Risk factors of chylous ascites and its relationship with long-term prognosis in laparoscopic D3 lymphadenectomy for right colon cancer.

BACKGROUND: Chylous ascites (CA) after laparoscopic D3 lymphadenectomy for right colon cancer is not rare. However, the risk factors for CA have not been fully explored. Few studies have investigated the effect of CA on long-term prognosis. METHODS: The clinical data of patients with right colon cancer who underwent laparoscopic D3 lymphadenectomy in five centers from January 2013 to December 2018 were retrospectively collected. Univariate and multivariate analyses were performed to determine the clinicopathological factors associated with CA. Then, the long-term prognosis of patients with and without CA was compared by propensity score matching and Kaplan-Meier survival analysis. RESULTS: The incidence of CA was 4.4% (48/1090). Pathological T stage (p = 0.025), dissection along the left side of the superior mesenteric artery (p < 0.001) and the number of retrieved lymph nodes (p < 0.001) were independent risk factors for CA. After propensity score matching, 48 patients in the CA group and 353 patients in the non-CA group were enrolled. Kaplan-Meier survival analysis indicated that CA was not associated with overall survival (p = 0.454) and disease-free survival (p = 0.163). In patients with stage III right colon cancer, there were no significant differences in overall survival (p = 0.501) and disease-free survival (p = 0.254). CONCLUSIONS: Pathological T stage, number of retrieved lymph nodes, and left side dissection along the superior mesenteric artery were independent risk factors for CA after laparoscopic D3 lymphadenectomy. CA does not impair the oncological outcomes of patients.

Identification of hub genes associated with neutrophils infiltration in colorectal cancer.

Colorectal cancer (CRC) is the leading cause of cancer-related mortality in the world. Accumulating evidence indicate that tumour infiltrating immune cells participated in cancer progression. Among them, tumour infiltrating neutrophils (TINs) are reported to play crucial role in various cancers. In this study, we used CIBERSORTx, a digital cytometry tool to evaluate the neutrophils infiltration in CRC based on gene expression data of CRC tissues from GSE39582 data set and The Cancer Genome Atlas data set (TCGA-COAD and TCGA-READ). Weighted gene co-expression network analysis (WGCNA) was conducted in GSE39582 data set to identify hub genes associated with neutrophil infiltration. The association of hub gene and neutrophils was then validated in TCGA cohorts and an independent RJ cohort. Functional analysis was performed to investigate the molecular mechanisms of the interested hub gene. We found that neutrophil infiltration is elevated in CRC tissues, and it is related to a poorer prognosis. A total of 18 gene modules are identified by WGCNA in GSE39582 data set, among which lightcyan module is significantly correlated with neutrophils infiltration. Furthermore, Superoxide Dismutase 2 (SOD2) in lightcyan module was proved to correlated with neutrophils infiltration in various cancer types. In addition, SOD2 expression is highly associated with several chemokines, including CXCL8, a neutrophils-related attractant, and functional analysis revealed that SOD2 is involved in neutrophils recruitment biological process. These results indicate that an 'SOD2-CXCL8-neutrophil recruitment' axis plays a potential role in colorectal cancer progression.

The Medial Border of Laparoscopic D3 Lymphadenectomy for Right Colon Cancer: Results from an Exploratory Pilot Study.

BACKGROUND: Opinions vary on the medial border of D3 lymphadenectomy for right colon cancer. Most surgeons place the medial border along the left side of the superior mesenteric vein, but some consider the left side of the superior mesenteric artery as the medial border. OBJECTIVES: This study investigated the clinical outcomes of laparoscopic D3 lymphadenectomy for right colon cancer with the medial border along the left side of superior mesenteric artery. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in specialized colorectal cancer department of 5 tertiary hospitals. PATIENTS: Patients receiving laparoscopic D3 lymphadenectomy for right colon cancer from January 2013 to December 2018 were included. MAIN OUTCOME MEASURES: After propensity score matching, 307 patients receiving laparoscopic D3 lymphadenectomy along the left side of the superior mesenteric artery were assigned to the superior mesenteric artery group and 614 patients were assigned to the superior mesenteric vein group. Univariate, multivariate, and Kaplan-Meier analyses were performed to assess the clinical data. RESULTS: The short-term outcomes were similar between the 2 groups; however, the superior mesenteric artery group had a higher rate of chylous leakage (p < 0.001). More lymph nodes were harvested from the superior mesenteric artery group than from the superior mesenteric vein group (p = 0.001). The number (p = 0.005) of metastatic lymph nodes and the lymph node ratio (p = 0.041) in main nodes were both higher in the superior mesenteric artery group. The 2 groups had similar long-term survival, but the superior mesenteric artery group tended to show better disease-free survival in patients with stage disease III (p = 0.056). LIMITATIONS: This was a retrospective, nonrandomized study. CONCLUSION: Laparoscopic D3 lymphadenectomy along the left side of the superior mesenteric artery, except for a higher rate of chylous leakage, had short-term outcomes comparable to the superior mesenteric vein group. The superior mesenteric artery group tended to achieve better disease-free survival in patients with stage III disease, but further study is required to better elucidate differences in these approaches because risks/benefits do exist.

