Laparoscopic ileocecal-sparing vs traditional right hemicolectomy for cancer of the hepatic flexure or proximal transverse colon: a dual-center propensity score-matched study.

Background: Traditional right hemicolectomy (TRH) is the standard treatment for patients with nonmetastatic right colon cancer. However, the ileocecum, a vital organ with mechanical and immune functions, is removed in these patients regardless of the tumor location. This study aimed to evaluate the technical and oncological safety of laparoscopic ileocecal-sparing right hemicolectomy (LISH). Method: Patients who underwent LISH at two tertiary medical centers were matched 1:2 with patients who underwent TRH by propensity score matching based on sex, age, body mass index, tumor location, and disease stage. Data on surgical and perioperative outcomes were collected. Oncological safety was evaluated in a specimen-oriented manner. Lymph nodes (LNs) near the ileocolic artery (ICA) were examined independently in the LISH group. Disease outcomes were recorded for patients who completed one year of follow-up. Results: In all, 34 patients in the LISH group and 68 patients in the TRH group were matched. LISH added 8 minutes to the dissection of LNs around the ileocolic vessels (groups 201/201d, 202, and 203 LNs), without affecting the total operation time, blood loss, or perioperative adverse event rate. Compared with TRH, LISH had a comparable lymphadenectomy quality, specimen quality, and safety margin while preserving a more functional bowel. The LISH group had no cases of LN metastasis near the ICA. No difference was detected in the recurrence rate at the 1-year follow-up time point between the two groups. Conclusion: In this dual-center study, LISH presented comparable surgical and oncological safety for patients with hepatic flexure or proximal transverse colon cancer.

Hepatic steatosis predicts metachronous liver metastasis in colorectal cancer patients: a nested case-control study and systematic review.

Nearly twenty-five percent of colorectal cancer (CRC) patients develop metachronous colorectal liver metastasis (CRLM) after curative surgery. Hepatosteatosis is the most prevalent liver condition worldwide, but its impact on the incidence of metachronous CRLM is understudied. In the present study, we aimed to investigate the predictive value of hepatic steatosis on the development of metachronous CRLM. First, a nested case-control study was conducted, enrolling stage I to III CRC patients in the National Colorectal Cancer Cohort (NCRCC) database. Metachronous CRLM patients and recurrence-free patients were matched via propensity-score matching. Fatty liver was identified based on treatment-naïve CT scans and the degree of hepatic fibrosis was scored. Multivariable analysis was conducted to investigate the association between fatty liver and metachronous CRLM. In our database, a total of 414 patients were included. Metachronous CRLM patients had considerably higher rates of hepatic steatosis (30.9% versus 15.9%, P<0.001) and highly fibrotic liver (11.6% versus 2.9%, P=0.001) compared to recurrence-free patients. Multivariable analysis showed that fatty liver (odds ratios [OR]=1.99, 95% confidence interval [CI] 1.19-3.30, P=0.008) and fibrotic liver (OR=4.27, 95% CI 1.54-11.81, P=0.005) were associated with high risk of metachronous CRLM. Further, a systematic literature review was performed to assess available evidence on the association between hepatosteatosis and development of metachronous CRLM. In the systematic review, 1815 patients were pooled from eligible studies, and hepatic steatosis remained a significant risk factor for metachronous CRLM (OR=1.90, 95% CI 1.35-2.66, P<0.001, I2=25.3%). In conclusion, our data suggest that patients with a steatotic liver and a high fibrosis score at CRC diagnosis have elevated risk of developing metachronous CRLM.

Circulation immune cell landscape in canonical pathogenesis of colorectal adenocarcinoma by CyTOF analysis.

