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Precise methods for risk stratification to guide adjuvant chemotherapy for stage III colon cancers are needed. Here, we combined circulating tumor DNA (ctDNA) with consensus molecular subtype (CMS) to improve risk stratification in stage III colon cancers.We conducted a prospective, observational cohort study of 165 patients with stage III colon cancers. Somatic variants in tumor tissues and plasmas collected pre- and post-chemo were detected via a targeted sequencing panel of 197 cancer-related genes. CMSs classification was characterized using a targeted RNA sequencing panel of 788 genes.We analyzed 151 pre-chemo and 124 post-chemo plasmas, while 130 patients were CMSs classified. ctDNA was detectable in 15.9% pre-chemo and 8.9% post-chemo samples. Significantly worse recurrence-free survival (RFS) was seen if ctDNA was detectable in pre-chemo samples (hazard ratio [HR], 3.585; P 0.001) or in post-chemo samples (HR, 3.337; P = 0.005). Pre-chemo ctDNA (HR, 5.538; P 0.001) and post-chemo ctDNA status (HR, 3.272; P = 0.037) remained independently associated with RFS in multivariate analysis. According to the redefined recurrence risk stratification, mid-risk patients (ctDNA-negative with CMS4/T4 or N2 tumors) were 5.3 times (HR, 5.269; P = 0.025) more likely to relapse than low-risk patients (ctDNA-negative with CMS1-3/T3N1 tumors), while high-risk patients (ctDNA-positive) were 14.6 times (HR, 14.590; P 0.001) more likely to relapse.Postoperative ctDNA indicating residual disease, combined with CMSs classification and clinical risk reflecting the intrinsic characteristics of tumors, can redefine risk stratification of stage III colon cancers and better predict relapse.

There is no effective method to predict chemotherapy response and postoperative prognosis of colorectal cancer liver metastasis (CRLM) patients. Patient-derived organoid (PDO) has become an important preclinical model. Herein, a living biobank with 50 CRLM organoids derived from primary tumors and paired liver metastatic lesions is successfully constructed. CRLM PDOs from the multiomics levels (histopathology, genome, transcriptome and single-cell sequencing) are comprehensively analyzed and confirmed that this organoid platform for CRLM could capture intra- and interpatient heterogeneity. The chemosensitivity data in vitro reveal the potential value of clinical application for PDOs to predict chemotherapy response (FOLFOX or FOLFIRI) and clinical prognosis of CRLM patients. Taken together, CRLM PDOs can be utilized to deliver a potential application for personalized medicine.

Background Necroptosis is a new form of programmed cell death that is associated with cancer initiation, progression, immunity, and chemoresistance. However, the roles of necroptosis-related genes (NRGs) in colorectal cancer (CRC) have not been explored comprehensively. Methods In this study, we obtained NRGs and performed consensus molecular subtyping by “ConsensusClusterPlus” to determine necroptosis-related subtypes in CRC bulk transcriptomic data. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of different cell types in the tumor microenvironment (TME). Single-cell transcriptomic analysis was performed to confirm classification related to NRGs. NRG_score was developed to predict patients’ survival outcomes with low-throughput validation in a patients’ cohort from Fudan University Shanghai Cancer Center. Results We identified three distinct necroptosis-related classifications (NRCs) with discrepant clinical outcomes and biological functions. Characterization of TME revealed that there were two stable necroptosis-related phenotypes in CRC: a phenotype characterized by few TME cells infiltration but with EMT/TGF-pathways activation, and another phenotype recognized as immune-excluded. NRG_score for predicting survival outcomes was established and its predictive capability was verified. In addition, we found NRCs and NRG_score could be used for patient or drug selection when considering immunotherapy and chemotherapy. Conclusions Based on comprehensive analysis, we revealed the potential roles of NRGs in the TME, and their correlations with clinicopathological parameters and patients’ prognosis in CRC. These findings could enhance our understanding of the biological functions of necroptosis, which thus may aid in prognosis prediction, drug selection, and therapeutics development.

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.

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.

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.