Pelvic peritoneum closure reduces postoperative complications of laparoscopic abdominoperineal resection: 6-year experience in single center.

BACKGROUND: To investigate feasibility of laparoscopic abdominoperineal resection with pelvic peritoneum closure (LAPR-PPC) for lower rectal cancer. METHODS: LAPR-PPC has been used for lower rectal cancer in our institution since 2014. In this study, we retrospectively analyzed the data from 86 patients who underwent LAPR-PPC and compared with the data from 96 patients who underwent laparoscopic APR without PPC (LAPR) from January 2013 to December 2018. RESULTS: The rate of perineal surgical site infection (SSI) (18.75% (18/96) vs. 5.81% (5/86), p < 0.01), delayed (> 4 weeks) perineal healing (12.50% (12/96) vs. 3.49% (3/86), p = 0.027), ileus (7.29% (7/96) vs 1.16% (1/86), p = 0.044), and postoperative perineal hernia (PPH, 5.21% (5/96) vs. 0% (0/86), p = 0.032) were significantly lower in LAPR-PPC group than LAPR group. The patients in LAPR-PPC group had shorter hospitalization time (21.32 ± 11.95 days vs. 13.93 ± 11.51 days, p < 0.01). CONCLUSIONS: PPC procedure enabled the reduction in perineal wound complications, ileus, PPH, and consequently shortened hospitalization time. LAPR-PPC is beneficial for the patients with lower rectal cancer.

Completely medial access by page-turning approach for laparoscopic right hemi-colectomy: 6-year-experience in single center.

BACKGROUND: To investigate the safety and feasibility of the completely medial access by page-turning approach (CMAP) for laparoscopic right hemi-colectomy. METHODS: In this retrospective study, the data from 72 patients who underwent laparoscopic right hemi-colectomy with CMAP were analyzed and compared with data from 124 patients who underwent the conventional medial approach performed by the same surgical team from September 2011 to March 2017. RESULT: Complete mesocolic excision (CME) was achieved in 67 of 72 patients (93.1%) with laparoscopic CMAP. The average operation time, blood loss, and specimen length was 135.9 ± 28.3 min, 63.2 ± 32.2 ml, and 23.9 ± 4.7 cm, respectively. The number of lymph nodes harvested was 20.6 ± 7.7, the time-to-flatus was 2.5 ± 0.8 days, the time-to-fluid intake was 3.2 ± 0.8 days, and the average hospital stay was 8.9 ± 4.7 days. No intra-operative complications occurred in this study. The vessel-related complication and total post-operative complication rate was 2.78% (2/72) and 6.94% (5/72), respectively. CONCLUSIONS: Laparoscopic CMAP was an alternative approach for CME in laparoscopic right hemi-colectomy, which was proved safe and feasible for right colon cancer.

Impact and potential value of immunosenescence on solid gastrointestinal tumors.

Solid gastrointestinal tumors often respond poorly to immunotherapy for the complex tumor microenvironment (TME), which is exacerbated by immune system alterations. Immunosenescence is the process of increased diversification of immune genes due to aging and other factors, leading to a decrease in the recognition function of the immune system. This process involves immune organs, immune cells, and the senescence-associated secretory phenotype (SASP). The most fundamental change is DNA damage, resulting in TME remodeling. The main manifestations are worsening inflammation, increased immunosuppressive SASP production, decreased immune cell antitumor activity, and the accumulation of tumor-associated fibroblasts and myeloid-derived suppressor cells, making antitumor therapy less effective. Senotherapy strategies to remove senescent cells and block key senescence processes can have synergistic effects with other treatments. This review focuses on immunoenescence and its impact on the solid TME. We characterize the immunosenescent TME and discuss future directions for antitumor therapies targeting senescence.