Current studies on the immune microenvironment of colorectal cancer (CRC) were mostly limited to the tissue level, lacking relevant studies in the peripheral blood, and failed to describe its alterations in the whole process of adenocarcinoma formation, especially of adenoma carcinogenesis. Here, we constructed a large-scale population cohort and used the CyTOF to explore the changes of various immune cell subsets in peripheral blood of CRC. We found monocytes and basophils cells were significantly higher in adenocarcinoma patients. Compared with early-stage CRC, effector CD4+T cells and naive B cells were higher in patients with lymph node metastasis, whereas the basophils were lower. We also performed random forest algorithm and found monocytes play the key role in carcinogenesis. Our study draws a peripheral blood immune cell landscape of the occurrence and development of CRC at the single-cell level and provides a reference for other researchers.

Screening, Construction, and Preliminary Evaluation of CLDN18.2-Specific Peptides for Noninvasive Molecular Imaging.

Recent global clinical trials have shown that CLDN18.2 is an ideal target for the treatment of gastric cancer and that patients with high CLDN18.2 expression can benefit from targeted therapy. Therefore, accurate and comprehensive detection of CLDN18.2 expression is important for patient screening and guidance in anti-CLDN18.2 therapy. Phage display technology was used to screen CLDN18.2-specific peptides from 100 billion libraries. 293TCLDN18.1 cells were used to exclude nonspecific binding and CLDN18.1 binding sequences, while 293TCLDN18.2 cells were used to screen CLDN18.2-specific binding peptides. The monoclonal clones obtained from phage screening were sequenced, and peptides were synthesized based on the sequencing results. Binding specificity and affinity were assessed with a fluorescein isothiocyanate (FITC)-conjugated peptide. A 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated peptide was also synthesized for 68Ga radiolabeling. The in vitro and in vivo stability, partition coefficients, in vivo molecular imaging, and biodistribution were also characterized. Overall, 54 monoclonal clones were selected after phage display screening. Subsequently, based on the cell ELISA results, CLDN18.2 preference monoclonal clones were selected for deoxyribonucleic acid (DNA) sequencing, and four 7-peptide sequences were obtained after sequence comparison; among them, a peptide named T37 was further validated in vitro and in vivo. The T37 peptide specifically recognized CLDN18.2 but not CLDN18.1 and bound strongly to CLDN18.2-positive cell membranes. The 68Ga-DOTA-T37 probe exhibits good in vitro properties and high stability as a hydrophilic probe; it has high biological safety, and positron emission tomography/computed tomography (PET/CT) studies have shown that it can specifically target CLDN18.2 protein and CLDN18.2-positive tumors in mice. 68Ga-DOTA-T37 demonstrated the superiority and feasibility of using a CLDN18.2-specific probe in PCT/CT imaging, which deserves further development and exploitation.

KIF15 knockdown inhibits colorectal cancer proliferation and migration through affecting the ubiquitination modification of NRAS.

As one of the most common malignancies, colorectal cancer (CRC) requires a thorough understanding of the mechanisms that promote its development and the discovery of new therapeutic targets. In this study, immunohistochemical staining confirmed significantly higher expression levels of KIF15 in CRC. qPCR and western blot results demonstrated the effective suppression of KIF15 mRNA and protein expression by shKIF15. Downregulation of KIF15 inhibited the proliferation and migration of CRC cells while promoting apoptosis. In addition, evidence from the xenograft experiments in nude mice demonstrated that KIF15 knockdown also suppressed tumor growth. Through bioinformatics analysis, the downstream molecular NRAS and Rac signaling pathway associated with KIF15 were identified. KIF15 knockdown was found to inhibit NRAS expression and disrupt Rac signaling pathway. Moreover, WB and Co-IP assays revealed that KIF15 reduced the ubiquitination modification of NRAS protein by interacting with the E3 ligase MDM2, thereby enhancing NRAS protein stability. Functionally, NRAS knockdown was shown to inhibit cell proliferation and migration. In conclusion, KIF15 promoted CRC progression by regulating NRAS expression and Rac signaling pathway.

Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

Single-cell characteristics and malignancy regulation of alpha-fetoprotein-producing gastric cancer.