Background To study the pattern and treatment outcome of rectal cancer (RC) with concurrent locoregional recurrence (LR) and distant metastasis (DM) after total mesorectal excision (TME) and to identify patient-, disease-, and treatment-related factors associated with differences in prognosis after concurrent LR and DM. Methods RC patients who were diagnosed with concurrent LR and DM after TME from May 2015 to June 2019 were included in our study. All patients received single or multiple treatment modalities under the guidance of multidisciplinary team (MDT) of colorectal cancer in Fudan University Shanghai Cancer Center. The prognostic value of various clinicopathological factors for survival were calculated by Kaplan–Meier curves and Cox regression analyses. Results A total of 74 RC patients with concurrent LR and DM who had undergone TME with a median follow-up of 27 months were eligible for analysis. The median survival of the included patients was 34 months, and 30 patients (41%) died. Fifty-nine patients (80%) underwent comprehensive treatments. Patients with oligometastatic disease (OMD) achieved no evidence of disease (NED) status more frequently than those with multiple metastases (P = 0.003). In the univariate analysis, patients achieving NED, diagnosed with OMD and five or less peritoneal metastases tended to have longer survival after LR and DM diagnosis (P P = 0.032). Survival after concurrent LR and DM in the non-NED group was significantly shorter than that in the NED group (median survival, 32 vs. 46 months; HR, 2.7; P = 0.014). Conclusions The pattern and treatment outcome of RC with concurrent LR and DM after TME has changed with the development of multiple treatment modalities. Although the prognosis remains poor, pursuing NED status through comprehensive treatments may improve the survival of RC patients with concurrent LR and DM after TME.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. After resection, patients need extensive follow-up to detect asymptomatic recurrences as early as possible to obtain optimal treatment. This study evaluated the prognostic value of circulating tumor DNA (ctDNA) for CRC recurrence.Two investigators independently conducted a systematic literature search of peer-reviewed studies that investigated the prognostic value of ctDNA in CRC. Fixed effects or random effects models were applied for all analyses based on the assessment of heterogeneity.A total of 189 studies were initially retrieved from all databases; ultimately, eight studies with 879 CRC patients were included in this analysis. The pooled median recurrence-free survival was 11.36 months for ctDNA-positive patients. Meta-analysis of hazard ratio (HR) suggested that postoperative ctDNA-positive patients were more likely to experience cancer recurrence than ctDNA-negative patients (pooled HR: 5.41; 95% confidence interval (CI): 2.37-8.45).Successive monitoring of ctDNA status and follow-up with postoperative computed tomography (CT)/magnetic resonance imaging (MRI) are useful tools to detect early recurrence in postoperative ctDNA-positive patients.

Early detection can benefit cancer patients with more effective treatments and better prognosis, but existing early screening tests are limited, especially for multi-cancer detection. This study investigated the most prevalent and lethal cancer types, including primary liver cancer (PLC), colorectal adenocarcinoma (CRC), and lung adenocarcinoma (LUAD). Leveraging the emerging cell-free DNA (cfDNA) fragmentomics, we developed a robust machine learning model for multi-cancer early detection. 1,214 participants, including 381 PLC, 298 CRC, 292 LUAD patients, and 243 healthy volunteers, were enrolled. The majority of patients (N = 971) were at early stages (stage 0, N = 34; stage I, N = 799). The participants were randomly divided into a training cohort and a test cohort in a 1:1 ratio while maintaining the ratio for the major histology subtypes. An ensemble stacked machine learning approach was developed using multiple plasma cfDNA fragmentomic features. The model was trained solely in the training cohort and then evaluated in the test cohort. Our model showed an Area Under the Curve (AUC) of 0.983 for differentiating cancer patients from healthy individuals. At 95.0% specificity, the sensitivity of detecting all cancer reached 95.5%, while 100%, 94.6%, and 90.4% for PLC, CRC, and LUAD, individually. The cancer origin model demonstrated an overall 93.1% accuracy for predicting cancer origin in the test cohort (97.4%, 94.3%, and 85.6% for PLC, CRC, and LUAD, respectively). Our model sensitivity is consistently high for early-stage and small-size tumors. Furthermore, its detection and origin classification power remained superior when reducing sequencing depth to 1× (cancer detection: ≥ 91.5% sensitivity at 95.0% specificity; cancer origin: ≥ 91.6% accuracy). In conclusion, we have incorporated plasma cfDNA fragmentomics into the ensemble stacked model and established an ultrasensitive assay for multi-cancer early detection, shedding light on developing cancer early screening in clinical practice.

