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Background For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial. Consensus molecular subtype (CMS) has been validated to be a prognostic tool for CRCs. In this study, CMS status was investigated as a prognostic biomarker for the efficacy of adjuvant chemotherapy for stage II colorectal cancer. Materials and Methods The tissue microarray was retrospectively constructed of 165 nonconsecutive, primary, and sporadic stage II CRCs. CMS status was determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, combining with microsatellite instability testing. The prognostic for adjuvant chemotherapy efficacy of CMS status was calculated by Kaplan‐Meier curves and Cox regression analysis. Subgroup analyses were conducted according to tumor location. Results Kaplan‐Meier curves indicated that CMS was associated with overall survival (OS) and disease‐free survival for stage II CRCs. Cox regression analysis showed that CMS was an independent risk factor for OS. Among high‐risk clinicopathological factors, patients with CMS2/3 (hazard ratio [HR]: 0.445, 95% confidence interval [CI]: 0.227–0.875), left‐sided tumors (HR: 0.488, 95% CI: 0.247–0.968), or fewer than 12 lymph nodes examined (HR: 0.307, 95% CI: 0.097–0.974) had survival benefit from adjuvant chemotherapy. Subgroup analysis showed that adjuvant chemotherapy only improved OS for patients with left‐sided tumors of CMS2/3 subtype. Regardless of CMS, right‐sided tumors had no benefit from adjuvant chemotherapy. Conclusion CMS is a better prognostic factor for adjuvant chemotherapy for stage II CRCs. Together with tumor location, CMS classification will aid in personalized treatment for stage II CRCs. Implications for Practice For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial, in that its minimal benefit (no more than 5% on average) is considered not worth the toxic effects of the drugs. There are still no effective prognostic and predictive biomarkers. This study showed that consensus molecular subtype (CMS) status is a predictive marker for adjuvant chemotherapy efficacy. Patients with left‐sided tumors of CMS2/3 subtype have survival benefit by receiving adjuvant chemotherapy, which will aid in personalized treatment for stage II CRCs. Moreover, this test of CMS based on immunohistochemistry is cheap, not time consuming, and easily conducted in the laboratories of most hospitals., Currently, no clinical evidence exists for the ability of consensus molecular subtype status to predict the efficacy of adjuvant chemotherapy for stage II colorectal cancer. This article reports results of a study that adopted an immunohistochemical‐based classifier to validate the feasibility of this approach, assessing the prognostic and predictive accuracy of consensus molecular subtype status as a biomarker for adjuvant chemotherapy compared with traditional clinicopathological high‐risk factors.

Tumor metastasis accounts for the majority of cancer-related deaths; it is therefore important to develop preclinical models that faithfully recapitulate disease progression. Here, we generated paired organoids derived from primary tumors and matched liver metastases in the same colorectal cancer (CRC) patients. Despite the fact that paired organoids exhibit comparable gene expression and cell morphology, organoids from metastatic lesions demonstrate more aggressive phenotypes, tumorigenesis, and metastatic capacity than those from primary lesions. Transcriptional analyses of the paired organoids reveal signature genes and pathways altered during the progression of CRC, including SOX2. Further study shows that inducible knockdown of SOX2 attenuated invasion, proliferation, and liver metastasis outgrowth. Taken together, we use patient-derived paired primary and metastatic cancer organoids to model CRC metastasis and illustrate that SOX2 is associated with CRC progression and may serve as a potential prognostic biomarker and therapeutic target of CRC.

Background Survival outcomes are significantly different in stage II colorectal cancer (CRC) patients with diverse clinicopathological features. The objective of this study is to establish a credible prognostic nomogram incorporating easily obtained parameters for stage II CRC patients. Methods A total of 1708 stage II CRC patients seen at Fudan University Shanghai Cancer Center (FUSCC) from 2008 to 2013 were retrospectively analyzed in this study. Cases were randomly separated into a training set (n = 1084) and a validation set (n = 624). Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors that were subsequently incorporated into a nomogram. The performance of the nomogram was evaluated by the predicted concordance index (C-index) and ROC curve to calculate the area under the curve (AUC). The clinical utility of the nomogram was evaluated using decision curve analysis (DCA). Results In univariate and multivariate analyses, eight parameters were correlated with disease-free survival (DFS), which were subsequently selected to generate a prognostic nomogram based on DFS. For DFS predictions, the C-index values of the nomogram were 0.842 (95% confidence interval (CI) 0.710–0.980), and 0.701 (95% CI 0.610–0.770) for the training and validation sets, respectively. The AUC values of the ROC curves for the nomogram to predicted 1, 3 and 5-year survival were 0.869, 0.858, and 0.777 (training group) and 0.673, 0.714, and 0.706 (validation group), respectively. The recurrence probability calibration curve showed good consistency between actual observations and nomogram-based predictions. DCA showed better clinical application value for the nomogram than the TNM staging system. Conclusion A novel nomogram was established and validated in a large population, and the nomogram is a simple-to-use tool for physicians to facilitate postoperative personalized prognostic evaluation and determine therapeutic strategies for stage II CRC patients.