OBJECTIVE: To characterize alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) at the single-cell level and to identify regulatory factors for AFP expression and malignancy. METHODS: ScRNA-seq was performed on two tumors collected from patients with AFPGC. InferCNV and sub-clustering were applied to identify typical AFPGC cells, followed by AddModuleScore, pathway enrichment, Pseudo-time, and Scenic analyses. Data from a gastric cancer (GC) cohort were collected for conjoint analysis. The analytical results were verified by cell experiments and immunohistochemistry. RESULTS: AFPGC cells are similar to hepatocytes in transcriptome and transcriptional regulation, with kinetic malignancy-related pathways, compared to the common malignant epithelium. In addition, compared to common GC cells, malignancy-related pathways, such as epithelial-mesenchymal transition (EMT) and angiogenesis, were upregulated in AFPGC. Mechanistically, Dickkopf-1 (DKK1) was found to be associated with AFP expression and malignant phenotype upon combining our scRNA-seq data with a public database, which was further verified by a series of in vitro experiments and immunohistochemistry. CONCLUSION: We demonstrated the single-cell characteristics of AFPGC and that DKK1 facilitates AFP expression and malignancy.

Hepatoid adenocarcinoma-Clinicopathological features and molecular characteristics.

Hepatoid adenocarcinoma (HAC) is a rare, malignant, extrahepatic tumor with histologic features similar to those of hepatocellular carcinoma. HAC is most often associated with elevated alpha-fetoprotein (AFP). HAC can occur in multiple organs, including the stomach, esophagus, colon, pancreas, lungs, and ovaries. HAC differs greatly from typical adenocarcinoma in terms of its biological aggression, poor prognosis, and clinicopathological characteristics. However, the mechanisms underlying its development and invasive metastasis remain unclear. The purpose of this review was to summarize the clinicopathological features, molecular traits, and molecular mechanisms driving the malignant phenotype of HAC, in order to support the clinical diagnosis and treatment of HAC.

The Contribution of Genetic Risk and Lifestyle Factors in the Development of Adult-Onset Inflammatory Bowel Disease: A Prospective Cohort Study.

INTRODUCTION: The joint associations across genetic risk, modifiable lifestyle factors, and inflammatory bowel disease (IBD) remains unclear. METHODS: Genetic susceptibility to Crohn's disease (CD) and ulcerative colitis (UC) was estimated by polygenic risk scores and further categorized into high, intermediate, and low genetic risk categories. Weighted healthy lifestyle scores were constructed based on 5 common lifestyle factors and categorized into favorable (4 or 5 healthy lifestyle factors), intermediate (3 healthy lifestyle factors), and unfavorable (0-2 healthy lifestyle factors) groups. Cox proportional hazards regression model was used to estimate the hazard ratios (HR) and 95% confidence interval (CI) for their associations. RESULTS: During the 12-year follow-up, 707 cases with CD and 1576 cases with UC were diagnosed in the UK Biobank cohort. Genetic risk and unhealthy lifestyle categories were monotonically associated with CD and UC risk with no multiplicative interaction between them. The HR of CD and UC were 2.24 (95% CI 1.75-2.86) and 2.15 (95% CI 1.82-2.53) for those with a high genetic risk, respectively. The HR of CD and UC for individuals with an unfavorable lifestyle were 1.94 (95% CI 1.61-2.33) and 1.98 (95% CI 1.73-2.27), respectively. The HR of individuals with a high genetic risk but a favorable lifestyle (2.33, 95% CI 1.58-3.44 for CD, and 2.05, 95% CI 1.58-2.66 for UC) were reduced nearly by half, compared with those with a high genetic risk but an unfavorable lifestyle (4.40, 95% CI 2.91-6.66 for CD and 4.44, 95% CI 3.34-5.91 for UC). DISCUSSION: Genetic and lifestyle factors were independently associated with susceptibility to incident CD and UC. Adherence to a favorable lifestyle was associated with a nearly 50% lower risk of CD and UC among participants at a high genetic risk.

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis.