Our study aims at developing an interferon-stimulated genes (ISGs) signature that could predict overall survival (OS) in cancer patients, which enrolled a total of 5643 pan-cancer patients. Linear models for microarray data method analysis were conducted to identify the differentially expressed prognostic genes in the global ISGs family. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival analysis were used to test the efficiency of a multi-gene signature in predicting the prognosis of pan-cancer patients. The prognostic performance and potential biological function of gene signature were verified by quantitative real-time PCR in a pan-cancer independent cohort. Three ISGs genes were finally identified to build a classifier, a specific risk score formula, with which patients were classified into the low- or high-risk groups. Time-dependent ROC analyses proved prognostic accuracy. Then, its prognostic value was validated in seven external validation series. A nomogram was constructed to guide the individualized treatment of patients with lung adenocarcinoma. Biological pathway and tumor immune infiltration analysis showed that the signature might cause poor prognosis by blocking NK cell activation. Finally, the signature in our centers was confirmed by real-time quantitative PCR. A robust ISGs-related feature was discovered to effectively classify pan-cancer patients into subgroups with different OS.

Ferroptosis is a non-apoptotic form of cell death recognized in recent years. Nonetheless, the potential role of ferroptosis-associated genes in immune regulation and tumor microenvironment formation remains unknown. In this study, we characterized the ferroptosis-associated patterns of colorectal cancer through integrative analyses of multiple datasets with transcriptomics, genomics, and single-cell transcriptome profiling. Three distinct ferroptosis-associated clusters (FAC1, FAC2 and FAC3) were identified from 1251 CRC bulk samples, which were associated with different clinical outcomes and biological pathways. The TME characterization revealed that the three patterns were highly consistent with known immune profiles: immune-desert (FAC1), immune-inflamed (FAC2) and immune-excluded (FAC3), respectively. Ferroptosis-associated immune and stromal-activated genes were obtained and characterized by corresponding function in CRC tumorigenesis. Further single-cell analyses identified the ferroptosis-associated immune responding tumor cells and ferroptosis-associated stromal cells infiltration pattern. Based on the Fersig score, which was extracted from the ferroptosis phenotype-related signature, patients with lower Fersig score were characterized by prolonged survival time and effective immune responses. Collectively, we uncovered the ferroptosis-associated patterns associated with TME diversity and immune response phenotype. The Fersig we constructed could be the potential therapeutic target genes to improve the efficacy of patients' immunotherapy. The Fersig scoring scheme could enhance the understanding of TME infiltration associated with ferroptosis and prediction of immunotherapy efficacy.

Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

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

High-dose radiation exposure induces gastrointestinal (GI) stem cell death, resulting in denudation of the intestinal mucosa and lethality from GI syndrome, for which there is currently no effective therapy. Studying an intestinal organoid-based functional model, we found that Sirtuin1(SIRT1) inhibition through genetic knockout or pharmacologic inhibition significantly improved mouse and human intestinal organoid survival after irradiation. Remarkably, mice administered with two doseages of SIRT1 inhibitors at 24 and 96 h after lethal irradiation promoted Lgr5+ intestinal stem cell and crypt recovery, with improved mouse survival (88.89% of mice in the treated group vs. 0% of mice in the control group). Moreover, our data revealed that SIRT1 inhibition increased p53 acetylation, resulting in the stabilization of p53 and likely contributing to the survival of intestinal epithelial cells post-radiation. These results demonstrate that SIRT1 inhibitors are effective clinical countermeasures to mitigate GI toxicity from potentially lethal radiation exposure.

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.

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.

Cancer cells are usually characterized by hyperactive glucose metabolism, which can often lead to glucose scarcity; thus, alternative pathways to rewire cancer metabolism are required. Here, we demonstrated that GLUT3 was highly expressed in colorectal cancer (CRC) and negatively linked to CRC patient outcomes, whereas GLUT1 was not associated with CRC prognosis. Under glucose-limiting conditions, GLUT3 expedited CRC cell growth by accelerating glucose input and fuelling nucleotide synthesis. Notably, GLUT3 had a greater impact on cell growth than GLUT1 under glucose-limiting stress. Mechanistically, low-glucose stress dramatically upregulated GLUT3 via the AMPK/CREB1 pathway. Furthermore, high GLUT3 expression remarkably increased the sensitivity of CRC cells to treatment with vitamin C and vitamin C-containing regimens. Together, the results of this study highlight the importance of the AMPK/CREB1/GLUT3 pathway for CRC cells to withstand glucose-limiting stress and underscore the therapeutic potential of vitamin C in CRC with high GLUT3 expression.