Bone metastasis (BM) can obviously affect the quality of life of patients in colorectal cancer (CRC), and the whole management of patients with BM would be attractive in current clinical practice. A total of 52,859 patients during 2010–2015 were collected from Surveillance, Epidemiology, and End Results (SEER) database. After propensity score matching (PSM), cancer-specific survival (CCS) and overall survival (OS) with BM were adopted to assess survival probability difference. Logistic regression was used to identify risk factors for BM; COX proportion hazard regression was applied to explore prognosticators for OS in patients with BM. Subsequently, nomograms were constructed and receiver operating curves (ROCs) were used to confirm the validation of nomogram. Three hundred and forty-two (0.65%) patients were diagnosed with synchronous BM. After PSM, 16 variables were balanced. Tumor site, histology, grade, T stage, N stage, CEA, radiochemotherapy, surgery, and liver/lung/brain metastases were associated with BM, and histology, grade, T stage, N stage, CEA, chemotherapy, surgery, and liver/lung metastases were prognosticators for BM survival. Nomograms were applied and the ROC curve proved the predictive effects. CRC patients with BM have worse real-world survival. Nomogram can predict incidence of BM in CRC patients and survival among patients with BM.

Background This study aims to develop functional nomograms to predict specific distant metastatic sites and overall survival (OS) of colorectal cancer (CRC) patients. Methods CRC case data were retrospectively recruited from a large population‐based public dataset. Nomograms were developed to predict the probabilities of specific distant metastatic sites and OS of CRC patients. The performance of nomogram was evaluated with the concordance index (C‐index), calibration curves, area under the curve (AUC), and decision curve analysis (DCA). Results A total of 142 343 cases were included in the current study. On the basis of univariate and multivariate analyses, clinicopathological features were correlated with specific distant metastatic sites and survival outcomes and were used to establish nomograms. The nomograms showed excellent accuracy in predicting specific distant metastatic sites. The C‐indexes for the prediction of liver, lung, bone, and brain metastases were 0.82 (95% confidence interval (CI), 0.81‐0.83), 0.80 (95% CI, 0.78‐0.81), 0.83 (95% CI, 0.79‐0.86), and 0.73 (95% CI, 0.72‐0.84), respectively. Then, a prognostic nomogram integrating clinicopathological features and specific distant metastatic sites was established to predict 1‐, 3‐, and 5‐year OS of CRC, with AUCs of 0.764 (95% CI, 0.741‐0.783), 0.762 (95% CI, 0.745‐0.781), and 0.745 (95% CI, 0.730‐0.761), respectively. DCA showed that the prognostic nomogram had a better clinical application value than current TNM staging system. Conclusions Based on clinicopathological features, original nomograms were constructed for clinicians to predict specific distant metastatic sites and OS of CRC patients. These models could help to support the postoperative personalized assessment.

Background Many patients surviving from colorectal cancer die of causes irrelevant to cancer. This study was designed to describe the leading causes of death among older patients diagnosed with colorectal cancer and assess factors that are related to colorectal cancer mortality versus mortality from other causes. Methods Patients over 65-year-old diagnosed with colorectal cancer between 2000 and 2014 were extracted from Surveillance, Epidemiology, and End Results (SEER) linked database. Results A total of 136,872 patients with colorectal cancer met the inclusion criteria. The median follow-up time was approximately 3 years. Forty-five point seven percent of them were alive at the end of follow-up, and colorectal cancer still accounted for the most cases of deaths. However, patients with tumor of Grade I or TNM stage I-II were more likely to die from other causes. The fully-adjusted relative hazards ratio (HR) shows age, gender, tumor site, chemotherapy, tumor characteristics of grade and TNM stage affected both types of mortality. Race only affected mortality of other causes. Cardiovascular disease (CVD) was a noticeable cause of death among patients with stage I colorectal cancer. With longer follow-up, deaths due to colorectal cancer decreased while deaths of CVD, pulmonary diseases and other cause of death increased. Conclusions Colorectal cancer still accounts for most deaths in elderly patients. However, comorbidities including CVD/COPD were associated with the deaths of colorectal cancer patients over 65. As survival time increases, comorbidities should be considered for cancer treatment. Management of CVD/COPD among elderly patients can help improve overall survival (OS) in colorectal cancer.

Accurate identification of patients with poor prognosis after radical surgery is essential for clinical management of colon cancer. Thus, we aimed to develop death and relapse specific radiomics signatures to individually estimate overall survival (OS) and relapse free survival (RFS) of colon cancer patients. In this study, 701 stage I‐III colon cancer patients were identified from Fudan University Shanghai Cancer Center. A total of 647 three‐dimensional features were extracted from computed tomography images. LASSO Cox was used to identify the significantly death‐ and relapse‐associated features and to build death and relapse specific radiomics signatures, respectively. A total of 13 death‐specific and 26 relapse‐specific features were identified from 647 screened radiomics features. The developed signatures can divide patients into two groups with significantly different death (Hazard Ratio (HR): 3.053; 95% CI, 1.78‐5.23; P

Objective This study was to evaluate the safety and effectiveness of carbon nanoparticles suspension in tracking lymph node metastases of colorectal cancer. Methods Eligible patients diagnosed with stages I–III colorectal cancer in Fudan University Shanghai Cancer Center between 1 May 2017 and 31 May 2018 fulfilling the inclusion criteria were included in this prospective randomized controlled study. All the patients were randomly allocated to two groups: the nanocarbon group and the control group. Patients’ clinicopathological characteristics were compared between the nanocarbon group and the control group. For continuous variables, data were presented as mean (±SD) and differences between the two groups were compared by the Mann–Whitney U test; for categorical variables, data was presented as frequency (%) and the Pearson’s chi-squared test was used to compare the differences between two groups. Results All the patients’ characteristics between two groups did not achieve statistical significance (P > 0.05). Patients in nanocarbon group were more likely to be associated with more lymph nodes retrieved totally compared with control group (19.84 ± 6.428 vs. 17.41 ± 7.229, P Conclusions Our study confirmed the safety of using carbon nanoparticles suspension as a tracer in colorectal cancer. More importantly, nanocarbon could significantly increase the detected number of lymph nodes in colorectal cancer, which can help improve the accuracy of lymph node staging and even improve patients’ survival.