BACKGROUND: Obg-like ATPase 1 (OLA1) is a highly conserved GTPase, which was over expressed in a variety of malignant tumors, but its role in colorectal cancer (CRC) was poorly studied. PATIENTS AND METHODS: Three public CRC gene databases were applied for OLA1 mRNA expression detection. The clinical data of 111 CRC patients were retrospectively collected from the Second Affiliated Hospital of Zhejiang University (SAHZU) for OLA1 protein expression and Kaplan-Meier Survival analysis. OLA1 stably knocked out CRC cell lines were conducted by CRISPR-Cas9 for experiments in vitro and in vivo. RESULTS: OLA1 was highly expressed in 84% CRC compared to matched surrounding tissues. Patients with OLA1 high expression had a significantly lower 5-year survival rate (47%) than those with OLA1 low expression (75%). OLA1 high expression was an independent factor of poor prognosis in CRC patients. OLA1-KO CRC cell lines showed lower ability of growth and tumorigenesis in vitro and in vivo. By mRNA sequence analysis, we found 113 differential express genes in OLA1-KO cell lines, of which 63 were hypoxic related. HIF1α was a key molecule in hypoxic regulation. Further molecular mechanisms showed HIF1α /CA9 mRNA and/or protein levels were heavily downregulated in OLA1-KO cell lines, which could explain the impaired tumorigenesis. According to previous studies, HIF1α was a downstream gene of GSK3ß, we verified GSK3ß was over-activated in OLA1-KO cell lines. CONCLUSION: OLA1 was a new gene that was associated with carcinogenesis and poor outcomes in CRC by activation of HIF1α/CA9 axis, which may be interpreted by GSK3ß.

Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells.

Tumor-infiltrating myeloid cells (TIMs) are crucial cell populations involved in tumor immune escape, and their functions are regulated by multiple epigenetic mechanisms. The precise regulation mode of RNA N6-methyladenosine (m6A) modification in controlling TIM function is still poorly understood. Our study revealed that the increased expression of methyltransferase-like 3 (METTL3) in TIMs was correlated with the poor prognosis of colon cancer patients, and myeloid deficiency of METTL3 attenuated tumor growth in mice. METTL3 mediated m6A modification on Jak1 mRNA in TIMs, the m6A-YTHDF1 axis enhanced JAK1 protein translation efficiency and subsequent phosphorylation of STAT3. Lactate accumulated in tumor microenvironment potently induced METTL3 upregulation in TIMs via H3K18 lactylation. Interestingly, we identified two lactylation modification sites in the zinc-finger domain of METTL3, which was essential for METTL3 to capture target RNA. Our results emphasize the importance of lactylation-driven METTL3-mediated RNA m6A modification for promoting the immunosuppressive capacity of TIMs.

Long-term risk of colorectal cancer after removal of adenomas during screening colonoscopies in a large community-based population in China.

Patients with conventional adenoma removal are recommended to undergo colonoscopy surveillance to prevent colorectal cancer (CRC). However, evidence supporting the guidelines of colonoscopy surveillance is limited, especially among the Chinese population. We investigated the association between colonoscopy adenoma findings and CRC risk among individuals aged 40 to 74 years who underwent baseline colonoscopy from 2007 to 2016 in Jiashan and Haining, Zhejiang, China; 34 382 participants were categorized into advanced adenoma, nonadvanced adenoma and no adenoma based on adenoma findings. A multivariable Cox regression model was used to estimate the hazard ratio (HR) of CRC incidence with adjustment for potential confounding factors. After a median follow-up time of 7.7 years, 113 incident cases of CRC were identified (18 occurred in 1632 participants with advanced adenoma, 16 in 3973 participants with nonadvanced adenoma and 79 in 28 777 participants with no adenoma). Compared to no adenoma group, the adjusted HR for CRC in advanced adenoma group was 4.01 (95% CI, 2.37-6.77). For nonadvanced adenomas, individuals with ≥3 adenomas showed an increased risk of CRC (HR, 3.65; 95% CI, 1.43-9.31), but no significantly increased risk of CRC was found for 1 to 2 nonadvanced adenomas, compared to those with no adenoma. Our study suggested that the risk of subsequent CRC increased in individuals with high-risk adenoma (at least one advanced adenoma or ≥3 nonadvanced adenomas), but not in those with 1 to 2 nonadvanced adenomas. These results provide the first evidence from the Chinese population for the current surveillance guidelines.

