Prognostic stratification of patients with pT4bN0M0 colorectal cancer following multivisceral resection: a multi-institutional case series analysis.

BACKGROUND: Colorectal cancer (CRC) patients with stage pT4b are a complex group as they show differences in tumor-infiltrated organs. Patients with the same stage often exhibit differences in prognosis after multivisceral resection (MVR). Thus far, some important prognostic factors have not been thoroughly investigated. Here, we identified the prognostic factors influencing CRC patients at pT4bN0M0 stage to better stratify the prognostic differences among patients. MATERIALS AND METHODS: A retrospective analysis was conducted on patients diagnosed to have locally advanced CRC and who underwent MVR at three medical institutions from January 2010 to December 2021. The prognostic factors affecting the survival of CRC patients at pT4bN0M0 stage were identified by multivariate Cox proportional hazard models. We then classified the prognosis into different grades on the basis of these independent prognostic factors. RESULTS: We enrolled 690 patients with locally advanced CRC who underwent MVR; of these, 172 patients with pT4bN0M0 were finally included. Patients with digestive system (OS: hazard ratio [HR]=0.441; 95% confidence interval [CI]=0.217-0.900; P=0.024; DFS: HR=0.416; 95% CI=0.218-0.796; P=0.008) or genitourinary system invasion (OS: HR=0.405; 95% CI=0.193-0.851; P=0.017; DFS: HR=0.505; 95% CI=0.267-0.954; P=0.035) exhibited significantly better overall survival (OS) and disease-free survival (DFS) as compared to those with gynecological system invasion, while the OS and DFS were similar between the diggestive system and genitourinary system invasion groups (OS: HR=0.941; 95% CI=0.434-2.042; P=0.878; DFS: HR=1.211; 95% CI=0.611-2.403; P=0.583). Multivariate analysis showed that age (OS: HR=2.121; 95% CI=1.157-3.886; P=0.015; DFS: HR=1.869; 95% CI=1.116-3.131; P=0.017) and type of organs invaded by CRC (OS: HR=3.107; 95% CI=1.121-8.609; P=0.029; DFS: HR=2.827; 95% CI=1.142-6.997; P=0.025) were the independent prognostic factors that influenced the overall survival (OS) and disease-free survival (DFS) of CRC patients with pT4bN0M0 disease. The OS and DFS of patients showing invasion of the gynecological system group were significantly worse (P=0.004 and P=0.003, respectively) than those of patients with invasion of non-gynecological system group. On the basis of the above-mentioned two independent prognostic factors, patients were assigned to high-, medium-, and low-risk groups. Subgroup analysis showed that the OS and DFS of the medium- and high-risk groups were significantly worse (P=0.001 and P=0.001, respectively) than those of the low-risk group. CONCLUSION: Patients with pT4bN0M0 CRC show significant differences in their prognosis. The type of organs invaded by CRC is a valuable indicator for prognostic stratification of CRC patients with pT4bN0M0.

Comparison of short- and long-term outcomes between laparoscopic and open multivisceral resection for clinical T4b colorectal cancer: A multicentre retrospective cohort study in China.

BACKGROUND: Laparoscopic surgery is controversial for patients with clinical T4b colorectal cancer (CRC) who require multivisceral resection (MVR). This study aims to explore and compare the safety and long-term oncological outcomes of laparoscopic surgery and open surgery for patients with clinical T4b CRC. MATERIALS AND METHODS: This study was a retrospective cohort study based on a multicentre database. According to the operation method, the patients were divided into a laparoscopic MVR group and an open MVR group. The short-term and long-term outcomes were compared. RESULTS: From January 2010 to December 2021, a total of 289 patients in the laparoscopic MVR group and 349 patients in the open MVR group were included. After propensity score matching, patients were stratified into a laparoscopic MVR group (n = 163) and an open MVR group (n = 163). Compared with the open MVR group, the laparoscopic MVR group had less blood loss (100 vs. 200, p < 0.001), a shorter time to first flatus (3 vs. 4, P < 0.001), a shorter postoperative hospital stay (10 vs. 12, P < 0.001), and a lower incidence of surgical site infection (2.5 % vs. 8.0 %, P = 0.043). The Kaplan-Meier curves showed that the two groups had similar overall survival (P = 0.283) and disease-free survival (P = 0.152). CONCLUSION: Compared with open MVR, laparoscopic MVR had less blood loss, fewer surgical site infection complications, faster recovery and a shorter hospital stay. The long-term survival outcome of laparoscopic MVR was not inferior to that of open MVR.

PFKP is a prospective prognostic, diagnostic, immunological and drug sensitivity predictor across pan-cancer.