With emphasis of surgical management, the lymph node (LN) status has been advocated to predict prognosis in colon cancer with distant metastatic. Therefore, we tend to compare the prognostic performance of American Joint Committee on Cancer (AJCC) N-staging relative to lymph node ratio (LNR), log odds of metastatic lymph nodes (LODDS), and N-score in stage IV colon cancer. About 20,961 patients who underwent primary surgical resection for stage IV colon cancer were extracted from Surveillance, Epidemiology, and End Results (SEER) Program database. Harrell’s C statistic (C-index) and Akaike’s Information Criterion (AIC) were used to distinguish the prognostic performance of the different LN-staging schemes. Of the 20,961 patients, 17,043 (81.3%) had been with lymph node metastasis, and the median number of examined lymph nodes (ELNs) was 15. When assessed as continuous values, the LODDS shown as the best system with greatest discriminatory power (C-index, 0.6241; AIC, 29114.29) generally and each subgroups divided by ELNs. When modeled as categorical cutoff variables for further clinical usage, the 8th AJCC N-stage outperformed the other three schemes with either ELNs less than 12 (C-index, 0.5770; AIC, 8992.638), between 12 and 25 (C-index, 0.6084; AIC, 13905.72), or more than 25(C-index, 0.6192; AIC, 3138.018) with increasing C-index and less AIC value. When assessed as categorical variables, N-stage performed superiorly regardless of ELNs. When assessed as a continuous variable, LODDS exhibited good discriminative ability and goodness of fit in predicting survival for colon cancer patients regardless of ELNs.

The aim of this study is to evaluate the epidemiology of and prognostic factors for appendiceal carcinomas (ACs). All cases of ACs registered in the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2014 were retrospectively identified in this study. Age-adjusted incidence and survival rates were calculated. We analyzed 7170 patients with ACs. We observed a significant increase in the reported annual age-adjusted incidence of ACs from 1973 (0.18/100,000) to 2014 (1.11/100,000). The elevation of the incidence was noted in all the histological types, stages, and grades. The most common histological type varied by race, with the appendiceal mucinous adenocarcinoma (AMA) being the most common in white, Asian/Pacific Islander, and American Indian/Alaskan Native patients, and the appendiceal adenocarcinoma (AA) being the most common in African American patients. In multivariate analysis of patients with all ACs, gender (P

Lymph node metastasis (LNM) is closely related to the postoperative recurrence of colorectal cancer (CRC), and greatly affects patient survival. Conducting Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA), we found that the epithelial-mesenchymal transition (EMT) signaling pathway is the signaling pathway most relevant to the process of LNM. An EMT-related gene signature was identified from a discovery dataset obtained 489 patients using LIMMA and LASSO Cox methods. Six external independent dataset analyses including a total of 1,045 CRC patients and stratification analysis showed that EMT-related gene signature could sort out those high- and low-risk CRC patients accurately. Functional analysis and loss-of-function exploration in vitro and in vivo indicated that the EMT-related-signature-associated coding genes might play functional roles in the sophisticated regulation of CRC proliferation and metastasis. Prognostic nomograms integrating the EMT-related gene signature and clinicopathological risk factors were constructed for use as numerical prediction tools to assess clinical prognosis and clinical decision-makings. The comprehensive transcriptomic analysis in this article highlights the prognostic value of an EMT-related gene signature for postoperative disease recurrence in CRC patients and reveals a potential prognostic and therapeutic biomarker for CRC.

BackgroundFecal immunochemical test (FIT), DNA mutation, DNA methylation, and microbial dysbiosis all showed promising in colorectal cancer (CRC) non-invasive detection. We assessed CRC detection with an assay combining all these strategies and investigated the effect of clinical features on the performance of this comprehensive test.MethodsWe performed a multidimensional analysis study using stool samples collected from 108 patients with CRC, 18 patients with colorectal adenoma, and 36 individuals with no evidence of colorectal disease. The multidimensional analysis of stool samples including FIT, stool DNA (sDNA) tests for three methylated genes (Septin9, NDRG4, BMP3) and three mutated genes (KRAS, BRAF, PI3KCA) using next generation sequencing as well as detection of stool bacteria level of Fusobacterium nucleatum and Parvimonas micra using qPCR method. We used a linear support vector classification model to analyze the data.ResultsThe sensitivity of FIT alone was 69.4% for CRC and 11.1% for adenoma. Separately, the sensitivity of the detection of intestinal bacteria, DNA mutation, and DNA methylation for CRC was 58.3, 50.0, and 51.9%, respectively. The combination of FIT and sDNA tests had a sensitivity of 81.5% for CRC (AUC: 0.93, better than FIT alone, P = 0.017) and 27.8% for adenoma with 94.4% specificity. Sensitivity of the multidimensional test to detect CRC with stage II (84.6%) and III (91.9%) CRC was relatively higher (88.2%) than that of patients with stage I (60.0%) and stage IV (75.0%) (P = 0.024). The rate of CRC detection increased with tumor size (P = 0.008) and age (P = 0.04). Interestingly, the rate of CRC detection was higher in smoking persons than non-smokers with marginal significance (P = 0.08).ConclusionsThe multidimensional assay of stool samples combining FIT and stool DNA tests further improved the diagnostic sensitivity for CRC. This could provide new approach for improvement of CRC screening and further demonstrations are warranted.