WWP1 inhibition increases SHP2 inhibitor efficacy in colorectal cancer.

Protein tyrosine phosphatase SHP2 activates RAS signaling, which is a novel target for colorectal cancer (CRC) therapy. However, SHP2 inhibitor monotherapy is ineffective for metastatic CRC and a combination therapy is required. In this study, we aimed to improve the antitumor efficacy of SHP2 inhibition and try to explore the resistance mechanism of SHP2 inhibitor. Results showed that WWP1 promoted the proliferation of CRC cells. Genetic or pharmacological inhibition of WWP1 enhanced the effect of SHP2 inhibitor in suppressing tumor growth in vitro and in vivo. WWP1 may mediate feedback reactivation of AKT signaling following SHP2 inhibition. Furthermore, nomogram models constructed with IHC expression of WWP1 and SHP2 greatly improved the accuracy of prognosis prediction for patients with CRC. Our findings indicate that WWP1 inhibitor I3C can synergize with SHP2 inhibitor and is expected to be a new strategy for clinical trials in treating advanced CRC patients.

Spatial transcriptomic revealed intratumor heterogeneity and cancer stem cell enrichment in colorectal cancer metastasis.

Metastasis is the main cause of mortality in colorectal cancer (CRC) patients. Exploring the mechanisms of metastasis is of great importance in both clinical and fundamental CRC research. CRC is a highly heterogeneous disease with variable therapeutic outcomes of treatment. In this study, we applied spatial transcriptomics (ST) to generate a tissue-wide transcriptome from two primary colorectal cancer tissues and their matched liver metastatic tissues. Spatial RNA information showed intratumoral heterogeneity (ITH) of both primary and metastatic tissues. The comparison of gene expressions across tissues revealed an apparent enrichment of cancer stem cells (CSCs) in metastatic tissues and identified FOXD1 as a novel metastatic CSC marker. Trajectory and pseudo-time analyses revealed distinct evolutionary trajectories and a dedifferentiation-differentiation process during metastasis. CellphoneDB analysis suggested a dominant interaction of CD74-MIF with tumor cells in metastatic tissues. Further analysis confirmed FOXD1 as a maker of CSCs and the predictor of patient survival, especially in metastatic diseases. Our study found ITH of primary and metastatic tissues and provides novel insights into the cellular mechanisms underlying liver metastasis of CRC and foundations for therapeutic strategies for CRC metastasis.

Multiregion single cell analysis reveals a novel subtype of cancer-associated fibroblasts located in the hypoxic tumor microenvironment in colorectal cancer.

BACKGROUND: The tumor microenvironment (TME) plays a critical role in shaping tumor progression and determining the outcome of the therapeutic response. In this study, we aimed to generate a comprehensive cellular landscape of the colorectal cancer (CRC) TME. METHODS: We generated a comprehensive single-cell atlas by collecting CRC cases that have been uploaded to the online database and conducting an in-depth secondary analysis. We then carried out spatial transcriptomic sequencing and multiple immunohistochemical analyses to verify the results of the single-cell analysis. Moreover, we applied our findings to the TCGA database and used tissue microarray (TMA) on CRC tissue specimens to validate clinical prognosis. FINDINGS: We re-analyzed the transcriptomes of 23785 cells, revealing a pattern of cell heterogeneity in the tumor region, leading-edge region, and non-tumor region. A subtype of COL11A1+INHBA+ tumor-resident cancer-associated fibroblasts (CAFs) was identified, and marker genes, transcription factors, and tissue-specific expression differences were noted and suggested to have potential roles in promoting cancer. We further confirmed that COL11A1+INHBA+ tumor-resident CAFs are mainly located in the hypoxic TME and we propose that they interact with CD44+ CRC cells via INHBA. Elevation of INHBA in CRC is associated with a poor prognosis. INTERPRETATION: Our results demonstrated a single cell landscape of CRC in different regions and identified in hypoxic TME a special subtype of CAFs producing INHBA, which promotes CRC development and correlates with poor prognosis. This special subtype of CAFs is a candidate target for translational research.

Impaired emotion perception in schizophrenia shows sex differences with channel- and category-specific effects: A pilot study.

