Overall Survival In Colorectal Cancer Research Articles

Abstract 1282: Gavage with Candida albicans leads to fungal colonization of colorectal tumors and decreased response to radiotherapy

Abstract The host microbiome in the gut and tumors have been shown to affect tumor growth and therapeutic response in cancer. Furthermore, the presence of specific fungal taxa are associated with tumor hypoxia, tumor progression, therapeutic response, and clinical outcomes in colorectal cancer (CRC). Preliminary data from our group found that the presence of Candida species increased tumor hypoxia and decreased overall survival in CRC. However, whether intratumoral Candida drive, support, or simply inhabit tumors with poor prognoses remains unclear. Here, we investigate a casual role for Candida albicans in tumor progression and therapy response using a syngeneic mouse model of microsatellite-instability high (MSI-H) colorectal cancer. We subcutaneously implanted MC38 colorectal cancer cells into C57BL/6 mice and then orally gavaged these mice with C. albicans, Saccharomyces cerevisiae, or PBS. The site of tumor formation was locally irradiated once (7.5 Gy), and growth of the tumor was measured over time. Differences in tumor volume were assessed by longitudinal mixed-effect models. Tumor sections were stained for fungi using calcofluor white (CFW) and underwent bulk RNA sequencing to detect differential gene expression, which were interpreted using gene set enrichment analysis (GSEA). Mice gavaged with C. albicans showed decreased response to radiation compared to mice gavaged with either S. cerevisiae (p<0.05) or PBS (p<0.001). Additionally, hyphae were observed in murine tumors gavaged with C. albicans, suggesting translocation of gavaged C. albicans from the gut to tumors. Further, tumors from mice gavaged with C. albicans displayed unique gene expression profiles, including decreased interferon alpha and IL-6 and STAT3 signaling, decreased oxidative phosphorylation, and decreased apoptosis-related gene expression. Here, we show that C. albicans may confer resistance to radiation therapy and affects immune and cancer cell activity in the MC38 (MSI-H) syngeneic in vivo model of colorectal cancer. Further, we show that hyphal fungi can be visualized in heterotopic murine tumors from our C. albicans gavage condition. These data establish that fungi can translocate from the gut to distal tumor sites, and that upon translocation, changes in gene expression and therapy response are observed. Future directions will explore the mechanism by which these effects occur and whether these findings can be leveraged to improve radiotherapy outcomes. Citation Format: Dennis J. Grencewicz, Alexander Loncar, Rebecca Hoyd, Aaditya Pallerla, Nyelia Williams, Martin Benej, McKenzie Kreamer, Yogita Mehra, Shiva Jahanbakhshi, Matthew Anderson, Nicholas Denko, Daniel Spakowicz. Gavage with Candida albicans leads to fungal colonization of colorectal tumors and decreased response to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1282.

CircFBXW4 Suppresses Colorectal Cancer Progression by Regulating the MiR-338-5p/SLC5A7 Axis.

Dysregulated circular RNAs (circRNAs) contribute to tumourigenesis and cancer progression. However, the expression patterns and biological functions of circRNAs in colorectal cancer (CRC) remain elusive. Here, RNA sequencing and bioinformatics analyses are applied to screen for aberrantly expressed circRNAs. The expression of circFBXW4 in CRC tissues and cell lines is determined by quantitative real-time PCR. A series of in vitro and in vivo biological function assays are implemented to assess the functions of circFBXW4. The regulatory mechanisms linking circFBXW4, miR-338-5p, and SLC5A7 are explored by western blotting, dual luciferase reporter assays, and RNA pull-down assays. CircFBXW4 is dramatically downregulated in CRC tissues and cell lines. circFBXW4 downregulation is clearly correlated with malignant features and patient overall survival in CRC. Functionally, ectopic expression of circFBXW4 strikingly impairs the proliferation, migration, and invasion capacities of CRC cells in vitro and in vivo, whereas circFBXW4 knockdown has the opposite effects. Mechanistically, circFBXW4 competitively binds to miR-338-5p and prevents it from interacting with and repressing its target SLC5A7, thus suppressing the progression of CRC. This study reveals the specific critical role of circFBXW4 in inhibiting CRC progression via the miR-338-5p/SLC5A7 axis and provides an additional target for eradicating CRC.