Long noncoding RNAs (lncRNAs) have been revealed to play critical roles in tumor initiation and progression. The antisense lncRNA LDLRAD4-AS1 is the longest lncRNA of LDLRAD4, and its expression levels, cellular localization, precise function, and mechanism in colorectal cancer (CRC) remain unknown. In this study, we observed that lncRNA LDLRAD4-AS1 was located in the nucleus of CRC cells and that lncRNA LDLRAD4-AS1 was upregulated in most CRC specimens and cell lines. Overexpression of lncRNA LDLRAD4-AS1 was correlated with poor prognosis in CRC patients. LncRNA LDLRAD4-AS1 upregulation enhanced the migration and invasion of CRC cells in vitro and facilitated CRC metastasis in vivo. Mechanistic investigations suggested that lncRNA LDLRAD4-AS1 could decrease the expression of LDLRAD4 by disrupting the stability of LDLRAD4 mRNA, resulting in epithelial-to-mesenchymal transition (EMT) through upregulating Snail, thereby promoting metastasis in CRC. Our results demonstrated a previously unrecognized LDLRAD4-AS1-LDLRAD4-Snail regulatory axis involved in epigenetic and posttranscriptional regulation that contributes to CRC progression and metastasis.

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/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 Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. Materials and methods The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. Results FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. Conclusion FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

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: Colon signet-ring cell carcinoma (SRCC) is a rare type of malignant dedifferentiated adenocarcinomas, and associated with poor survival. However, an in-depth study of the biological features of colon SRCC is hampered by lack of in vitro model. Our study was designed to establish and characterize cell cultures from SRCC for further translational and biological research. Methods: By harnessing the power of organoid culture system, we established a human colon SRCC organoid line from surgical sample of one patient with colon SRCC. The organoid line was characterized at the morphology, histology, ultrastructure, chromosome stability level and its tumorigenic ability was verified by xenografts. Capture-based targeted DNA sequencing combining with drug screen based on a bespoke 88 compound library identified the possible target and the treatment response was confirmed by in vivo organoid system and in vitro xenografts. Findings: Our data showed that the colon SRCC organoid line, YQ-173, resemble histological and growth characteristics of the original tumor cells and have high tumor formation rate. DNA sequencing indicated JAK2 might be the treatment target. In vitro drug screen found that AT9283 and Pacritinib could be the effective JAK2 inhibitors, which was consistent with in vivo xenografts' response. Interpretation: We report, for the first time, the establishment of SRCC organoid line allowing in-depth study of SRCC biology, as well as a strategy to assess in vitro drug testing in a personalized fashion. Funding: This work was supported by National Natural Science Foundation of China (31470826, 31670858, 81672374), Science and Technology Commission of Shanghai Municipality (16411966300), and Shanghai Sailing Program (19YF1409500). Declaration of Interest: The authors declare no potential conflicts of interest. Ethical Approval: The tissue was obtained with informed consent for experimentation with the patient and this study was approved by the ethical committee of Fudan University Shanghai Cancer Center. All animal experiments were performed according to the guidelines for the care and use of laboratory animals and were approved by Institutional Animal Care and Use Committee of Fudan University.

// 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.

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.

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.

F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between FBW7 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The impact of FBW7 on migration was further validated in vitro. Whole-genome expression microarray (GEO,accession numbers GSE76443), was then analyzed to find the possible target of FBW7. The results were verified by functional experiments in vitro and IHC staining of TMA. Finally, luciferase and chromatin immunoprecipitation (ChIP) assays were carried out to identify the possible mechanisms. The expression level of FBW7 in TMA was negatively correlated with serum CEA level, venous invasion, N stage and M stage, and positively associated with the survival of CRC patients(P