Phosphofructokinase, platelet (PFKP) is a rate-limiting enzyme of glycolysis that plays a decisive role in various human physio-pathological processes. PFKP has been reported to have multiple functions in different cancer types, including lung cancer and breast cancer. However, no systematic pancancer analysis of PFKP has been performed; this type of analysis could elucidate the clinical value of PFKP in terms of diagnosis, prognosis, drug sensitivity, and immunological correlation. Systematic bioinformation analysis of PFKP was performed based on several public datasets, including The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Genotype-Tissue Expression Project (GTEx), and Human Protein Atlas (HPA). Prospective carcinogenesis of PFKP across cancers was estimated by expression analysis, effect on patient prognosis, diagnosis significance evaluation, and immunity regulation estimation. Then, pancancer functional enrichment of PFKP was also assessed through its effect on the signaling score and gene expression profile. Finally, upstream expression regulation of PFKP was explored by promoter DNA methylation and transcription factor (TF) prediction. Our analysis revealed that high expression of PFKP was found in most cancer types. Additionally, a high level of PFKP displayed a significant correlation with poor prognosis in patients across cancers. The diagnostic value of PFKP was performed based on its positive correlation with programmed cell death-ligand 1 (PD-L1). We also found an obvious immune-regulating effect of PFKP in most cancer types. PFKP also had a strong negative correlation with several cancer drugs. Finally, ectopic expression of PFKP may depend on DNA methylation and several predicated transcription factors, including the KLF (KLF transcription factor) and Sp (Sp transcription factor) families. This pancancer analysis revealed that a high expression level of PFKP might be a useful biomarker and predictor in most cancer types. Additionally, the performance of PFKP across cancers also suggested its meaningful role in cancer immunity regulation, even in immunotherapy and drug resistance. Overall, PFKP might be explored as an auxiliary monitor for pancancer early prognosis and diagnosis.

Short- and long-term results of open vs laparoscopic multisegmental resection and anastomosis for synchronous colorectal cancer located in separate segments.

BACKGROUND: It remains unclear whether laparoscopic multisegmental resection and anastomosis (LMRA) is safe and advantageous over traditional open multisegmental resection and anastomosis (OMRA) for treating synchronous colorectal cancer (SCRC) located in separate segments. AIM: To compare the short-term efficacy and long-term prognosis of OMRA as well as LMRA for SCRC located in separate segments. METHODS: Patients with SCRC who underwent surgery between January 2010 and December 2021 at the Cancer Hospital, Chinese Academy of Medical Sciences and the Peking University First Hospital were retrospectively recruited. In accordance with the inclusion and exclusion criteria, 109 patients who received right hemicolectomy together with anterior resection of the rectum or right hemicolectomy and sigmoid colectomy were finally included in the study. Patients were divided into the LMRA and OMRA groups (n = 68 and 41, respectively) according to the surgical method used. The groups were compared regarding the surgical procedure's short-term efficacy and its effect on long-term patient survival. RESULTS: LMRA patients showed markedly less intraoperative blood loss than OMRA patients (100 vs 200 mL, P = 0.006). Compared to OMRA patients, LMRA patients exhibited markedly shorter postoperative first exhaust time (2 vs 3 d, P = 0.001), postoperative first fluid intake time (3 vs 4 d, P = 0.012), and postoperative hospital stay (9 vs 12 d, P = 0.002). The incidence of total postoperative complications (Clavien-Dindo grade: ≥ II) was 2.9% and 17.1% (P = 0.025) in the LMRA and OMRA groups, respectively, while the incidence of anastomotic leakage was 2.9% and 7.3% (P = 0.558) in the LMRA and OMRA groups, respectively. Furthermore, the LMRA group had a higher mean number of lymph nodes dissected than the OMRA group (45.2 vs 37.3, P = 0.020). The 5-year overall survival (OS) and disease-free survival (DFS) rates in OMRA patients were 82.9% and 78.3%, respectively, while these rates in LMRA patients were 78.2% and 72.8%, respectively. Multivariate prognostic analysis revealed that N stage [OS: HR hazard ratio (HR) = 10.161, P = 0.026; DFS: HR = 13.017, P = 0.013], but not the surgical method (LMRA/OMRA) (OS: HR = 0.834, P = 0.749; DFS: HR = 0.812, P = 0.712), was the independent influencing factor in the OS and DFS of patients with SCRC. CONCLUSION: LMRA is safe and feasible for patients with SCRC located in separate segments. Compared to OMRA, the LMRA approach has more advantages related to short-term efficacy.

