The ligation between ERMAP, galectin-9 and dectin-2 promotes Kupffer cell phagocytosis and antitumor immunity.

Kupffer cells, the liver tissue resident macrophages, are critical in the detection and clearance of cancer cells. However, the molecular mechanisms underlying their detection and phagocytosis of cancer cells are still unclear. Using in vivo genome-wide CRISPR-Cas9 knockout screening, we found that the cell-surface transmembrane protein ERMAP expressed on various cancer cells signaled to activate phagocytosis in Kupffer cells and to control of liver metastasis. ERMAP interacted with ß-galactoside binding lectin galectin-9 expressed on the surface of Kupffer cells in a manner dependent on glycosylation. Galectin-9 formed a bridging complex with ERMAP and the transmembrane receptor dectin-2, expressed on Kupffer cells, to induce the detection and phagocytosis of cancer cells by Kupffer cells. Patients with low expression of ERMAP on tumors had more liver metastases. Thus, our study identified the ERMAP-galectin-9-dectin-2 axis as an 'eat me' signal for Kupffer cells.

Molecular Profiling Provides Clinical Insights Into Targeted and Immunotherapies as Well as Colorectal Cancer Prognosis.

BACKGROUND & AIMS: Tumor genetic testing is indispensable in the management of primary and metastatic colorectal cancer (CRC), yet the indications for genomics-guided precision medicine and immunotherapy must be better understood and defined. METHODS: We prospectively sequenced tumors from 869 Chinese patients with CRC by a large panel and evaluated the clinical significance of single-gene somatic mutations and co-occurring events in metastatic CRC, as well as their functional effects and tumorigenic mechanisms. We systematically assessed the heterogeneity of the tumor immune microenvironment in different genomic contexts through the combined analysis of Immunoscore, multiplex immunostaining, whole-exome sequencing, transcriptome, and single-cell sequencing. RESULTS: Single-gene somatic mutations in BRAF or RBM10 were associated with shorter progression-free survival in patients with metastatic CRC. Functional studies suggested RBM10 acts as a tumor suppressor in CRC development. Co-mutations of KRAS/AMER1 or KRAS/APC were enriched in the metastatic cohort, which had poor progression-free survival and did not benefit from bevacizumab due to accelerated drug metabolism. Forty patients (4.6%) carried pathogenic or likely pathogenic germline alterations in the DNA damage repair pathway and 37.5% of these tumors had secondary-hit events with loss of heterozygosity or biallelic alterations. A high tumor insertion or deletion burden with high microsatellite instability suggested immunogenicity with numerous activated tumor-infiltrating lymphocytes, whereas polymerase epsilon exonuclease mutation with ultrahigh tumor mutation burden indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunologic interactions were reflected in the divergent neoantigen presentation and depletion, immune checkpoint expression, PD-1/PD-L1 interaction, and T-cell responsiveness to pembrolizumab. CONCLUSIONS: Our integrated analysis provides insights into CRC prognostic stratification, drug response, and personalized genomics-guided targeted and immunotherapies.

Integrated Multi-Omics Landscape of Liver Metastases.

BACKGROUND & AIMS: Lack of thorough knowledge about the complicated immune microenvironment (IM) within a variety of liver metastases (LMs) leads to inappropriate treatment and unsatisfactory prognosis. We aimed to characterize IM subtypes and investigate potential mechanisms in LMs. METHODS: Mass cytometry was applied to characterize immune landscape of a primary liver cancers and liver metastases cohort. Transcriptomic and whole-exome sequencing were used to explore potential mechanisms across distinct IM subtypes. Single-cell transcriptomic sequencing, multiplex fluorescent immunohistochemistry, cell culture, mouse model, Western blot, quantitative polymerase chain reaction, and immunohistochemistry were used for validation. RESULTS: Five IM subtypes were revealed in 100 LMs and 50 primary liver cancers. Patients featured terminally exhausted (IM1) or rare T-cell-inflamed (IM2 and IM3) immune characteristics showed worse outcome. Increased intratumor heterogeneity, enriched somatic TP53, KRAS, APC, and PIK3CA mutations and hyperactivated hypoxia signaling accounted for the formation of vicious subtypes. SLC2A1 promoted immune suppression and desert via increasing proportion of Spp1+ macrophages and their inhibitory interactions with T cells in liver metastatic lesions. Furthermore, SLC2A1 promoted immune escape and LM through inducing regulatory T cells, including regulatory T cells and LAG3+CD4+ T cells in primary colorectal cancer. CONCLUSIONS: The study provided integrated multi-omics landscape of LM, uncovering potential mechanisms for vicious IM subtypes and confirming the roles of SLC2A1 in regulating tumor microenvironment remodeling in both primary tumor and LM lesions.