Purpose: To reveal changes in the incidence, treatment, and survival of patients with colorectal lymphoma.Methods: Patients diagnosed with primary colorectal lymphoma (PCL) or lymphoma between 1973 and 2014 were identified in the SEER registry. The incidence was estimated by age and join-point analysis. The incidence of different subtypes and the surgical resection rates were compared over different time periods.Results: The PCL incidence increased from 1.4 per 1 000 000 people in 1973 to 3.5 in 2014, with an annual percentage change (APC) of 1.98% (95% confidence interval [CI]: 1.29–2.68%, P < 0.001) from 1985 to 2014. No statistically significant change was found between 1973 and 1984. For people younger than 60 years, there was a slight increase in PCL incidence, from 0.6 to 1.4%, from 1973 to 2014. For people age 60 or older, there was a statistically significant increase in PCL incidence from 5.4 to 14.1% over the same time period. The 5-year cause-specific survival (CSS) for PCL improved markedly from 41.6% in the period 1973–1976 to 80.2% in the period 2009–2012 (P < 0.001). Conversely, the proportion of patients who received surgical therapy decreased gradually from 83.3–100 to 47.7–52.6% throughout the studied time period.Conclusions: The incidence of PLC has increased in recent decades. The 5-year CSS of PCL increased continuously, while the rate of surgical resection decreased steadily. These changes in survival trends and therapy strategies indicate that PCL can be well-managed with newer therapeutic reagents.

Background Methylation of N6 adenosine (m6A) plays important regulatory roles in diverse biological processes. The purpose of this research was to explore the potential mechanism of m6A modification level on the clinical outcome of stage III colorectal cancer (CRC). Methods Gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) were adopted to reveal the signal pathway which was most likely affected by m6A methylation. The linear models for microarray data (LIMMA) method and the least absolute shrink-age and selection operator (LASSO) Cox regression model were used to identify the signature. The signature can sensitively separate the patients into high and low risk indicating the relapse-free survival (RFS) time based on time-dependent receiver operating characteristic (ROC) analysis. Then, the multi-gene signature was validated in GSE14333 and the Cancer Genome Atlas (TCGA) cohort. The number of the samples in GSE14333 and TCGA cohort are 63 and 150. Finally, two nomograms were set up and validated to predict prognosis of patients with stage III CRC. Results The hematopoietic cell lineage (HCL) signaling pathway was disclosed through GSEA and GSVA. Seven HCL-related genes were determined in the LASSO model to construct signature, with AUC 0.663, 0.708, and 0.703 at 1-, 3-, and 5-year RFS, respectively. Independent datasets analysis and stratification analysis indicated that the HCL-related signature was reliable in distinguishing high- and low-risk stage III CRC patients. Two nomograms incorporating the signature and pathological N stage were set up, which yielded good discrimination and calibration in the predictions of prognosis for stage III CRC patients. Conclusions A novel HCL-related signature was developed as a predictive model for survival rate of stage III CRC patients. Nomograms based on the signature were advantageous to facilitate personalized counseling and treatment in stage III CRC.

Many patients with metastatic colorectal cancer (mCRC) have better prognosis than the prediction at diagnosis. Compared with invariable traditional Kaplan Meier assessment, conditional survival (CS) assessment has become a more accurate and informative assessment method to predict survival time.Patients with mCRC between 2010 and 2015 were extracted from Surveillance, Epidemiology and End Results linked database. CS analysis was applied to depict exact survival for patients who have survived for specific year and standardized difference (d) was used to evaluate the differences between subgroups in CS analysis. Based on variables selected by Lasso analysis, nomograms for each year after diagnosis were fitted to estimate 3-year survival of stage IV CRC, respectively.Of 9732 patients, overall actuarial survival (OS) decreased from 24% at 4-year to 16% at 6-year, while corresponding 3-year CS (CS3) increased from 33% at 1-year to 48% at 3-year. Overall, CS3 was higher than corresponding actuarial survival. All clinicopathological characteristics were associated with actuarial survival (p 0.05). However, in CS3 analysis, survival difference caused by gender, race and tumor size gradually disappeared over time (|d|0.1→ |d|0.1). Furthermore, survival difference caused by histological type, brain metastasis and chemotherapy reversed over time (d 0→d0 or d0→d0). Based on lasso analysis, nomograms for 1st, 2nd and 3rd year after diagnosis were conducted respectively. The AUC of nomogram for 1st year was 0.705, for 2nd year was 0.675, and for 3rd year was 0.648.Patients with mCRC demonstrated a substantial increase in CS over time. Risk factors collected at diagnosis may change gradually. Nomograms constructed by survival time can predict more accurate survival for patients with mCRC. Conditional survival assessments provide important quantitative information about the probability of survival and are therefore of great value to patients and health care professionals.

Background It is critical for determining the optimum therapeutic solutions for T1‐2 colorectal cancer (CRC) to accurately predict lymph node metastasis (LNM) status. The purpose of the present study is to establish and verify a nomogram to predict LNM status in T1‐2 CRCs. Methods A total of 16 600 T1‐2 CRC patients were enrolled and classified into the training, internal validation, and external validation cohorts. The independent predictive parameters were determined by univariate and multivariate analyses to develop a nomogram to predict the probability of LNM status. The calibration curve, the area under the receiver operating characteristic curve (AUROC), and decision curve analysis (DCA) were used to evaluate the performance of the nomogram, and an external verification cohort was to verify the applicability of the nomogram. Results Seven independent predictors of LNM in T1‐2 CRC were identified in the multivariable analysis, including age, tumor site, tumor grade, perineural invasion, preoperative carcinoembryonic antigen, clinical assessment of LNM, and T stage. A nomogram incorporating the seven predictors was constructed. The nomogram yielded good discrimination and calibration, with AUROCs of 0.72 (95% confidence interval [CI]: 0.70‐0.75), 0.70 (95% CI: 0.67‐0.74), and 0.74 (95% CI: 0.71‐0.79) in the training, internal validation, and external validation cohorts, respectively. DCA showed that the predictive scoring system had high clinical application value. Conclusions We proposed a novel predictive model for LNM in T1‐2 CRC patients to assist physicians in making treatment decisions. The nomogram is advantageous for tailoring therapy in T1‐2 CRC patients.