Persistent descending mesocolon as a vital risk factor for anastomotic failure and prolonged operative time for sigmoid colon and rectal cancers.

BACKGROUND: The diagnostic criteria and effect of persistent descending mesocolon (PDM) on sigmoid and rectal cancers (SRCs) remain controversial. This study aims to clarify PDM patients' radiological features and short-term surgical results. METHOD: From January 2020 to December 2021, radiological imaging data from 845 consecutive patients were retrospectively analyzed using multiplanar reconstruction (MRP) and maximum intensity projection (MIP). PDM is defined as the condition wherein the right margin of the descending colon is located medially to the left renal hilum. Propensity score matching (PSM) was used to minimize database bias. The anatomical features and surgical results of PDM patients were compared with those of non-PDM patients. RESULTS: Thirty-two patients with PDM and 813 patients with non-PDM were enrolled into the study who underwent laparoscopic resection. After 1:4 matching, patients were stratified into PDM (n = 27) and non-PDM (n = 105) groups. The lengths from the inferior mesenteric artery (IMA) to the inferior mesenteric vein (1.6 cm vs. 2.5 cm, p = 0.001), IMA to marginal artery arch (2.7 cm vs. 8.4 cm, p = 0.001), and IMA to the colon (3.3 cm vs. 10.2 cm, p = 0.001) were significantly shorter in the PDM group than those in the non-PDM group. The conversion to open surgery (11.1% vs. 0.9%, p = 0.008), operative time (210 min vs. 163 min, p = 0.001), intraoperative blood loss (50 ml vs. 30 ml, p = 0.002), marginal arch injury (14.8% vs. 0.9%, p = 0.006), splenic flexure free (22.2% vs. 3.8%, p = 0.005), Hartmann procedure (18.5% vs. 0.0%, p < 0.001) and anastomosis failure (18.5% vs. 0.9%, p = 0.001) were significantly higher in the PDM group. Moreover, PDM was an independent risk factor for prolonged operative time (OR = 3.205, p = 0.004) and anastomotic failure (OR = 7.601, p = 0.003). CONCLUSION: PDM was an independent risk factor for prolonged operative time and anastomotic failure in SRCs surgery. Preoperative radiological evaluation using MRP and MIP can help surgeons better handle this rare congenital variant.

Laparoscopic radical transverse colectomy with transrectal specimen extraction: A novel natural orifice specimen extraction procedure: A case report.

Transverse colon cancer accounts for about 10% of all colonic cancers. The resection of cancers in the transverse colon is technically more challenging, compared with other cancer locations in the colon because the variable anatomy of the middle colic vessels demands excellent surgical skills and the anatomical location of the transverse colon is related to major organs. We report a novel laparoscopic technique for the first time used in surgery of transverse colon cancer which combines a total intracorporeal anastomosis with natural orifice specimen extraction to solve the problems of traditional laparoscopic surgery. A 48-year-old male patient, whose diagnosis was transverse colon adenocarcinoma, was admitted to the hospital. The surgery was performed in accordance with the procedure of totally laparoscopic right hemicolectomy and the specimen was extracted by opening the rectum. Natural orifice specimen extraction surgery has many advantages, including less pain, better cosmesis and minimising risks of complications and also has comparable long-term outcomes compared to conventional laparoscopic surgery.

Surgical outcomes of left hemicolon sparing resection versus extensive resection in treating synchronous colorectal cancer involving the right-sided colon and sigmoid colon or rectum.

BACKGROUND: There are different surgical strategies that can treat synchronous colorectal cancer (SCRC) involving separate segments, namely extensive resection (EXT) and left hemicolon-sparing resection (LHS). We aim to comparatively analyze short-term surgical results, bowel function, and long-term oncological outcomes between SCRC patients treated with the two different surgical strategies. METHODS: One hundred thirty-eight patients with SCRC lesions located in the right hemicolon and rectum or sigmoid colon were collected at the Cancer Hospital, Chinese Academy of Medical Sciences, and the Peking University First Hospital from January 2010 to August 2021 and divided into EXT group (n = 35) and LHS group (n = 103), depending on their surgical strategies. These two groups of patients were compared for postoperative complications, bowel function, the incidence of metachronous cancers, and prognosis. RESULTS: The operative time for the LHS group was markedly shorter compared with the EXT group (268.6 vs. 316.9 min, P = 0.015). The post-surgery incidences of total Clavien-Dindo grade ≥ II complications and anastomotic leakage (AL) were 8.7 vs. 11.4% (P = 0.892) and 4.9 vs. 5.7% (P = 1.000) for the LHS and EXT groups, respectively. The mean number of daily bowel movements was significantly lower for the LHS group than for the EXT group (1.3 vs. 3.8, P < 0.001). The proportions of no low anterior resection syndrome (LARS), minor LARS, and major LARS for the LHS and EXT groups were 86.5 vs. 80.0%, 9.6 vs. 0%, and 3.8 vs. 20.0%, respectively (P = 0.037). No metachronous cancer was found in the residual left colon during the 51-month (median duration) follow-up period. The overall and disease-free survival rates at 5 years were 78.8% and 77.5% for the LHS group and 81.7% and 78.6% for the EXT group (P = 0.565, P = 0.712), respectively. Multivariate analysis further confirmed N stage, but not surgical strategy, as the risk factor that independently affected the patients' survival. CONCLUSIONS: LHS appears to be a more appropriate surgical strategy for SCRC involving separate segments because it exhibited shorter operative time, no increase in the risk of AL and metachronous cancer, and no adverse long-term survival outcomes. More importantly, it could better retain bowel function and tended to reduce the severity of LARS and therefore improve the post-surgery life quality of SCRC patients.