Individuals with schizophrenia reportedly demonstrate deficits in emotion perception. Relevant studies on the effects of decoder's sex, communication channels and emotion categories have produced mixed findings and seldom explored the interactions among these three key factors. The present pilot study examined how male and female individuals with schizophrenia and healthy controls perceived emotional (e.g., angry, happy, and sad) and neutral expressions from verbal semantic and nonverbal prosodic and facial channels. Twenty-eight (11 females) individuals with schizophrenia and 30 healthy controls (13 females) were asked to recognize emotional facial expressions, emotional prosody, and emotional semantics. Both accuracy and response time showed subpar performance for all communication channels and emotional categories in the schizophrenia group. More severe emotion perception deficits were found with the nonverbal (not the verbal) materials. There was also a reduced level of impairment with anger perception, especially in the female individuals with schizophrenia while biased perception towards emotional semantics was more pronounced in male individuals with schizophrenia. These findings, although preliminary, indicate the channel- and category-specific nature of emotion perception with potential sex differences among people with schizophrenia, which has important theoretical and practical implications.

Clinicopathological features and prognosis of synchronous and metachronous colorectal cancer: a retrospective cohort study.

BACKGROUND: To investigate the clinicopathological features and prognosis of synchronous and metachronous multiple primary colorectal cancer. MATERIALS AND METHODS: Patients who underwent operation for synchronous and metachronous colorectal cancer at the colorectal surgery department of Shanghai Changhai Hospital between January 2000 and December 2021 were included. Perioperative indicators were comprehensively compared and included in the survival analyses. RESULTS: In total, 563 patients with synchronous ( n =372) and metachronous ( n =191) colorectal cancer were included. Patients with synchronous colorectal cancer were more likely to have a long onset time, positive carcinoembryonic antigen, advanced TNM stage, large tumor, perineural invasion, p53 high expression, and mismatch repair proficient. Compared with metachronous colorectal cancer, patients with synchronous colorectal cancer showed worse 5-year overall survival (68.6±3.0% vs 81.9±3.5%, P =0.018) and 5-year disease-free survival (61.2±3.1% vs 71.0±3.9%, P =0.022). In the subgroup analysis, segmental resection was an independent risk factor for the long-term outcomes of bilateral synchronous colorectal cancer. CONCLUSIONS: Clinicopathological and molecular features were different between synchronous and metachronous colorectal cancer. Patients with synchronous colorectal cancer showed a worse prognosis than those with metachronous colorectal cancer. Bilateral synchronous colorectal cancer requires extended resection to achieve improved long-term outcomes.

Single-cell sequencing technology in colorectal cancer: a new technology to disclose the tumor heterogeneity and target precise treatment.

Colorectal Cancer (CRC) is one of the most common gastrointestinal tumors, and its high tumor heterogeneity makes traditional sequencing methods incapable of obtaining information about the heterogeneity of individual cancer cells in CRC. Therefore, single-cell sequencing technology can be applied to better analyze the differences in genetic and protein information between cells, to obtain genomic sequence information of single cells, and to more thoroughly analyze the cellular characteristics and interactions in the CRC microenvironment. This will provide a more comprehensive understanding of colorectal cancer development and metastasis and indicate the treatment plan and prognosis. In this study, we review the application of single-cell sequencing to analyze the tumor microenvironment of CRC, explore the mechanisms involved in CRC metastasis and progression, and provide a reference for potential treatment options.

DSTN Hypomethylation Promotes Radiotherapy Resistance of Rectal Cancer by Activating the Wnt/ß-Catenin Signaling Pathway.