Methylation of NRIP3 Is a Synthetic Lethal Marker for Combined PI3K and ATR/ATM Inhibitors in Colorectal Cancer.

The aim of this study was to investigate the epigenetic regulation and underlying mechanism of NRIP3 in colorectal cancer (CRC). Eight cell lines (SW480, SW620, DKO, LOVO, HT29, HCT116, DLD1, and RKO), 187 resected margin samples from colorectal cancer tissue, 146 cases with colorectal adenomatous polyps, and 308 colorectal cancer samples were used. Methylation-specific PCR, Western blotting, RNA interference assay, and a xenograft mouse model were used. NRIP3 exhibited methylation in 2.7% (5/187) of resected margin samples from colorectal cancer tissue, 32.2% (47/146) of colorectal adenomatous polyps, and 50.6% (156/308) of CRC samples, and the expression of NRIP3 was regulated by promoter region methylation. The methylation of NRIP3 was found to be significantly associated with late onset (at age 50 years or older), poor tumor differentiation, lymph node metastasis, and poor 5-year overall survival in CRC (all P < 0.05). In addition, NRIP3 methylation was an independent poor prognostic marker ( P < 0.05). NRIP3 inhibited cell proliferation, colony formation, invasion, and migration, while induced G1/S arrest. NRIP3 suppressed CRC growth by inhibiting PI3K-AKT signaling both in vitro and in vivo . Methylation of NRIP3 sensitized CRC cells to combined PI3K and ATR/ATM inhibitors. NRIP3 was frequently methylated in both colorectal adenomatous polyps and CRC. The methylation of NRIP3 may potentially serve as an early detection, late-onset, and poor prognostic marker in CRC. NRIP3 is a potential tumor suppressor. NRIP3 methylation is a potential synthetic lethal marker for combined PI3K and ATR/ATM inhibitors.

Quantitative peritumoral magnetic resonance imaging fingerprinting improves machine learning-based prediction of overall survival in colorectal cancer.

To investigate magnetic resonance imaging (MRI)-based peritumoral texture features as prognostic indicators of survival in patients with colorectal liver metastasis (CRLM). From 2007-2015, forty-eight patients who underwent MRI within 3 months prior to initiating treatment for CRLM were identified. Clinicobiological prognostic variables were obtained from electronic medical records. Ninety-four metastatic hepatic lesions were identified on T1-weighted post-contrast images and volumetrically segmented. A total of 112 radiomic features (shape, first-order, texture) were derived from a 10 mm region surrounding each segmented tumor. A random forest model was applied, and performance was tested by receiver operating characteristic (ROC). Kaplan-Meier analysis was utilized to generate the survival curves. Forty-eight patients (male:female = 23:25, age 55.3 years ± 18 years) were included in the study. The median lesion size was 25.73 mm (range 8.5-103.8 mm). Microsatellite instability was low in 40.4% (38/94) of tumors, with Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation detected in 68 out of 94 (72%) tumors. The mean survival was 35 months ± 21 months, and local disease progression was observed in 35.5% of patients. Univariate regression analysis identified 42 texture features [8 first order, 5 gray level dependence matrix (GLDM), 5 gray level run time length matrix (GLRLM), 5 gray level size zone matrix (GLSZM), 2 neighboring gray tone difference matrix (NGTDM), and 17 gray level co-occurrence matrix (GLCM)] independently associated with metastatic disease progression (P < 0.03). The random forest model achieved an area under the curve (AUC) of 0.88. MRI-based peritumoral heterogeneity features may serve as predictive biomarkers for metastatic disease progression and patient survival in CRLM.

Identification of glutamine metabolism-related gene signature to predict colorectal cancer prognosis.