Deciphering the Pyroptosis-Related Prognostic Signature and Immune Cell Infiltration Characteristics of Colon Cancer.

Background: Colon cancer (CC) remains one of the most common malignancies with a poor prognosis. Pyroptosis, referred to as cellular inflammatory necrosis, is thought to influence tumor development. However, the potential effects of pyroptosis-related regulators (PRRs) on the CC immune microenvironment remain unknown. Methods: In this study, 27 PRRs reported in the previous study were used to cluster the 1,334 CC samples into three pyroptosis-related molecular patterns. Through subtype pattern differential analysis and structure network mining using Weighted Gene Co-expression Network Analysis (WGCNA), 854 signature genes associated with the PRRs were discovered. Further LASSO-penalized Cox regression of these genes established an eight-gene assessment model for predicting prognosis. Results: The CC patients were subtyped based on three distinct pyroptosis-related molecular patterns. These pyroptosis-related patterns were correlated with different clinical outcomes and immune cell infiltration characteristics in the tumor microenvironment. The pyroptosis-related eight-signature model was established and used to assess the prognosis of CC patients with medium-to-high accuracy by employing the risk scores, which was named "PRM-scores." Greater inflammatory cell infiltration was observed in tumors with low PRM-scores, indicating a potential benefit of immunotherapy in these patients. Conclusions: This study suggests that PRRs have a significant effect on the tumor immune microenvironment and tumor development. Evaluating the pyroptosis-related patterns and related models will promote our understanding of immune cell infiltration characteristics in the tumor microenvironment and provide a theoretical basis for future research targeting pyroptosis in cancer.

Integrative Analysis of Biomarkers Through Machine Learning Identifies Stemness Features in Colorectal Cancer.

Background: Cancer stem cells (CSCs), which are characterized by self-renewal and plasticity, are highly correlated with tumor metastasis and drug resistance. To fully understand the role of CSCs in colorectal cancer (CRC), we evaluated the stemness traits and prognostic value of stemness-related genes in CRC. Methods: In this study, the data from 616 CRC patients from The Cancer Genome Atlas (TCGA) were assessed and subtyped based on the mRNA expression-based stemness index (mRNAsi). The correlations of cancer stemness with the immune microenvironment, tumor mutational burden (TMB), and N6-methyladenosine (m6A) RNA methylation regulators were analyzed. Weighted gene co-expression network analysis (WGCNA) was performed to identify the crucial stemness-related genes and modules. Furthermore, a prognostic expression signature was constructed using the Lasso-penalized Cox regression analysis. The signature was validated via multiplex immunofluorescence staining of tissue samples in an independent cohort of 48 CRC patients. Results: This study suggests that high-mRNAsi scores are associated with poor overall survival in stage IV CRC patients. Moreover, the levels of TMB and m6A RNA methylation regulators were positively correlated with mRNAsi scores, and low-mRNAsi scores were characterized by increased immune activity in CRC. The analysis identified 34 key genes as candidate prognosis biomarkers. Finally, a three-gene prognostic signature (PARPBP, KNSTRN, and KIF2C) was explored together with specific clinical features to construct a nomogram, which was successfully validated in an external cohort. Conclusion: There is a unique correlation between CSCs and the prognosis of CRC patients, and the novel biomarkers related to cell stemness could accurately predict the clinical outcomes of these patients.

A novel risk stratification for predicting prognosis of colorectal cancer patients with bone metastasis.