PURPOSE: Although surgical resection combined with neoadjuvant radiation therapy can reduce the local recurrence rate of rectal cancer, not all patients benefit from neoadjuvant radiation therapy. Therefore, screening for patients with rectal cancer who are sensitive or resistant to radiation therapy has great clinical significance. METHODS AND MATERIALS: Patients with rectal cancer were selected according to postoperative tumor regression grade, and tumor samples were taken for detection. Differential genes between radiation-resistant and radiation-sensitive tissues were screened and validated by Illumina Infinium MethylationEPIC BeadChip, proteomics, Agena MassARRAY methylation, reverse transcription quantitative real-time polymerase chain reaction, and immunohistochemistry. In vitro and in vivo functional experiments verified the role of DSTN. Protein coimmunoprecipitation, western blot, and immunofluorescence were used to investigate the mechanisms of DSTN-related radiation resistance. RESULTS: DSTN was found to be highly expressed (P < .05) and hypomethylated (P < .01) in rectal cancer tissues resistant to neoadjuvant radiation therapy. Follow-up data confirmed that patients with high expression of DSTN in neoadjuvant radiation therapy-resistant rectal cancer tissues had shorter disease-free survival (P < .05). DSTN expression increased after methyltransferase inhibitor inhibition of DNA methylation in colorectal cancer cells (P < .05). In vitro and in vivo experiments showed that knockdown of DSTN promoted the sensitivity of colorectal cancer cells to radiation therapy, and overexpression of DSTN promoted the resistance of colorectal cancer cells to radiation (P < .05). The Wnt/ß-catenin signaling pathway was activated in colorectal cancer cells overexpressing DSTN. ß-catenin was highly expressed in radiation therapy-resistant tissues, and there was a linear correlation between the expression of DSTN and ß-catenin (P < .0001). Further studies showed that DSTN can bind to ß-catenin and increase its stability. CONCLUSIONS: The degree of DNA methylation and the expression level of DSTN can be used as biomarkers to predict the sensitivity of neoadjuvant radiation therapy for rectal cancer. DSTN and ß-catenin are also expected to become a reference for the selection of neoadjuvant radiation therapy.

Optimal examined lymph node number for accurate staging and long-term survival in rectal cancer: a population-based study.

BACKGROUND: Although the recommended minimal examined lymph node (ELN) number in rectal cancer (RC) is 12, this standard remains controversial because of insufficient evidence. We aimed to refine this definition by quantifying the relationship between ELN number, stage migration and long-term survival in RC. METHODS: Data from a Chinese multi-institutional registry (2009-2018) and the Surveillance, Epidemiology, and End Results (SEER) database (2008-2017) on stages I-III resected RC were analysed to determine the relationship between ELN count, stage migration, and overall survival (OS) using multivariable models. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a Locally Weighted Scatterplot Smoothing (LOWESS) smoother, and structural breakpoints were determined using the Chow test. The relationship between ELN and survival was evaluated on a continuous scale using restricted cubic splines (RCS). RESULTS: The distribution of ELN count between the Chinese registry ( n =7694) and SEER database ( n =21 332) was similar. With increasing ELN count, both cohorts exhibited significant proportional increases from node-negative to node-positive disease (SEER, OR, 1.012, P <0.001; Chinese registry, OR, 1.016, P =0.014) and serial improvements in OS (SEER: HR, 0.982; Chinese registry: HR, 0.975; both P <0.001) after controlling for confounders. Cut-point analysis showed an optimal threshold ELN count of 15, which was validated in the two cohorts, with the ability to properly discriminate probabilities of survival. CONCLUSIONS: A higher ELN count is associated with more precise nodal staging and better survival. Our results robustly conclude that 15 ELNs are the optimal cut-off point for evaluating the quality of lymph node examination and stratification of prognosis.

Neoadjuvant chemoradiation therapy combined with immunotherapy for microsatellite stable ultra-low rectal cancer (CHOICE II): study protocol of a multicentre prospective randomised clinical trial.

INTRODUCTION: Neoadjuvant chemoradiotherapy (nCRT) could bring tumour shrinking and downstaging and increase the probability of organ preservation for patients with low rectal cancer. But for ultra-low rectal cancer, there is little possibility for organ preservation. Immunotherapy has been shown to have significant survival benefits in microsatellite instability-high patients but poor response in microsatellite stable (MSS) patients. Studies have demonstrated that radiotherapy and immunotherapy have synergistic effects in cancer treatment. There is no existing evidence about the clinical efficacy of immunotherapy combined with nCRT for patients with MSS ultra-low rectal cancer. METHOD AND ANALYSIS: This trial is an open-labelled multicentre prospective randomised controlled trial (NCT05215379) with two parallel groups and allocation ratio 1:1 (nCRT+immunotherapy vs nCRT group). Eligible participants will be aged 18-75 years, with a desire for anus preservation, confirmed cT1-3aN0-1M0 rectal adenocarcinoma, confirmed MSS type, inferior margin of ≤5 cm from the anal verge. The primary endpoint of this trial is complete clinical response (cCR) rate. Immunotherapy is added after 1 week of chemoradiotherapy for two cycles, and then the patients will be administered two cycles of immunotherapy and CAPOX. The evaluations will be carried out after the completion of the whole neoadjuvant therapy. We expect the programme to improve the cCR rate and the quality of life for patients with ultra-low rectal cancer. ETHICS AND DISSEMINATION: This trial was approved by the Ethics committee of Changhai Hospital and other medical centres (Grant number:CHEC2022-118). The results of this study will provide further insight into the clinical efficacy of immunotherapy in combination with nCRT in patients with MSS ultra-low rectal cancer. TRIAL REGISTRATION NUMBER: NCT05215379.