Cohort profile: The National Colorectal Cancer Cohort (NCRCC) study in China.

PURPOSE: The National Colorectal Cancer Cohort (NCRCC) study aims to specifically assess risk factors and biomarkers related to endpoints across the colorectal cancer continuum from the aetiology through survivorship. PARTICIPANTS: The NCRCC study includes the Colorectal Cancer Screening Cohort (CRCSC), which recruited individuals who were at high risk of CRC between 2016 and 2020 and Colorectal Cancer Patients Cohort (CRCPC), which recruited newly diagnosed patients with CRC between 2015 and 2020. Data collection was based on questionnaires and abstraction from electronic medical record. Items included demographic and lifestyle factors, clinical information, survivorship endpoints and other information. Multiple biospecimens including blood, tissue and urine samples were collected. Participants in CRCSC were followed by a combination of periodic survey every 5 years and annual linkage with regional or national cancer and death registries for at least 10 years. In CRCPC, follow-up was conducted with both active and passive approaches at 6, 12, 18, 24, 36, 48 and 60 months after surgery. FINDINGS TO DATE: A total of 19 377 participants and 15 551 patients with CRC were recruited in CRCSC and in CRCPC, respectively. In CRCSC, 48.0% were men, and the average age of participants at enrolment was 58.7±8.3 years. In CRCPC, 61.4% were men, and the average age was 60.3±12.3 years with 18.9% of participants under 50 years of age. FUTURE PLANS: Longitudinal data and biospecimens will continue to be collected. Based on the cohorts, several studies to assess risk factors and biomarkers for CRC or its survivorship will be conducted, ultimately providing research evidence from Chinese population and optimising evidence-based guidelines across the CRC continuum.

The Disulfiram/Copper Complex Induces Autophagic Cell Death in Colorectal Cancer by Targeting ULK1.

Colorectal cancer (CRC) is highly prevalent worldwide, but there has been limited development of efficient and affordable treatment. Induced autophagy has recently been recognized as a novel therapeutic strategy in cancer treatment, and disulfiram (DSF), a well-known antialcohol drug, is also found to inhibit tumor growth in various malignancies. Recently, DSF has been reported to induce excessive autophagy in oral squamous cells; however, little is known about whether it can induce autophagy and suppress proliferation in CRC. In this study, we investigate the effect of DSF with copper (DSF/Cu) on CRC both in vitro and in vivo and find that the combination significantly inhibits CRC cell viability and mainly induces autophagy instead of apoptosis. Furthermore, we use whole genome CRISPR library screening and identify a new mechanism by which DSF triggers autophagy by ULK1. Overall, these findings provide a potential CRC treatment.

Efficacy of rigosertib, a small molecular RAS signaling disrupter for the treatment of KRAS-mutant colorectal cancer.