BACKGROUND: Our understanding in prognosis of bone metastasis (BM) from colorectal cancer (CRC) is limited. We aimed to establish a clinical risk stratification for individually predicting the survival of CRC patients with BM. METHODS: A total of 200 CRC patients with BM were included in this study. Survival time from BM diagnosis was estimated using the Kaplan-Meier method. The multivariable COX regression model identified the risk factors on cancer specific survival (CSS). Based on weighted scoring system, the stratification model was constructed to classify patients with BM according to prognostic risk. Discrimination power and calibration ability of risk stratification were measured. RESULTS: The median CSS time was 11 months after BM diagnosis. Lymph node metastasis, Carbohydrate antigen 199 (CA199) levels, bone involvement, Karnofsky Performance Status (KPS) scores, primary tumor resection, bisphosphonates therapy and radiotherapy were identified as predictors of CSS. Four risk groups were stratified according to weighted scoring system, including low risk, medium risk, medium-high risk and high risk group, with 35, 16, 9 and 5 months of median CSS, respectively (P=0.000). The risk stratification displayed good accuracy in predicting CSS, with acceptable discrimination and calibration. CONCLUSIONS: This novel risk stratification predicts CSS in CRC patient with BM using easily accessible clinicopathologic factors, which is recommended for use in individualized clinical decision making in patient with BM.

lncRNA-PACER upregulates COX-2 and PGE2 through the NF-κB pathway to promote the proliferation and invasion of colorectal-cancer cells.

BACKGROUND: p50-associated cyclooxygenase-2 extragenic RNA (PACER) is a recently identified antisense long non-coding RNA (lncRNA) located on the upstream of the promoter region of cyclooxygenase-2 (COX-2). Preliminary studies have suggested that PACER is involved in the regulation of COX-2 expression in macrophagocyte and osteosarcoma cells. However, the role of this lncRNA in colorectal cancer (CRC) remains elusive. Here, we investigated the expression of PACER and its effect on cell proliferation and invasion to explore the role of PACER in CRC. METHODS: Real-time quantitative PCR (RT-qPCR) analysis was used to evaluate the expression of PACER in CRC tissues and cells. Methyl thiazolyl tetrazolium (MTT) analysis was then used to investigate the inhibition effect of PACER knock-down in cell proliferation. The promoting role of this lncRNA on invasion by CRC cells was analysed by wound-healing assays, colony-formation assay, and transwell assays. We then used fluorescence in situ hybridization (FISH) to establish the subcellular localization of PACER. COX-2 protein levels were quantified by Western blot analysis and grayscale scanning analysis following the knock-down of PACER. Luciferase assay was carried out to monitor the modulation of the COX-2 promoter region by PACER. Tumor xenografts models were used to investigate the impact of PACER on the tumorigenesis of CRC cells in vivo. Enzyme-linked immunosorbent assay (ELISA) was then used to quantify prostaglandin E2 (PGE2) production upon knock-down of PACER. RESULTS: RT-qPCR analysis revealed that PACER was highly expressed in CRC tissues and cells, and a high PACER-expression level was associated with poor prognosis. MTT assay, wound-healing assay, colony-formation assay, and transwell assay revealed that PACER enhanced CRC-cell proliferation, invasion, and metastasis in vitro. Analysis of lncRNA localization by FISH showed that it mainly resided in the nucleus. RT-qPCR showed that PACER increased mRNA levels of COX-2. Western blot analysis demonstrated, under normal circumstances, that knock-down of PACER decreased the COX-2 protein level. In the case of p50 absence, COX-2 protein increased rapidly and remained highly expressed after knocking down PACER. Luciferase assay revealed that PACER modulated the COX-2 promoter region. Mouse xenograft models of CRC revealed that PACER promoted colorectal tumorigenesis in vivo. ELISA revealed that PACER knock-down inhibited PGE2 production. CONCLUSIONS: PACER modulates COX-2 expression through the nuclear factor kappa B (NF-κB) pathway in CRC. An increased level of PACER enhances proliferation, migration, and invasion of tumor cells by increasing COX-2 and PGE2 synthesis.

The Distinction of Clinicopathological Characteristics, Treatment Strategy and Outcome in Colorectal Cancer Patients With Synchronous vs. Metachronous Bone Metastasis.

