.0, and >6.0 cm was 81.6, 86.2, and 86.7 % respectively (P = 0.003). In the multivariate analysis of colon cancer, using ≤2.5-cm tumors as reference, decreased hazard ratio (HR) of CSS was observed in 2.6–6.0 cm (HR, 0.736; 95 % confidence interval (CI), 0.599–0.905; P = 0.004) and >6.0 cm (HR, 0.770; 95 % CI, 0.619–0.958; P = 0.019) tumors. In stage IIA colon cancer, small tumor size represented a subset with decreased CSS. Further studies are merited to validate the unfavorable prognostic role of small tumor size in stage IIA colon cancer.

Long noncoding RNAs (lncRNAs) have recently emerged as a major class of regulatory molecules, which were involved in a broad range of biological processes and complex diseases. Research on lncRNAs may shed light on tumorigenesis and progression of colorectal cancer (CRC). The purpose of the present study was to identify lncRNAs correlated with CRC and then investigate their potential functions. We selected 92 patients for this prospective study and then collected the tumor samples and clinical records. First, the global lncRNA expression profiles in tumor and adjacent normal tissues of patients with non-metastatic CRC and patients with metastatic CRC were measured by microarray assay. Then, a noteworthy lncRNAs RP11-462C24.1 whose function was previously unknown was explored in detail on the aspect of the association of its expression level and clinicopathological features of CRC and patients’ survival. We found that RP11-462C24.1 expression level was lower in cancer tissues compared with adjacent normal samples (P

Background Colon cancer with lymph node metastases has been considered as advanced stage and to have poor survival. We postulated that patients with solitary lymph node metastasis are a distinct subset with better colon cancer-specific survival than those with multiple lymph node metastases. Methods In this retrospective study, we searched Surveillance, Epidemiology, and End-Results (SEER) population-based data and identified 86,674 patients who had been diagnosed with colon cancer without distant metastases and with less than three metastatic nodes between 1991 and 2005. We divided lymph node status into three subgroups: pN0, pN1a, and pN1b and obtained 5-year colon cancer-specific survival for each pT stage. We used Kaplan–Meier and multivariate Cox regression models to assess correlations between risk factors and survival outcomes. Results Analysis of SEER data confirmed that patients with solitary lymph node metastases had better 5-year cancer-specific survival than pN1b according to both univariate and multivariate analysis. This finding was confirmed by further analyses in five pT subgroups. Cancer-specific survival of patients with pT1-2N1a was comparable to that of those with pIIA but higher than those with pIIB. In addition, survival of patients with pT3-4aN1a was better than those with pIIC. Conclusion Colon cancer patients with solitary lymph node metastasis are a distinct subset with a favorable prognosis; full consideration should be given to this in clinical practice.

Gene expression profiling of whole blood is showing great promise for the discovery of novel biomarkers for colorectal cancer (CRC) detection. Given the relatively low incidence rate of CRC in the general population, most blood samples collected prior to a colonoscopy were confirmed to be noncancerous afterward. Previous studies have relied on blood samples collected after a colonoscopy to reach the sufficient number of CRC cases. The present study aimed to determine the colonoscopy-induced variability in the blood transcriptome and its potential impact on biomarker discovery. Whole blood gene expression profiling was conducted using Affymetrix HG-U133Plus2 arrays. We analyzed 20 paired blood samples collected from healthy controls before and after colonoscopy, and 20 blood samples collected from CRC patients after colonoscopy. Utilizing hierarchical clustering analysis, samples collected before and after colonoscopy from the same subjects were closely clustered together, suggesting that the blood gene expression profiles primarily reflect the heterogeneity within each individual. A total of 914 genes were differentially expressed between controls and CRC patients, while gene expression did not differ between samples collected before and after colonoscopy. Using real-time PCR technology, we further validated six genes from published biomarkers in this study. Our results confirmed that the biomarkers identified in previous studies were not likely to be biased due to the colonoscopy effect. Our results showed that the colonoscopy-induced variations were minute compared to individuals’ heterogeneity and disease-induced variations. These findings may serve as a basis for future development of blood-based transcriptomic biomarkers for the diagnosis and treatment of CRC.

Purpose The aim of the study is to identify the risk factors of synchronous ILN metastasis for lower rectal cancer involving the anal canal. Methods Patients with lower rectal cancer who underwent radical resection at the Fudan University Shanghai Cancer Center were retrospectively analyzed. The synchronous ILN metastasis was defined as the metastasis occurring within 6 months after the diagnosis of rectal cancer. Patients’ gender, age, tumor diameter, dentate line invasion, differentiation level, histological type, depth of invasion, perirectal LN metastasis, lymphovascular invasion or perineural invasion were analyzed in the study. The correlation between synchronous ILN involvement and clinicopathological features were analyzed with Chi-square test/fisher’s exact test. Variables with p

Chemoradiotherapy has been commonly used as neoadjuvant therapy for rectal cancer to allow for less aggressive surgical approaches and to improve quality of life. In cancer, it has been reported that CXCL10 has an anti-tumor function. However, the association between CXCL10 and chemoradiosensitivity has not been fully investigated. We performed this study to investigate the relationship between CXCL10 expression and chemoradiosensitivity in rectal cancer patients. Ninety-five patients with rectal cancer who received neoadjuvant chemoradiotherapy (NCRT) were included. Clinical parameters were compared with the outcome of NCRT and CXCL10 messenger RNA (mRNA) expression between the pathological complete response (pCR) group and non-pathological complete response (npCR) group. CXCL10 mRNA and protein expressions between groups were analyzed using the Student’s t test and chi-square test. The mean mRNA level of CXCL10 in the pCR group was significantly higher than that in the npCR group (p = 0.010). In the pCR group, 73.7 % of the patients had high CXCL10 mRNA expression, and 61.4 % of the patients in the npCR group had low CXCL10 mRNA expression. Subjects with high CXCL10 mRNA expression demonstrated a higher sensitivity to NCRT (p = 0.011). The receiver operating characteristic curve showed that the diagnostic performance of CXCL10 mRNA expression had an area under the curve of 0.720 (95 % confidence interval, 0.573–0.867). There were no differences between the pCR and npCR groups in CXCL10 protein expression (p > 0.05). High CXCL10 mRNA expression is associated with a better tumor response to NCRT in rectal cancer patients and may predict the outcome of NCRT in this malignancy.

Objective To compare the long-term survival of colorectal cancer (CRC) in young patients with elderly ones. Methods Using Surveillance, Epidemiology, and End Results (SEER) population-based data, we identified 69,835 patients with non-metastatic colorectal cancer diagnosed between January 1, 1988 and December 31, 2003 treated with surgery. Patients were divided into young (40 years and under) and elderly groups (over 40 years of age). Five-year cancer specific survival data were obtained. Kaplan-Meier methods were adopted and multivariable Cox regression models were built for the analysis of long-term survival outcomes and risk factors. Results Young patients showed significantly higher pathological grading (p