Backgrounds: Colorectal cancer (CRC) is a highly malignant gastrointestinal malignancy with a poor prognosis, which imposes a significant burden on patients and healthcare providers globally. Previous studies have established that genes related to glutamine metabolism play a crucial role in the development of CRC. However, no studies have yet explored the prognostic significance of these genes in CRC. Methods: CRC patient data were downloaded from The Cancer Genome Atlas (TCGA), while glutamine metabolism-related genes were obtained from the Molecular Signatures Database (MSigDB) database. Univariate COX regression analysis and LASSO Cox regression were utilized to identify 15 glutamine metabolism-related genes associated with CRC prognosis. The risk scores were calculated and stratified into high-risk and low-risk groups based on the median risk score. The model's efficacy was assessed using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve analysis. Cox regression analysis was employed to determine the risk score as an independent prognostic factor for CRC. Differential immune cell infiltration between the high-risk and low-risk groups was assessed using the ssGSEA method. The clinical applicability of the model was validated by constructing nomograms based on age, gender, clinical staging, and risk scores. Immunohistochemistry (IHC) was used to detect the expression levels of core genes. Results: We identified 15 genes related to glutamine metabolism in CRC: NLGN1, RIMKLB, UCN, CALB1, SYT4, WNT3A, NRCAM, LRFN4, PHGDH, GRM1, CBLN1, NRG1, GLYATL1, CBLN2, and VWC2. Compared to the high-risk group, the low-risk group demonstrated longer overall survival (OS) for CRC. Clinical correlation analysis revealed a positive correlation between the risk score and the clinical stage and TNM stage of CRC. Immune correlation analysis indicated a predominance of Th2 cells in the low-risk group. The nomogram exhibited excellent discriminatory ability for OS in CRC. Immunohistochemistry revealed that the core gene CBLN1 was expressed at a lower level in CRC, while GLYATL1 was expressed at a higher level. Conclusions: In summary, we have successfully identified and comprehensively analyzed a gene signature associated with glutamine metabolism in CRC for the first time. This gene signature consistently and reliably predicts the prognosis of CRC patients, indicating its potential as a metabolic target for individuals with CRC.

Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1.

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased NF-κB-dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features.

Prognostic significance of HLA-G in patients with colorectal cancer: a meta-analysis and bioinformatics analysis

PurposeHuman leukocyte antigen-G (HLA-G) has been reported to be aberrantly expressed in colorectal cancer (CRC); however, its prognostic value remains controversial. Hence, our meta-analysis aims to assess the prognostic value of HLA-G in CRC patients based on published literature and The Cancer Genome Atlas (TCGA) datasets.MethodsA systematic search was conducted on relevant studies retrieved from four electronic databases including PubMed, Embase, Web of Science and Cochrane Library. Hazard ratios (HRs) with 95% confidence intervals (CIs) were recorded to be applied as effective values. Fixed-effects models or random-effects models were applied on the basis of the value of heterogeneity (I2). Publication bias was analyzed by Begg’s and Egger’s tests. In addition, the results were validated by using TCGA datasets.ResultsThirteen studies comprising 3896 patients were incorporated into this meta-analysis. The pooled results showed that HLA-G expression was significantly associated with poor overall survival (OS) in both the univariate analysis (HR = 1.44, 95% CI: 1.14–1.83, P = 0.002) and the multivariate analysis (HR = 1.55, 95% CI: 1.23–1.95, P < 0.001). Nevertheless, the expression of HLA-G is not related to age, sex, tumor type, tumor differentiation, TNM stage, or distant metastasis but lymph node metastasis. Notably, the prognosis of colorectal cancer was not consistent with the analysis result from TCGA data.ConclusionHLA-G expression was significantly related to poor OS in CRC according to the results of our meta-analysis. However, we found that the prognostic significance was inconsistent with our results according to the TCGA data in CRC. Hence, more research is still needed to further illustrate the prognostic role of HLA-G in CRC.

S190 Epidemiological Analysis and Overall Survival of Colorectal Cancer in a Developing Middle Eastern Country Over 18 Years

S190 Epidemiological Analysis and Overall Survival of Colorectal Cancer in a Developing Middle Eastern Country Over 18 Years

Emergency resection is an independent risk factor for decreased long-term overall survival in colorectal cancer: a matched-pair analysis