Background: The impact of the timing of bone metastasis (BM) diagnosis on colorectal cancer (CRC) patients is unclear. Our study aimed to explore the differences in clinicopathological characteristics, treatments and prognosis between synchronous BM (SBM) and metachronous BM (MBM) from CRC. Methods: We retrospectively investigated clinical data of CRC patients with SBM or MBM from 2008 to 2017 at Chinese National Cancer Center. Cancer specific survival (CSS) after BM diagnosis was estimated using the Kaplan-Meier method. The multivariable COX regression model identified the prognostic factors of CSS. Results: Finally, 63 CRC patients with SBM and 138 CRC patients with MBM were identified. Compared to SBM from CRC, MBM significantly was more involving multiple bone lesions (63.0 vs. 7.9%; p < 0.001), and more frequently originated from rectal cancer (60.9 vs. 41.3%; p = 0.033). The therapeutic strategies in SBM and MBM group were contrasted including systemic treatment, bisphosphonates, radiotherapy and metastasectomy for BM. 85.5% of patients in MBM group and 25.4% of patients in SBM group underwent primary tumor resection at initial diagnosis (p < 0.001). The median CSS was 11 months in both SBM and MBM group (p = 0.556), yet MBM patients developed from CRC in early AJCC stage presented obviously longer survival than those from advanced stage. Furthermore, patients could have improved CSS from primary tumor resection while there might be no survival benefit from targeted therapy in both SBM and MBM groups. Bisphosphonates was associated with a better CSS for patients with SBM, while radiotherapy for BM was related to a better CSS for patients with MBM. Conclusion: The CRC patients in SBM and MBM group represented different clinicopathological characteristics and treatment modalities, which affected the prognosis in different ways. Distinct consideration for CRC patients with SBM and MBM in clinical decision making is required.

Evaluation of clinical significance of claudin 7 and construction of prognostic grading system for stage II colorectal cancer.

BACKGROUND: Claudin 7 is often abnormally expressed in cancers and promotes the progression of some malignancies. However, the role of claudin 7 in stage II colorectal cancer (CRC) has not been studied. AIM: To assess the expression and prognostic value of claudin 7 in stage II CRC. METHODS: We retrospectively studied 231 stage II CRC patients who underwent radical surgery at our hospital from 2013 to 2014. The protein expression level of claudin 7 was assessed and its relationship with clinicopathological features and prognosis was statistically analyzed. The independent prognostic factors were identified by Cox proportional hazards models. A prognostic grading system was constructed to stratify the survival of CRC patients. RESULTS: The expression of claudin 7 was significantly reduced in cancer tissues compared with normal tissues (P < 0.001), and its low expression was closely related to recurrence of the disease (P = 0.017). Multivariate analysis confirmed that claudin 7 low expression (claudin 7-low) (P = 0.028) and perineural invasion positivity (PNI+) (P = 0.026) were independent predictors of poor disease-free survival (DFS). A prognostic grading system based on the status of claudin 7 and PNI classified the patients into three prognostic grades: grade A (claudin 7-high and PNI-), grade B (claudin 7-low and PNI-, claudin 7-high and PNI+), and grade C (claudin 7-low and PNI+). The DFS was significantly different among the three grades (grade B vs grade A, P = 0.032; grade C vs grade A, P < 0.001; grade C vs grade B, P = 0.040). CONCLUSION: Claudin 7 can be used as a new prognostic marker to predict the DFS of patients with stage II CRC. The prognostic grading system with the addition of claudin 7 can further improve prognosis stratification of patients.

A prognostic index model to individually predict clinical outcomes for colorectal cancer with synchronous bone metastasis.

Background: The prognosis of synchronous bone metastasis (BM) in colorectal cancer (CRC) is poor and rarely concerned. A clinical tool to evaluate the prognosis and clinical outcomes for BM would be attractive in current clinical practice. Methods: A total of 342 CRC patients with synchronous BM were identified from Surveillance, Epidemiology, and End Results (SEER) database. The cancer specific survival (CSS) was estimated with the Kaplan-Meier method. Prognostic factors were identified from multivariate Cox model, and the final clinical nomogram was developed to predict the CSS. The concordance index (C-index) was used to assess the discriminative ability. Calibration curves were provided to internally validate the performance of the nomogram. Results: The nomogram finally consisted of 6 prognostic factors including age, tumor grade, AJCC N stage, carcinoembryonic antigen (CEA) levels, primary tumor resection and chemotherapy, which translated the effects of prognostic factors into certain scores to predict the 1-, 2- and 3-year CSS for the synchronous BM in CRC patients. The nomogram presented a good accuracy for predicting the CSS with the C-index of 0.742. The calibration of the nomogram predictions was also accurate. Conclusions: This nomogram was accurate enough to predict the CSS of CRC patients with synchronous BM using readily available clinicopathologic factors and could provide individualized clinical decisions for both physicians and patients.

Leptin Overexpression as a Poor Prognostic Factor for Colorectal Cancer.