OBJECTIVE: Mutant KRAS, the principal isoform of RAS, plays a pivotal role in the oncogenesis of colorectal cancer by constitutively activating the RAF/MEK/ERK and PI3K/AKT pathways. Effective targeted therapies are urgently needed. We investigated whether rigosertib, a benzyl styryl sulfone RAS signaling disruptor, could selectively kill KRAS-mutant colorectal cancer cells. METHODS: CCK-8 was used to determine the cell viability. Patient-derived tumor and cancer cell xenograft models were used to detect the inhibitory efficacy of rigosertib. Flow cytometry was used to evaluate the apoptosis and cell cycle progression. Apoptosis and cell cycle arrest markers were detected by Western blot. DCFH-DA was used to determine the reactive oxygen species. Immunohistochemistry staining and Western blot were performed to characterize RAS signaling markers in colorectal cancer tissues and cells. RESULTS: Rigosertib (RGS) exhibited a cytotoxic effect against colorectal cancer cells, which was greater in KRAS-mutant cells. Furthermore, RGS induced mitotic arrest and oxidative stress-dependent apoptosis in KRAS-mutant DLD1 and HCT116 cells. Besides, RGS disrupted RAS signaling, and the inhibition of RAS/MEK/ERK was independent of cellular oxidative stress. Using patient-derived xenograft models, the response and tumor inhibition of RGS were significantly higher in the KRAS-mutant subgroup, while p-MEK, p-ERK, and p-AKT levels of RGS-treated tumors were significantly decreased. Finally, in a KRAS-mutant, chemotherapy-resistant patient-derived xenograft model, RGS showed a stronger therapeutic effect than the combination standard therapy involving fluoropyrimidine + oxaliplatin/irinotecan + bevacizumab. CONCLUSIONS: These data showed that targeting RAS signaling using RGS could be a therapeutic treatment for KRAS-mutant colorectal cancer patients.

A predictive model for early recurrence of colorectal-cancer liver metastases based on clinical parameters.

BACKGROUND: The prognosis for patients with colorectal-cancer liver metastases (CRLM) after curative surgery remains poor and shows great heterogeneity. Early recurrence, defined as tumor recurrence within 6 months of curative surgery, is associated with poor survival, requiring earlier detection and intervention. This study aimed to develop and validate a bedside model based on clinical parameters to predict early recurrence in CRLM patients and provide insight into post-operative surveillance strategies. MATERIAL AND METHODS: A total of 202 consecutive CRLM patients undergoing curative surgeries between 2012 and 2019 were retrospectively enrolled and randomly assigned to the training (n = 150) and validation (n = 52) sets. Baseline information and radiological, pathological, and laboratory findings were extracted from medical records. Predictive factors for early recurrence were identified via a multivariate logistic-regression model to develop a predictive nomogram, which was validated for discrimination, calibration, and clinical application. RESULTS: Liver-metastases number, lymph-node suspicion, neurovascular invasion, colon/rectum location, albumin and post-operative carcinoembryonic antigen, and carbohydrate antigen 19-9 levels (CA19-9) were independent predictive factors and were used to construct the nomogram for early recurrence after curative surgery. The area under the curve was 0.866 and 0.792 for internal and external validation, respectively. The model significantly outperformed the clinical risk score and Beppu's model in our data set. In the lift curve, the nomogram boosted the detection rate in post-operative surveillance by two-fold in the top 30% high-risk patients. CONCLUSION: Our model for early recurrence in CRLM patients after curative surgeries showed superior performance and could aid in the decision-making for selective follow-up strategies.

The Clinicopathological Characteristics of Alpha-Fetoprotein-Producing Adenocarcinoma of the Gastrointestinal Tract-A Single-Center Retrospective Study.

Alpha-fetoprotein (AFP)-producing adenocarcinoma from the gastrointestinal tract (APA-GI) is a rare type of highly malignant tumor with a poor prognosis. It may originate from any site along the GI tract with similar clinicopathological characteristics. As limited research had ever described the characteristics of APA-GI, the present article intends to systemically investigate the clinicopathological characteristics of APA-GI from a single center's retrospective study to deepen the understanding of the disease. A total of 177 patients pathologically diagnosed with APA-GI between 2010 and 2017 at the Second Affiliated Hospital of Zhejiang University, School of Medicine, were included. Also, clinical data of 419 gastric cancers and 609 colorectal cancers from The Cancer Genome Atlas database were also extracted. Clinical information of patients from Second Affiliated Hospital of Zhejiang University, School of Medicine, was collected, and a median follow-up of 14.5 months was performed to investigate clinical characteristics of APA-GI. For the pathological characteristics of APA-GI, hematoxylin-eosin sections were reviewed, and immunohistochemistry of AFP was performed. The results showed that the primary tumor could develop through the whole GI tract, including the esophagus (0.6%), stomach (83.1%), duodenum (1.1%), ileum (0.6%), appendix (0.6%), colon (5.1%), and rectum (7.9%). Hepatoid adenocarcinoma is the main pathological feature of APA-GI. AFP expression level in tumor tissue was not strictly associated with serum AFP or hepatoid differentiation. The prognosis of APA-GI was worse than that of common adenocarcinoma of the GI tract and liver metastasis, and high AFP levels suggest poor prognosis in patients with APA-GI. Therefore, the present study was the first research to systemically explore the clinicopathological characteristics of APA-GI. APA-GI occurs through the whole GI tract with a significantly worse prognosis than common adenocarcinoma of GI. APA-GI should be regarded as one kind of disease for its similar clinicopathological characteristics within patients.