BACKGROUND: With recommendation of surgical management in primary site, both the positive and negative lymph nodes (LNs) retrieved have been emphasized to predict prognosis in stage IV rectum cancer. Therefore, we attempt to compare the prognostic performance of American Joint Committee on Cancer (AJCC) N-stage relative to lymph node ratio (LNR), log odds of metastatic lymph nodes (LODDS), and N-score in stage IV rectal cancer. METHODS: Total 5,090 patients taken surgical resection of primary site in rectum cancer with distant metastasis were extracted from Surveillance, Epidemiology, and End Results Program (SEER) database. Harrell’s C statistic (C-index) and Akaike’s Information Criterion (AIC) were used to evaluate the discriminative ability of the different LN staging systems. RESULTS: Of the 3,243 patients without radiotherapy, 82.46% (n=2,675) had been found with lymph nodes metastasis with median number of 16 lymph nodes collected (IQR: 11–22). Modeled as categorical cutoff variables for further clinical usage, when number of LNs was between 12 and 25 (C-index: 0.5997, AIC: 1,698.015), 8(th) AJCC N-stage outperformed other three schemas with increasing C-index and less AIC value. Assessed as continuous values, the LODDS shown as the best schemas with greatest discriminatory power (C-index: 0.5971, AIC: 3,680.017), generally. On the other hand, in the cohorts of other 1274 patients taken radiation, the median number of lymph nodes retrieved was 13 (IQR: 9–18). LODDS still remained remarkable performance as continuous (C-index: 0.5912; AIC: 1,058.765) and categorical variables (C-index: 0.5700; AIC: 1,061.703), while N-staging outperformed with less than 25 lymph nodes retrieved (LNs

The purpose of our study was to develop a multigene signature based on transcriptome profiles of both mRNAs and lncRNAs to identify a group of patients who are at high risk of early relapse in stages II-III colon cancer. Firstly, propensity score matching was conducted between patients in early relapse group and long-term survival group from GSE39582 training series (N = 359) and patients were matched 1:1. Global transcriptome analysis was then performed between the paired groups to identify tumor specific mRNAs and lncRNAs. Finally, using LASSO Cox regression model, we built a multigene early relapse classifier incorporating 15 mRNAs and three lncRNAs. The prognostic and predictive accuracy of the signature was internally validated in 102 colon cancer patients and externally validated in other 241 patients. In the training set, patients with high risk score were more likely to suffer from relapse than those with low risk score (HR: 2.67, 95% CI: 2.07-3.46, P < 0.001). The results were validated in the internal validation set (HR: 2.23, 95% CI: 1.23-3.78, P = 0.003) and external validation (HR 1.88, 95% CI 1.42-2.48; P < 0.001) set. Time-dependent receiver operating curve at 1 year showed that the integrated mRNA-lncRNA signature [area under curve (AUC) = 0.742] had better prognostic accuracy than AJCC TNM stage (AUC = 0.615) in the entire 702 patients. In addition, survival decision curve analyses at 12 months revealed a good clinical usefulness of the integrated mRNA-lncRNA signature. In conclusion, we successfully developed an integrated mRNA-lncRNA signature that can accurately predict early relapse.

Colon cancer patients experiencing early relapse consistently exhibited poor survival. The aim of our study was to develop an mRNA signature that can help to detect early relapse cases in stage I–III colon cancer. Public microarray datasets of stage I–III colon cancer samples were extracted from the Gene Expression Omnibus database. Propensity score matching analysis was performed between patients in the early relapse group and the long‐term survival group from GSE39582 discovery series (N = 386), and patients were 1 : 1 matched. Global mRNA expression changes were then analyzed between the paired groups to identify the differentially expressed genes. Lasso Cox regression modeling analysis was conducted for the selection of prognostic mRNA. Fifteen mRNA were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into a high‐risk group and a low‐risk group. Relapse‐free survival was significantly different between the two groups in every series, including discovery [hazard ratio (HR): 2.547, 95% confidence interval (CI): 1.708–3.797, P

Background: When compared with patients harboring stage IIB and stage IIC disease, those with stage IIIA colorectal cancer have a better prognosis. We aimed to compare the cause-specific survival (CSS) of the patients with stage IIA rectal cancer with that of the patients with stage IIIA rectal cancer. Methods: Data analyzed about patients with stage IIA and stage IIIA rectal cancer was from the US Surveillance, Epidemiology, and End Results (SEER) database. We then validated the results using data derived from Fudan University Shanghai Cancer Center (FUSCC). Results: A total of 16,788 patients (13,551 staged IIA and 3,237 staged IIIA) were identified in SEER database. A multivariate analysis manifested that patients with stage IIIA disease were more likely to have a better CSS (HR 0.894, 95% CI 0.816-0.979, p=0.016) compared with patients with stage IIA rectal cancer. In the subgroup of patients whose number of lymph nodes harvested (LNH)