Leptin acts as an adipocytokine functions via the leptin receptor, which stimulates growth, migration, and invasion of cancer cells. This study is aimed at identifying leptin as a prognostic factor in colorectal cancer (CRC). The differentially expressed genes with prognostic value in CRC tissues either with or without liver metastasis were assessed based on The Cancer Genomic Atlas (TCGA). Leptin was considered a candidate gene for further analysis. Its expression features of 206 CRC patients without liver metastasis and 201 patients with metastasis on tissue microarrays were assessed by immunochemical staining, and the effect of leptin on survival was assessed by Kaplan-Meier analyses. Overexpressed leptin indicated a poorer prognosis for CRC patients in overall survival (p < 0.05, log-rank test) based on the TCGA database. The leptin expression significantly correlated with metastasis stage (p < .010) and lymph node involvement (p < .010). Multivariate analysis also indicated that strong leptin expression was an independent adverse prognosticator in CRC (p = .017). Leptin may be valued as a prognostic marker could contribute to predicting a clinical outcome for patients with CRC.

Prognostic scoring system for synchronous brain metastasis at diagnosis of colorectal cancer: A population-based study.

BACKGROUND: Brain metastasis (BM) from colorectal cancer (CRC) is rarely encountered clinically, and its prognosis has not been fully evaluated. AIM: To construct a scoring system and accurately predict the survival of patients with synchronous BM at diagnosis of CRC. METHODS: A retrospective study of 371 patients with synchronous BM from CRC was performed, using the data from 2010 to 2014 from the Surveillance, Epidemiology, and End Results database. Survival time and prognostic factors were statistically analyzed by the Kaplan-Meier method and Cox proportional hazards models, respectively. A scoring system was developed using the independent prognostic factors, and was used to measure the survival difference among different patients. RESULTS: For the 371 patients, the median overall survival was 5 mo, survival rates were 27% at 1 year and 11.2% at 2 years. Prognostic analysis showed that age, carcinoembryonic antigen level and extracranial metastasis to the liver, lung or bone were independent prognostic factors. A scoring system based on these three prognostic factors classified the patients into three prognostic subgroups (scores of 0-1, 2-3, and 4). The median survival of patients with scores of 0-1, 2-3 and 4 was 14, 5 and 2 mo, respectively (P < 0.001). Subgroup analysis showed that there were significant differences in prognosis among the groups. Score 2-3 vs 0-1: hazard ratio (HR) = 2.050, 95%CI: 1.363-3.083; P = 0.001; score 4 vs 0-1: HR = 3.721, 95%CI: 2.225-6.225; P < 0.001; score 2-3 vs 4: HR = 0.551, 95%CI: 0.374-0.812; P = 0.003. CONCLUSION: The scoring system effectively distinguishes long-term and short-term survivors with synchronous BM from CRC. These results are helpful in providing a reference for guiding therapy.

Brain metastasis from colorectal cancer: clinical characteristics, timing, survival and prognostic factors.

Background: Brain metastasis (BM) from colorectal cancer (CRC) seriously affects the survival and quality of life of patients. However, this disease is not fully understood. It is not clear when follow-up monitoring should be conducted to achieve early diagnosis. Furthermore, the reported prognostic factors have varied among different studies. Our study aims to determine the clinicopathological, survival and prognostic factors, as well as the timing of BM occurrence.Methods: We retrospectively studied the patients with BM from CRC between January 2000 and July 2017. The clinicopathologic features were assessed, and the time from primary tumor surgery and extracranial metastases (lung, liver and bone) to the occurrence of BM was calculated, respectively. Survival time after BM was statistically analyzed. Multivariate Cox analysis was carried out to determine the independent factors that affected survival.Results: 52 patients were analyzed. Most of the patients (86.5%) had combined extracranial metastases when BM was diagnosed, and lung was the commonest extracranial metastasis location. The median time interval from CRC surgery to the diagnosis of BM was 20.5 months, and the median time interval from lung, liver and bone metastases to BM was 7, 5 and 2 months, respectively. After diagnosis of BM, the median survival was 9 months. Extracranial metastases (p =.012) and Karnofsky performance status (p =.025) were independent prognostic factors based on multivariate analysis.Conclusion: BM from colorectal cancer often occur in the late stage, and has an extremely poor prognosis. Identifying the timing of brain metastasis can help to detect this disease early.

A clinical model to predict the risk of synchronous bone metastasis in newly diagnosed colorectal cancer: a population-based study.