High expression of phosphorylated focal adhesion kinase predicts a poor prognosis in human colorectal cancer.

Background: Phosphorylated Focal adhesion kinase (FAK) has been reported to be intimately involved in various malignant tumors. The effect of p-FAK on colorectal cancer (CRC) is still disputable. The purpose of this study is to investigate the role of p-FAK in the prognosis of colorectal cancer. Methods: The clinical significance of p-FAK expression in CRC was evaluated by immunohistochemistry in a large cohort, including carcinoma and para-carcinoma tissues from 908 patients, and normal tissues, adenoma, and metastasis tissues. The correlation between p-FAK expression and CRC occurrence was investigated in tumor and other tissues. Factors contributing to prognosis were evaluated using Kaplan-Meier survival analysis and Cox regression model. Results: p-FAK is apparently overexpressed in CRC and metastasis tissues. Compared with low p-FAK expression, patients with high p-FAK expression had shorter overall survival [hazard ratio (HR), 2.200; 95% confidence interval (CI), 1.265-3.452; p < 0.01] and disease-free survival (HR, 2.004; 95% CI 1.262-3.382; p < 0.01) in multivariate Cox analysis after adjusting other prognostic factors. High p-FAK expression was also related to a worse chemotherapeutic response in patients who achieved adjuvant chemotherapy (p < 0.01). Conclusion: Expression level of p-FAK is an independent risk factor and can serve as a prognostic biomarker for CRC. High p-FAK expression predicts an unfavorable prognosis of CRC as well as poor chemotherapeutic response.

Trends of sphincter-preserving surgeries for low lying rectal cancer: A 20-year experience in China.

Background: Over the last 2 decades, patients with low rectal cancer have had better outcomes from improvements in surgical techniques in sphincter preservation. We aimed to quantify the trends in sphincter-preserving surgeries for low rectal cancer over 20 years in a top tertiary hospital in China. Methods: Between 1999 and 2021, a cohort of patients with primary malignant rectal tumor ≤5cm from the anal verge and who received elective surgeries at Changhai Hospital, Shanghai, China, was identified. Data were extracted from electronic medical records. A Joinpoint Regression Model was used to analyze trends in surgical procedures by average annual percentage change (AAPC). Adjusted Cox proportional hazards regression model was used to assess overall survival. Results: Among a total of 4,172 patients during the study period, 3,111 (74.6%) underwent a sphincter-preserving surgery and 1,061 (25.4%) received APR. Sphincter-preserving surgery increased 3.6% per year (95%CI, 2.3-4.9). Low anterior resection was the most performed procedure (86.3%) and maintained a steady trend, while intersphincteric resection increased 49.4% annually (95%CI, 19.5-86.7) after initiation. Laparoscopic techniques increased 15.1% per year (95%CI, 8.4-43.4) after initiation. Sphincter-preserving surgery increased annually for tumors ≤2cm, 2-≤3cm and 3-≤4cm from the anal verge (AAPC 7.1, 4.5-9.8; 4.7, 3.1-6.3; 2.7, 1.7-3.6, respectively). Furthermore, patients with sphincter-preserving surgery had a better overall survival than abdominoperineal resection (APR) patients (adjusted HR 0.78, 95% CI, 0.65-0.93, p=.01). Conclusions: Utilization of sphincter-preserving surgeries increased significantly over the last 20 years. Patients with low rectal cancer who underwent sphincter preservation had better survival than similar patients who underwent APR.

Development and Validation of an 8-Gene Signature to Improve Survival Prediction of Colorectal Cancer.