Background/Aims: Alpha-fetoprotein-producing colorectal cancer (AFPP-CRC) is quite rarely seen. This study aimed to elucidate the clinicopathologic characteristics and prognostic factors of AFPP-CRC. Methods: Among 5,051 colorectal cancer patients receiving surgery in the Fudan University Shanghai Cancer Center from 2006 to 2016, we identified 78 patients with elevated serum level of AFP (> 10 µg/L) preoperatively. A propensity score matching (PSM) analysis was performed which matched 75 AFPP-CRC patients to the same number of AFP-negative colorectal cancer (AFPN-CRC) patients. Kaplan-Meier curves were compared using the log-rank test and multivariable analysis was performed to evaluate the effect of AFP-positivity while adjusting confounding factors. 27 patients were available for immunohistochemical analysis. We conducted functional experiments to characterize the tumorigenicity of AFP. Results: Patients with AFPP-CRC had a significantly higher incidence of advanced TNM stage and liver metastasis. Overall survival was significantly different between two groups before and after PSM, and AFP-positivity was one of the strongest predictors of overall survival in the multivariable model (HR 4.11, CI 95%: 1.43-11.76, p = 0.009) after PSM. We further investigated prognostic factors affecting prognosis in AFPP-CRC and found that the presence of liver metastasis was the only independent prognostic factor (HR 4.95, CI 95%: 1.48-16.48, p = 0.009). AFP expression was significantly positively correlated with HGF and c-Met expression. Transwell invasion assay revealed significantly increased cell motility with AFP overexpression. Conclusion: AFP-positivity is a significant negative predictor of overall survival in patients with colorectal cancer, which may be mediated by HGF/c-Met signaling pathway.

Background: Survival rates for Colorectal cancer (CRC) patients who experienced early relapse have usually been relatively low. Our study aims at developing an autophagy signature that could help to detect early relapse cases in CRC. Methods: Propensity score matching analysis was carried out between patients from the early relapse group and the long-term survival group from GSE39582. For both groups, respectively, global autophagy expression changes were then analyzed to identify the differentially expressed prognostic autophagy related genes by conducting Linear Models for Microarray data method analysis. Then, the multi-gene signature was validated in TCGA and Fudan University Shanghai Cancer Center (FUSCC) cohorts. Time-dependent ROC were used to test the efficiency of this signature feature in predicting the prognosis of CRC patients. Results: 5 autophagy genes were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into low- or high-risk group. Time-dependent ROC analyses proved its prognostic accuracy, with AUC 0.841 and 0.803 at 1 and 3 years, respectively. Then, we validated its prognostic value in two external validation series (GSE17538 and GSE33113) and proved that the result is indeed significant irrespective of datasets in two external independent validation cohorts (TCGA and FUSCC cohorts). A nomogram was constructed to guide individualized treatment of patients with CRC. Conclusions: The identification of robust autophagy-related features can effectively classify CRC patients into groups with low and high risk of early relapse. This signature may be used to help select high-risk CRC patients who require more aggressive treatment interventions.

Background The role of horizontal growth index of tumor size in survival prediction is still underappreciated in colon cancer because of the identification of vertical infiltration index reflected by T stage. We sought to reveal the impact of T stage on the prognostic and predictive value of tumor size in colon cancer. Materials and methods Data of patients with stage I-III colon cancer were extracted from Surveillance, Epidemiology, and End Results Program (SEER) and Fudan University Shanghai Cancer Center (FUSCC) databases. Harrell's concordance index (c-index) and time-dependent receiver operating characteristic curve (ROC) were used to analyze the discriminative ability of prognostic factors. Results Stratified analyses based on T stage found that the increase of T stage significantly and negatively repressed the effect of tumor size on death and recurrence risk. In addition, tumor size showed the greatest hazard ratio of cancer-specific death and relapse in T1 colon cancer. Even more importantly, the discriminatory ability of tumor size outperformed any other widely accepted prognostic clinical features in predicting cancer-specific survival (SEER: c-index 0.637, area under the ROC [AUC] 0.649; FUSCC: c-index 0.673, AUC 0.686) and disease-free survival (FUSCC: c-index 0.645, AUC 0.656) in T1 stage colon cancer. Conclusion Tumor size is a critical clinical factor with considerable prognostic and predictive value for T1 colon cancer, and it should be selectively incorporated into the current staging system to facilitate prediction of death and recurrence risk. Implications for practice To date, no consensus has been reached about the prognostic and predictive value of tumor size in colon cancer. Although tumor size is an independent prognostic factor for patients with colon cancer, the impact of tumor size on death or recurrence risk decreased notably with the increase of T stage. More importantly, the discriminative ability of tumor size outperformed any other clinical factors including N stage in patients with T1 colon cancer. Therefore, tumor size should be recommended to be incorporated into current staging systems to facilitate prognosis prediction for patients with T1 colon cancer.

Background: For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial. Consensus molecular subtype (CMS) status have been validated to be a prognostic tool for colorectal cancer. In this study, CMS status was investigated as prognostic biomarkers for the efficacy of adjuvant chemotherapy for stage II colorectal cancer. Methods: The tissue microarray (TMA) was retrospectively constructed of 165 non-consecutive, primary, and sporadic stage II CRCs. CMS status was determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, combining with MSI testing. The prognostic for adjuvant chemotherapy efficacy of CMS status was calculated by Kaplan-Meier curves and Cox regression analysis. Subgroup analyses were conducted according to tumor location. Findings: CMS status was associated with overall survival (OS, P=0.014) and disease-free survival (DFS, P=0.027) for stage II CRCs and it's an independent risk factor for OS (P=0.029). Among all high-risk clinicopathological factors, patients with CMS2/3 (P=0.010, HR: 0.445, 95%CI: 0.227-0.875), left-sided tumors (P=0.028, HR: 0.488, 95%CI:0.247-0.968) or