Prognostic Risk Model of Immune-Related Genes in Colorectal Cancer.

PURPOSE: We focused on immune-related genes (IRGs) derived from transcriptomic studies, which had the potential to stratify patients' prognosis and to establish a risk assessment model in colorectal cancer. SUMMARY: This article examined our understanding of the molecular pathways associated with intratumoral immune response, which represented a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of colorectal cancer. More and more evidence shows that IRGs play an important role in tumors. We have used data analysis to screen and identify immune-related molecular biomarkers of colon cancer. We selected 18 immune-related prognostic genes and established models to assess prognostic risks of patients, which can provide recommendations for clinical treatment and follow-up. Colorectal cancer (CRC) is a leading cause of cancer-related death in human. Several studies have investigated whether IRGs and tumor immune microenvironment (TIME) could be indicators of CRC prognoses. This study aimed to develop an improved prognostic signature for CRC based on IRGs to predict overall survival (OS) and provide new therapeutic targets for CRC treatment. Based on the screened IRGs, the Cox regression model was used to build a prediction model based on 18-IRG signature. Cox regression analysis revealed that the 18-IRG signature was an independent prognostic factor for OS in CRC patients. Then, we used the TIMER online database to explore the relationship between the risk scoring model and the infiltration of immune cells, and the results showed that the risk model can reflect the state of TIME to a certain extent. In short, an 18-IRG prognostic signature for predicting CRC patients' survival was firmly established.

Identifying Stage II Colorectal Cancer Recurrence Associated Genes by Microarray Meta-Analysis and Building Predictive Models with Machine Learning Algorithms.

BACKGROUND: Stage II colorectal cancer patients had heterogeneous prognosis, and patients with recurrent events had poor survival. In this study, we aimed to identify stage II colorectal cancer recurrence associated genes by microarray meta-analysis and build predictive models to stratify patients' recurrence-free survival. METHODS: We searched the GEO database to retrieve eligible microarray datasets. The microarray meta-analysis was used to identify universal recurrence associated genes. Total samples were randomly divided into the training set and the test set. Two survival models (lasso Cox model and random survival forest model) were trained in the training set, and AUC values of the time-dependent receiver operating characteristic (ROC) curves were calculated. Survival analysis was performed to determine whether there was significant difference between the predicted high and low risk groups in the test set. RESULTS: Six datasets containing 651 stage II colorectal cancer patients were included in this study. The microarray meta-analysis identified 479 recurrence associated genes. KEGG and GO enrichment analysis showed that G protein-coupled glutamate receptor binding and Hedgehog signaling were significantly enriched. AUC values of the lasso Cox model and the random survival forest model were 0.815 and 0.993 at 60 months, respectively. In addition, the random survival forest model demonstrated that the effects of gene expression on the recurrence-free survival probability were nonlinear. According to the risk scores computed by the random survival forest model, the high risk group had significantly higher recurrence risk than the low risk group (HR = 1.824, 95% CI: 1.079-3.084, p = 0.025). CONCLUSIONS: We identified 479 stage II colorectal cancer recurrence associated genes by microarray meta-analysis. The random survival forest model which was based on the recurrence associated gene signature could strongly predict the recurrence risk of stage II colorectal cancer patients.