Background: Most prognostic signatures for colorectal cancer (CRC) are developed to predict overall survival (OS). Gene signatures predicting recurrence-free survival (RFS) are rarely reported, and postoperative recurrence results in a poor outcome. Thus, we aim to construct a robust, individualized gene signature that can predict both OS and RFS of CRC patients. Methods: Prognostic genes that were significantly associated with both OS and RFS in GSE39582 and TCGA cohorts were screened via univariate Cox regression analysis and Venn diagram. These genes were then submitted to least absolute shrinkage and selection operator (LASSO) regression analysis and followed by multivariate Cox regression analysis to obtain an optimal gene signature. Kaplan-Meier (K-M), calibration curves and receiver operating characteristic (ROC) curves were used to evaluate the predictive performance of this signature. A nomogram integrating prognostic factors was constructed to predict 1-, 3-, and 5-year survival probabilities. Function annotation and pathway enrichment analyses were used to elucidate the biological implications of this model. Results: A total of 186 genes significantly associated with both OS and RFS were identified. Based on these genes, LASSO and multivariate Cox regression analyses determined an 8-gene signature that contained ATOH1, CACNB1, CEBPA, EPPHB2, HIST1H2BJ, INHBB, LYPD6, and ZBED3. Signature high-risk cases had worse OS in the GSE39582 training cohort (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.42 to 1.67) and the TCGA validation cohort (HR = 1.39, 95% CI = 1.24 to 1.56) and worse RFS in both cohorts (GSE39582: HR = 1.49, 95% CI = 1.35 to 1.64; TCGA: HR = 1.39, 95% CI = 1.25 to 1.56). The area under the curves (AUCs) of this model in the training and validation cohorts were all around 0.7, which were higher or no less than several previous models, suggesting that this signature could improve OS and RFS prediction of CRC patients. The risk score was related to multiple oncological pathways. CACNB1, HIST1H2BJ, and INHBB were significantly upregulated in CRC tissues. Conclusion: A credible OS and RFS prediction signature with multi-cohort and cross-platform compatibility was constructed in CRC. This signature might facilitate personalized treatment and improve the survival of CRC patients.

PSMC5 Promotes Proliferation and Metastasis of Colorectal Cancer by Activating Epithelial-Mesenchymal Transition Signaling and Modulating Immune Infiltrating Cells.

We designed the present study to access the roles and mechanisms of PSMC5 in colorectal cancer (CRC). Transcriptomic and clinical data from public datasets and our center were retrospectively analyzed. Functional assays were performed to investigate the effects of PSMC5 on CRC cells. The results showed that PSMC5 was significantly higher in cancer than normal tissues. Moreover, patients with higher expression of PSMC5 showed poorer prognosis. Silencing of PSMC5 dramatically suppressed the proliferation and invasion of CRC cells, while overexpression led to the opposite. In addition, we screened downstream targets and found that PSMC5 regulates multiple pathways including epithelial-mesenchymal transition, hypoxia, and immune response. Consistently, we found that PSMC5 was negatively correlated with levels of CD8 + T cells and B cells while promoting infiltration of macrophages and neutrophils. Collectively, these findings suggested that PSMC5 was a promising biomarker and target for immune therapy for CRC.

Machine learning-based random forest predicts anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Anastomotic leakage (AL) is one of the commonest and most serious complications after rectal cancer surgery. The previous analyses on predictors for AL included small-scale patients, and their prediction models performed unsatisfactorily. METHODS: Clinical data of 5,220 patients who underwent anterior resection for rectal cancer were scrutinized to create a prediction model via random forest classifier. Additionally, data of 836 patients served as the test dataset. Patients diagnosed with AL within 6 months' follow-up were recorded. A total of 20 candidate factors were included. Receiver operating characteristic (ROC) curve was conducted to determine the clinical efficacy of our model, and compare the predictive performance of different models. RESULTS: The incidence of AL was 6.2% (326/5,220). A multivariate logistic regression analysis and the random forest classifier indicated that sex, distance of tumor from the anal verge, bowel stenosis or obstruction, preoperative hemoglobin, surgeon volume, diabetes, neoadjuvant chemoradiotherapy, and surgical approach were significantly associated with AL. After propensity score matching, the temporary stoma was not identified as a protective factor for AL (P=0.58). Contrastingly, the first year of performing laparoscopic surgery was a predictor (P=0.009). We created a predictive random forest classifier based on the above predictors that demonstrated satisfactory prediction efficacy. The area under the curve (AUC) showed that the random forest had higher efficiency (AUC =0.87) than the nomogram (AUC =0.724). CONCLUSIONS: Our findings suggest that eight factors may affect the incidence of AL. Our random forest classifier is an innovative and practical model to effectively predict AL, and could provide rational advice on whether to perform a temporary stoma, which might reduce the rate of stoma and avoid the ensuing complications.