Development and validation of the chemotherapy-induced peripheral neuropathy integrated assessment - oxaliplatin subscale: a prospective cohort study.

BACKGROUND: Current chemotherapy-induced peripheral neuropathy (CIPN) assessment tools mostly have poor sensitivity and weak anti-interference, so that it is sometimes difficult to provide substantive guidance for clinical intervention. This study aimed to develop an assessment tool dedicated for oxaliplatin to address these limitations. METHODS: This study screened 445 OIPN-related literatures for producing a symptom list, and developed the questionnaire module through expert supplement, item generation, content correlation analysis, pre-testing, and item improvement. The validation phase used a Chinese population-based prospective cohort study from June 2021 to July 2022. Patients were requested to complete the tested questionnaire, QLQ-CIPN20 and the CTCAE grading one day before cycles 2-6 of chemotherapy. Cronbach's α coefficient and intraclass correlation coefficient (ICC) were calculated for the internal consistency and stability analysis, respectively. Exploratory factor analysis was conducted to investigate the construct validity. The correlations among the tested questionnaire, QLQ-CIPN20 and CTCAE were compared for the criterion validity analysis. Wilcoxon signed-rank sum test was utilized to compare the sensitivity between the tested questionnaire and QLQ-CIPN20. RESULT: A 20-item CIPN assessment tool named chemotherapy-induced peripheral neuropathy integrated assessment - oxaliplatin subscale (CIPNIA-OS) was developed. The validation phase included 186 patients. Cronbach's α coefficient of CIPNIA-OS was 0.764 (> 0.7), and ICC was 0.997 (between 0.9 and 1). The structure of CIPNIA-OS containing seven factors was examined. The correlation coefficient between CIPNIA-OS and CTCAE was 0.661 (95%CI 0.623 to 0.695), which was significantly higher than that between QLQ-CIPN20 and CTCAE (0.417, 95%CI 0.363 to 0.469, p < 0.01). Besides, the total score of CIPNIA-OS was mostly higher than QLQ-CIPN20, with an average difference of 2.189 (CI 95% 2.056 to 2.322), and the difference gradually expanded with the progress of chemotherapy (p < 0.05). CONCLUSION: This study developed an original CIPN questionnaire which was dedicated for OIPN assessment. It was a comprehensive tool that covered acute OIPN symptoms and integrated features from several proven CIPN assessment tools. The validation results supported that CIPNIA-OS had satisfactory reliability, stability, construct, criterion validity, and was more accuracy and sensitive than QLQ-CIPN20 in the evaluation of OIPN.

Noninvasive predictive models based on lifestyle analysis and risk factors for early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.

Bulk and single-cell transcriptome profiling reveal necroptosis-based molecular classification, tumor microenvironment infiltration characterization, and prognosis prediction in colorectal cancer.

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.

The Critical Role of Tumor Size in Predicting Prognosis for T1 Colon Cancer.

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.

A clinical-radiomics nomogram for the preoperative prediction of lymph node metastasis in colorectal cancer.

BACKGROUND: Accurate lymph node metastasis (LNM) prediction in colorectal cancer (CRC) patients is of great significance for treatment decision making and prognostic evaluation. We aimed to develop and validate a clinical-radiomics nomogram for the individual preoperative prediction of LNM in CRC patients. METHODS: We enrolled 766 patients (458 in the training set and 308 in the validation set) with clinicopathologically confirmed CRC. We included nine significant clinical risk factors (age, sex, preoperative carbohydrate antigen 19-9 (CA19-9) level, preoperative carcinoembryonic antigen (CEA) level, tumor size, tumor location, histotype, differentiation and M stage) to build the clinical model. We used analysis of variance (ANOVA), relief and recursive feature elimination (RFE) for feature selection (including clinical risk factors and the imaging features of primary lesions and peripheral lymph nodes), established classification models with logistic regression analysis and selected the respective candidate models by fivefold cross-validation. Then, we combined the clinical risk factors, primary lesion radiomics features and peripheral lymph node radiomics features of the candidate models to establish combined predictive models. Model performance was assessed by the area under the receiver operating characteristic (ROC) curve (AUC). Finally, decision curve analysis (DCA) and a nomogram were used to evaluate the clinical usefulness of the model. RESULTS: The clinical-primary lesion radiomics-peripheral lymph node radiomics model, with the highest AUC value (0.7606), was regarded as the candidate model and had good discrimination and calibration in both the training and validation sets. DCA demonstrated that the clinical-radiomics nomogram was useful for preoperative prediction in the clinical environment. CONCLUSION: The present study proposed a clinical-radiomics nomogram with a combination of clinical risk factors and radiomics features that can potentially be applied in the individualized preoperative prediction of LNM in CRC patients.

FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer.

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.

Nomogram to predict the risk and survival of synchronous bone metastasis in colorectal cancer: a population-based real-world analysis.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: CRC patients with BM have worse real-world survival. Nomogram can predict incidence of BM in CRC patients and survival among patients with BM.

Prognostic accuracy of different lymph node staging system in predicting overall survival in stage IV colon cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 safety and effectiveness of carbon nanoparticles suspension in tracking lymph node metastases of colorectal cancer: a prospective randomized controlled trial.

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 < 0.001). The number of lymph nodes retrieved in nanocarbon group were more likely to be ≥12 than that in the control group (P = 0.005). 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.

Increasing age-related survival gap among patients with colorectal cancer: a population-based retrospective study.

BACKGROUND: Survival for patients with colorectal cancer (CRC) has improved over the past decades. However, it is unclear whether older patients have benefited to the same extent as younger patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) 9 registries database was queried for CRC patients from 1975 to 2009. We presented yearly data for survival with overlying loess-smoothing lines across all age groups. Another cohort was created using the SEER 18 registries database for patients diagnosed with CRC from 1973 to 2014. Yearly data for surgery-performed rate, stage proportion, and multivariate hazard ratio were performed with overlying smoothing lines across all age groups. RESULTS: In the analysis SEER 9, 5-year cause-specific survival (CSS) of patients aged ≤ 54, 55-64, and 65-74 years showed robust increase since 1975; however, the survival of patients aged 75-84 years remained low despite modest improvement, and patients aged 85 or older even showed no survival gains since 1990. In the analysis of SEER 18, there has been a steady increase in the survival of patients aged ≤ 54, 55-64, 65-74, and 75-84 years as time period advanced; however, of CRC patients aged ≥ 85 years, the survival curves of period 1990-1999 and 2000-2012 could not be distinguished from each other presented with negligibly a small gap from the curve of 1980-1989. CONCLUSIONS: The strong interaction between age and year of diagnosis implies that older patients have benefited less over time than younger patients, especially for patients aged ≥ 85 years.

Prognostic and predictive value of an autophagy-related signature for early relapse in stages I-III colon cancer.

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

17-allylamino-17-demethoxygeldanamycin impeded chemotherapy through antioxidant activation via reducing reactive oxygen species-induced cell death.

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

Prognostic nomograms for predicting cause-specific survival and overall survival of stage I-III colon cancer patients: a large population-based study.

BACKGROUND: The purpose of this study was to build functional nomograms based on significant clinicopathological features to predict cause-specific survival (CSS) and overall survival (OS) in patients with stage I-III colon cancer. METHODS: Data on patients diagnosed with stage I-III colon cancer between 2010 and 2015 were downloaded from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were used to identify independent prognostic factors, which were used to construct nomograms to predict the probabilities of CSS and OS. The performance of the nomogram was assessed by C-indexes, receiver operating characteristic (ROC) curves and calibration curves. Decision curve analysis (DCA) was used to compare clinical usage between the nomogram and the tumor-node-metastasis (TNM) staging system. RESULTS: Based on the univariate and multivariate analyses, features that correlated with survival outcomes were used to establish nomograms for CSS and OS prediction. The nomograms showed favorable sensitivity at predicting 1-, 3-, and 5-year CSS and OS, with a C-index of 0.78 (95% confidence interval (CI) 0.77-0.80) for CSS and 0.74 (95% CI 0.73-0.75) for OS. Calibration curves and ROC curves revealed excellent predictive accuracy. The clinically and statistically significant prognostic performance of the nomogram generated with the entire group of patients and risk scores was validated by a stratified analysis. DCA showed that the nomograms were more clinically useful than TNM stage. CONCLUSION: Novel nomograms based on significant clinicopathological characteristics were developed and can be used as a tool for clinicians to predict CSS and OS in stage I-III colon cancer patients. These models could help facilitate a personalized postoperative evaluation.

Overexpression of MTA1 inhibits the metastatic ability of ZR-75-30 cells in vitro by promoting MTA2 degradation.