BACKGROUND: The early detection of synchronous bone metastasis (BM) in newly diagnosed colorectal cancer (CRC) affects its initial management and prognosis. A clinical model to individually predict the risk of developing BM would be attractive in current clinical practice. METHODS: A total of 55,869 CRC patients were identified from Surveillance, Epidemiology, and End Results (SEER) database, of whom 317 patients were diagnosed with synchronous BM. Risk factors for BM in CRC patients was identified using multivariable logistic regression. A weighted scoring system was built with beta-coefficients (P < 0.05). A random sample of 75% of the CRC patients was used to establish the risk model, and the remaining 25% was used to validate its accuracy of this model. The performance of risk model was estimated by receiver operating curve (ROC) analysis. RESULTS: The risk model consisted of 8 risk factors including rectal cancer, poorly-undifferentiation, signet-ring cell carcinoma, CEA positive, lymph node metastasis, brain metastasis, liver metastasis and lung metastasis. The areas under the receiver operating curve (AUROC) were 0.903 and 0.889 in the development and validation cohort. Patients with scores from 0 to 4 points had about 0.1% risk of developing BM, and the risk increased to about 30% in patients with scores ≥15 points. CONCLUSIONS: This clinical risk model is accurate enough to identify the CRC patients with high risk of synchronous BM and to further provide more individualized clinical decision.

GGN Promotes Tumorigenesis by Regulating Proliferation and Apoptosis in Colorectal Cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. GGN is a germ cell-specific gene, but its function in CRC has been rarely reported to date. The aim of this study was to investigate the potential role of GGN in CRC tumorigenesis. Therefore, in this study, we examined the expression of GGN in CRC cell lines and tissues and its effects on cellular proliferation and apoptosis. We then explored the underlying mechanism. Our results showed that GGN was significantly overexpressed in both CRC cell lines and tissues. Silencing GGN robustly inhibited proliferation of CRC cells, and it also promoted apoptosis of CRC cells. Moreover, knockdown of GGN inhibited the expression of p-Akt in CRC cells. Taken together, these results showed that knockdown of GGN inhibits proliferation and promotes apoptosis of CRC cells through the PI3K/Akt signaling pathway. Our findings revealed for the first time a potential oncogenic role for GGN in CRC progress. This finding may provide a unique perspective on how a germ cell-specific gene might serve as a biomarker, or even as a therapeutic target, for CRC.

MALAT1 sponges miR-106b-5p to promote the invasion and metastasis of colorectal cancer via SLAIN2 enhanced microtubules mobility.

BACKGROUND: The low expression of miR93/25 (members of miR-106b~25 cluster) promoted the invasion and metastasis of colon cancer cells, which predicted poor survival. However, the role of miR-106b-5p, the member of miR-106b~25 cluster, in colorectal cancer (CRC) remains unclear. METHODS: Bioinformatics methods were used to predict the potential pairs of lncRNA-miRNA-mRNA. In situ hybridization and qPCR were used to evaluate the expression of MALAT1 and miR-106b-5p in the paraffin-embedded normal and CRC tissues. Kaplan-Meier analysis with the log-rank test was used for survival analyses. Immunohistochemistry staining was applied to investigate the expression of SLAIN2. Fluorescence recovery after photobleaching assay was applied to observe the microtubule (MT) mobility. In vitro and in vivo invasion and metastasis assays were used to explore the function of MALAT1/miR-106b-5p/SLAIN2 in the progression of CRC. FINDINGS: miR-106b-5p was identified as a suppressor in CRC. Functionally, ectopic or silencing the expression of miR-106b-5p inhibited or promoted the invasion and metastasis of CRC cells in vitro and in vivo. The long non-coding RNA MALAT1 regulated the miR-106b-5p expression and further mediated the mobility of SLAIN2-related MTs by functioning as a competing endogenous RNA in vitro and in vivo, which resulted in the progression of CRC. Clinically, low miR-106b-5p expression predicted poor survival of CRC patients, especially in combination with high MALAT1/ SLAIN2 expression. INTERPRETATION: miR-106b-5p served as a suppressor in combination with MALAT1/miR-106b-5p/SLAIN2, which might be a group of potential prognostic biomarkers in the prognosis of CRC. FUND: This work was supported by National Program Project for Precision Medicine in National Research and Development Plan of China (2016YFC0905300), National Natural Science Foundation of China (81572930), National Key Research and Development Program of the Ministry of Science and Technology of China (2016YFC0905303, 2016YFC1303200), Beijing Science and Technology Program (D17110002617004), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2018PT32012), CAMS Innovation Fund for Medical Sciences (CIFMS) (2016-I2M-1-001), Incentive Fund for Academic Leaders of Oncology Hospital, Chinese Academy of Medical Sciences (RC2016003), and Beijing Hope Run Special Fund from Cancer Foundation of China (LC2017A19). The project of Shanghai Jiaotong Univversity (YG2017QN30).