// Ben Huang 1, * , Shaobo Mo 1, * , Liang Zhu 1 , Tianhong Xu 1 , Guoxiang Cai 1 1 Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 20032, People’s Republic of China * These authors have contributed equally to this work Correspondence to: Guoxiang Cai, email: gxcfuscc@163.com Keywords: rectal cancer, stage IIIA, stage II, survival Received: August 02, 2016 Accepted: October 17, 2016 Published: October 28, 2016 ABSTRACT Background: Stage IIIA rectal cancer has distinctive oncological features, including limited depth of intestinal wall invasion and early regional lymph node metastasis. We aim to compare survival outcomes and clinicopathological features for stage IIIA rectal cancer with those for stage II rectal cancer. Method: We analyzed patients with stage II or stage IIIA rectal cancer treated with surgery without receiving preoperative radiotherapy based on data from the US Surveillance, Epidemiology, and End Results (SEER) database between 1988 and 2003. Survival curves were plotted using the Kaplan-Meier method. Multivariate Cox proportional analyses were utilized to analyze independent prognostic factors for cancer-specific survival (CSS). Results: We included 12,036 rectal cancer patients (10,132 stage II and 1,904 stage IIIA) from the SEER database. Patients with stage IIIA rectal cancer had smaller tumor size than patients with stage II rectal cancer. A multivariate analysis suggested that compared with patients with stage IIIA rectal cancer, patients with stage II disease were more likely to have more unfavorable CSS (HR 1.195, 95% CI 1.079-1.324, p=0.001). When stage II rectal cancer was further analyzed as stage IIA, IIB and IIC rectal cancer, the multivariate analysis indicated that compared with patients with stage IIIA rectal cancer, patients with stage IIA rectal cancer (HR 1.113, 95% CI 1.003-1.235, p=0.044), stage IIB rectal cancer (HR 1.493, 95% CI 1.267-1.758, p

Lymph node ratio (LNR) is considered a better staging system than N stage in rectal cancer. More recently, log odds of positive lymph nodes (LODDS) was identified as a novel prognostic classifier in many malignancies. Accordingly, our study aims to compare the predictive ability of LODDS with LNR for cancer-specific survival (CSS) in patients with stage III rectal cancer.We analyzed a subpopulation of the Surveillance, Epidemiology and End Results (SEER) database containing patients with stage III rectal cancer. The patients were categorized into four groups (LNR1 to 4) according to the LNR cut-off values 0.25, 0.50 and 0.75. The patients were divided into five groups (LODDS1 to LODDS5) according to the LODDS cut-off values of LODDS -1, 0, 1 and 2. Univariate and multivariate analyses using the Cox proportional hazards model were performed to analyze the risk factors for survival outcome.A total of 17,632 patients were included from the SEER database. Patients with LNR4 could be further divided into LODDS4 and LODDS5 and had a 5-year CSS of 39.1% and 23.3%, respectively (p 0.001). A multivariate analysis without the inclusion of LODDS showed that the LNR was an independent prognostic factor (HR 2.254, 95% confidence interval (CI) 2.034-2.497, p 0.001). However, after adjusting for LODDS, the LNR was no longer associated with CSS (HR 0.709, 95% CI 0.481-1.045, p = 0.083), and LODDS was identified as an independent prognostic factor (HR 1.303, 95% CI 1.197-1.419, p 0.001).The prognostic value of LNR can be confounded by LODDS. In stage III rectal cancer patients, LODDS has superior discrimination power over LNR and can more accurately evaluate CSS.

Peritoneum is one of the common sites of metastasis in advanced stage colorectal cancer patients. Colorectal cancer patients with peritoneal metastases (PM) are traditionally believed to have poor prognosis, which indicates it is of no value to adopt surgical treatment. With the advancement of surgical techniques, hyperthermic intraperitoneal chemotherapy (HIPEC), and multidisciplinary treatment in recent years, the cognition and treatment strategies of colorectal peritoneal metastases (CPM) have changed dramatically. In terms of prognosis, CPM under the palliative systemic treatment shows an inferior outcome compared with nonperitoneal metastasis. Nevertheless, some CPM patients amenable to the complete peritoneal cytoreductive surgery (CRS) combined with HIPEC may achieve long-term survival. The prognostic factors of CPM comprise peritoneal carcinomatosis index (PCI), completeness of cytoreduction score (CC score), the presence of extraperitoneal metastasis (liver, etc.), Peritoneal Surface Disease Severity Score (PSDSS), Japanese peritoneal staging, and so forth. Taken together, literature data suggest that a multimodality approach combining complete peritoneal CRS plus HIPEC, systemic chemotherapy, and targeted therapy may be the best treatment option for PM from colorectal cancer.

Purpose To establish and validate a combined clinical-radiomics model for preoperative prediction of synchronous peritoneal metastasis (PM) in patients with colorectal cancer (CRC). Method We enrolled 779 patients (585 in the training set: 553 with nonmetastasis (NM) and 32 with PM; 194 in the validation set: 184 with NM and 10 with PM) with clinicopathologically confirmed CRC. The significant clinical risk factors were used to build the clinical model; the least absolute shrinkage and selection operator (LASSO) algorithm was adopted to construct a radiomics signature, which included imaging features of the primary lesion and the largest peripheral lymph node, and stepwise logistic regression was applied to select the significant variables to develop the clinical-radiomics model. We used the Akaike information criterion (AIC) and receiver operating characteristic analysis to compare the goodness of fit and the prediction performance of the three models respectively. An independent validation cohort, containing 139 consecutive patients from February to September 2018, was used to evaluate the performance of the optimal model. Results Among the three models, the clinical-radiomics model (AUC = 0.855; AIC = 1043.2) was identified as the optimal model, with the maximum AUC value and the minimum AIC value (the clinical-only model: AUC = 0.771, AIC = 1277.7; the radiomics-only model: AUC = 0.764, AIC = 1280.5). The clinical-radiomics model also showed good discrimination in both the validation cohort (AUC = 0.793) and the independent validation cohort (AUC = 0.781). Conclusions The present study proposes a clinical-radiomics model created with the CT-based radiomics signature and key clinical features that can potentially be applied in the individual preoperative prediction of synchronous PM for CRC patients.