BACKGROUND: As the first member of the metastasis-associated protein (MTA) family, MTA1 and another MTA family member, MTA2, have both been reported to promote breast cancer progression and metastasis. However, the difference and relationship between MTA1 and MTA2 have not been fully elucidated. METHODS: Transwell assays were used to assess the roles of MTA1 and MTA2 in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. Immunoblotting and qRT-PCR were used to evaluate the effect of MTA1 overexpression on MTA2. Proteases that cleave MTA2 were predicted using an online web server. The role of neutrophil elastase (NE) in MTA1 overexpression-induced MTA2 downregulation was confirmed by specific inhibitor treatment, knockdown, overexpression and immunocytochemistry, and NE cleavage sites in MTA2 were confirmed by MTA2 truncation and mutation. The effect of MTA1 overexpression on the intrinsic inhibitor of NE, elafin, was detected by qRT-PCR, immunoblotting and treatment with inhibitors. RESULTS: MTA1 overexpression inhibited, while MTA2 promoted the metastasis of ZR-75-30 cells in vitro. MTA1 overexpression downregulated MTA2 expression at the protein level rather than the mRNA level. NE was predicted to cleave MTA2 and was responsible for MTA1 overexpression-induced MTA2 degradation. NE was found to cleave MTA2 in the C-terminus at the 486, 497, 542, 583 and 621 sites. MTA1 overexpression activated NE by downregulating elafin in a histone deacetylase- and DNA methyltransferase-dependent manner. CONCLUSIONS: MTA1 and MTA2 play opposing roles in the metastasis of ZR-75-30 luminal B breast cancer cells in vitro. MTA1 downregulates MTA2 at the protein level by epigenetically repressing the expression of elafin and releasing the inhibition of neutrophil elastase, which cleaves MTA2 in the C-terminus at multiple specific sites.

Epidemiology of and prognostic factors for appendiceal carcinomas: a retrospective, population-based study.

BACKGROUND: The aim of this study is to evaluate the epidemiology of and prognostic factors for appendiceal carcinomas (ACs). METHODS: 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. RESULTS: 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 < 0.001), year of diagnosis (P < 0.001), age (P < 0.001), race (P < 0.001), tumor grade (P < 0.001), disease stage (P < 0.001), retrieved regional lymph nodes (P < 0.001), type of surgery performed (P = 0.002), and histologic subtype (P < 0.001) were predictors of outcome. Survival time for all ACs increased from the 1973-1993 period to the 1994-2014 period (HR 0.76; 95% CI, 0.69 to 0.85). Additionally, the 5-year survival rates were 88% for malignant carcinoid, 70% for goblet cell carcinoid, 51% for colonic type adenocarcinoma, 59% for mucinous adenocarcinoma, and 25% for signet ring cell type. CONCLUSIONS: We observed increased reported incidence of ACs and increased survival durations over time, suggesting that clinicians pay more attention to ACs and mastering the characteristic of these tumors.

Transcriptome profiling reveals an integrated mRNA-lncRNA signature with predictive value of early relapse in colon cancer.

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.

Prognostic Impact of Hypochloremia in Patients With Stage I to III Colorectal Cancer After Radical Resection.

BACKGROUND: Recent studies have suggested that electrolyte disorders might be a negative prognostic factor for some diseases. OBJECTIVE: The purpose of this study was to systematically evaluate the prognostic role of electrolyte disorders in patients with stage I to III colorectal cancer who received radical surgical resection. DESIGN: This study was retrospectively performed. SETTINGS: The study was conducted at a single tertiary care center. PATIENTS: Patients with colorectal cancer who underwent radical resection in between April 2007 and April 2014 were included. MAIN OUTCOME MEASURES: The Kaplan-Meier method was adopted to estimate the overall and disease-free survival with and without propensity score matching. RESULTS: In total, our study recruited 5089 eligible patients. In prematching analysis, patients with hypochloremia showed both shorter overall survival (HR = 0.943 (95% CI, 0.908-0.980); p = 0.003) and disease-free survival (HR = 0.957 (95% CI, 0.933-0.981); p < 0.001) than those with normal serum chloride levels. In postmatching analysis, 770 patients from each group were compared, and the results further confirmed that hypochloremia was significantly associated with worse overall survival (HR = 0.646 (95% CI, 0.489-0.855); p = 0.002) and disease-free survival (HR = 0.782 (95% CI, 0.647-0.944); p = 0.01), with the hypochloremia group as a reference. LIMITATIONS: The study was limited by its retrospective nature. CONCLUSIONS: Hypochloremia diagnosed before treatment can independently prognosticate the overall and disease-free survival for patients with stage I to Ш colorectal cancer after radical resection. Intensive surveillance and management might improve the survival outcome for patients with hypochloremia. See Video Abstract at http://links.lww.com/DCR/A727.