31 Background: Survival outcomes are significant different in stage II colorectal cancer (CRC) patients with diverse clinicopathological features. Objective of this study is to establish a credible prognostic nomogram incorporating easily obtained parameters for stage II CRC patients. Methods: A total of 1708 stage II CRC patients at Fudan University Shanghai Cancer Center (FUSCC) during 2008 to 2013 were retrospectively analyzed in this study. Cases were randomly separated into training set (n = 1084) and validation set (n = 624). Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors which were subsequently incorporated into a nomogram. The performance of the nomogram was evaluated by C-index and ROC curve to calculate the area under the curve (AUC). The clinical utility of the nomogram was evaluated using decision curve analysis (DCA). Results: In univariate and multivariate analyses, eight parameters were correlated with disease free survival (DFS), which were subsequently selected to draw prognostic nomogram based on DFS. For DFS predictions, the predicted concordance index (C-index) of the nomogram was 0.842 (95% confidence interval (CI), 0.710-0.980), and 0.701 (95% CI, 0.610-0.770) for training and validation set, respectively. The AUC values of ROC predicted 1, 3 and 5-year survival of nomogram in the training and validation groups were 0.869, 0.858, 0.777 and 0.673, 0.714, 0.706, respectively. The recurrence probability calibration curve showed good consistency between actual observations and nomogram-based predictions. DCA showed better clinical application value for the nomogram compared with TNM staging system. Conclusions: A novel nomogram based on a large population study was established and validated, which is a simple-to-use tool for physicians to facilitate the postoperative personalized prognostic evaluation and determine therapeutic strategies for stage II CRC patients.

29 Background: Adjuvant chemotherapy (ACT) is the standard treatment for stage III colorectal cancers (CRC). However, optimal biomarker were still needed for individualized adjuvant strategies. Here, we conducted a prospective study in patients with stage III CRCs with combined ACT, to explore the prognostic effect of circulating tumor DNA (ctDNA) before and after ACT. Methods: The study enrolled 130 patients with stage III colon and rectal cancer (≥10cm from anal) who received curative resection without neoadjuvant therapy at Fudan University Shanghai Cancer Center. All patients received 3 or 6 months of ACT. The Roche AVENIO Surveillance Kit was used to assess somatic mutations by next-generation sequencing (NGS) in tissue, pre- and post-chemo plasma samples. The plasmas were collected 3-5 weeks after surgery and after last cycle of ACT, respectively. Patients were classified as ctDNA (+) or (-) based on the detection of SNVs identified in tumor tissue at an AF of at least 5%. Results: In the interim analysis, 116 tissues, 123 pre-chemo and 98 post-chemo plasmas were prospectively collected and detected, and a total of 86 matched samples were analyzed with a median follow-up of 12.0 months. ctDNA was detectable in 14 of 86 patients (16.3%) before ACT, and in 10 (11.6%) patients after ACT. After 1-year follow-up, longitudinal ctDNA analysis identified 6 of 12 early relapses (50.0%), while 6 in 69 patients (8.7%) who were both ctDNA (-) in pre- and post-chemo samples had early relapse. Before ACT, ctDNA(+) patients were 7 times more likely to relapse early than ctDNA(-) patients (HR, 7.372; 95% CI, 1.543-35.22; P = 0.012). Similarly, after ACT, ctDNA(+) patients were 13 times (HR, 13.37; 95% CI, 2.026-88.23; P = 0.007) more likely to relapse. Monitoring after ACT indicated that 7 of the 14 ctDNA(+) patients (50.0%) were cleared, and the early relapse rate decreased from 43.9% (3/7) to 28.6% (2/7) if ctDNA turned negative. Conclusions: ctDNA analysis can potentially change the postoperative management and surveillance strategies for stage III CRC by enabling risk stratification, monitoring ACT efficacy, and detecting early relapse. Clinical trial information: ChiCTR1800018754.

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.

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.

Marital status has been found as an independent prognostic factor for survival in colorectal cancer (CRC). However, it is unclear whether patients with different marital status have benefited the same from the treatment improvement. We queried the Surveillance, Epidemiology, and End Results (SEER) 9 database for patients diagnosed with CRC from 1975 to 2009. Yearly survival data was presented with overlying loess smoothing lines, stratifying by marital status. We further referred to the SEER 18 database for patients diagnosed with CRC from 1973 to 2014. We also performed yearly data for stage proportion, surgery-performed rate, cancer-specific survival (CSS), and multivariate hazard ratio with overlying loess smoothing lines across all marital status. Five-year CSS of married, single, and separated/divorced patients showed remarkable increase since 1975; however, survival of widowed patients remained low and no survival gains were observed since 1990. The same trends persisted after stratifying patients by stage and gender. Married and widowed patients tended to have more localized disease and less distant disease compared with the other two groups, and married patients were more likely to receive surgery. Multivariate analysis revealed the hazard ratio of widowed patients dropped dramatically when including age at diagnosis. Widowed patients have not benefited substantially from the remarkable treatment improvement over the past four decades, which may be the result of the older age of this particular group. This study is a wake-up call to the medical community for additional care for the widowed patients.