BackgroundColorectal cancer is one of the most common malignant neoplasms worldwide. Up to 30% of the patients present in an emergency setting despite an established screening program. Emergency colorectal resection is associated with increased mortality and morbidity as well as worse oncological outcome. This study aims to analyze the impact on tumor recurrence and survival in patients with an emergency colorectal resection, independent of sex, age, and tumor stage.MethodsPatients, who underwent an oncological resection for colorectal cancer at the Medical University of Innsbruck, Department of Visceral, Transplant and Thoracic Surgery, between January 2003 and December 2018 were analyzed retrospectively and screened for emergency resections. Matched pairs were formed to analyze the impact of emergency operations on long-term outcomes, considering tumor stage, sex, and age, comparing it with elective patients.ResultsIn total, 4.5% out of 1297 patients underwent surgery in an emergency setting. These patients had higher UICC (Union internationale contre le cancer) stages than elective patients. After matching the patients for age, sex, and tumor stage, emergency patients still had higher mortality. The incidence of recurrence was higher (47.5% vs. 25.4%, p = 0.003) and the 5-year overall survival decreased (35.6% vs. 64.4%, p < 0.001) compared to the matched patients with elective resection. Correcting for 90-day mortality still a reduction in the 5-year overall survival was demonstrated (44% vs. 70%, p = 0,001). The left-sided colon tumors were more common in the emergency group (45.8% vs. 25.4%, p = 0.006) and the rectal tumors in the elective one (21.2% vs. 3.4%, p = 0.002).ConclusionPatients undergoing emergency resection for colorectal cancer have a decreased tumor-specific and overall survival compared to patients after elective resection, independent of age, sex, and tumor stage, even after correcting for 90-day mortality. These findings confirm the importance of colorectal cancer awareness and screening to reduce emergency resections.

Loss of SATB2 and CDX2 expression is associated with DNA mismatch repair protein deficiency and BRAF mutation in colorectal cancer.

The relationship between the expression of the SATB2 and CDX2 proteins and common molecular changes and clinical prognosis in colorectal cancer (CRC) still needs further clarification. We collected 1180 cases of CRC and explored the association between the expression of SATB2 and CDX2 and clinicopathological characteristics, molecular alterations, and overall survival of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The lack of expression of SATB2 and CDX2 was associated with poor histopathological features of CRC. In multivariate analysis, negative expression of SATB2 (P = 0.030), negative expression of CDX2 (P = 0.043) and late clinical stage (P = 0.000) were associated with decreased overall survival of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. SATB2 and CDX2 are prognostic biomarkers in patients with CRC.

SETDB1 Methylates MCT1 Promoting Tumor Progression by Enhancing the Lactate Shuttle.

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post-transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post-translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip-mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri-methylation promotes tumor glycolysis and M2-like polarization of tumor-associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri-methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1-mediated tri-methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.

Association of perioperative allogeneic blood transfusions and long-term outcomes following radical surgery for gastric and colorectal cancers: systematic review and meta-analysis of propensity-adjusted observational studies.

Previous meta-analyses reporting significant associations between perioperative allogeneic blood transfusions and poor prognosis in gastric cancer or colorectal cancer had a high risk of confounding bias. This meta-analysis explored this issue using observational studies that applied propensity score analysis. PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for manuscripts published between 2013 and 2022. Studies applying propensity score analysis were included to investigate the association between perioperative allogeneic blood transfusions and prognosis in gastric cancer or colorectal cancer after radical surgery. Pooled HRs for overall survival and disease-free survival were calculated using a fixed-effect model or random-effect model according to heterogeneity. Twelve retrospective cohort studies with 17 607 patients reported were included. Ten studies applied propensity score matching and two applied inverse probability of treatment weighting using propensity score. A total of 5962 patients were analysed after propensity score adjustment. After propensity score adjustment, perioperative allogeneic blood transfusions did not correlate with disease-free survival in gastric cancer (HR 1.16; 95 per cent c.i. 0.96-1.39; heterogeneity was assessed by the chi-squared test and inconsistency index (I2) = 57 per cent) or colorectal cancer (HR 1.12; 95 per cent c.i. 0.84-1.49; I2 = 54 per cent). However, after propensity score adjustment, perioperative allogeneic blood transfusions were significantly associated with worse overall survival in gastric cancer (HR 1.20; 95 per cent c.i. 1.08-1.32; I2 = 25 per cent) and colorectal cancer (HR 1.40; 95 per cent c.i. 1.06-1.85; I2 = 52 per cent). Subgroup analyses showed that perioperative allogeneic blood transfusions did not correlate with overall survival in colorectal cancer when major postoperative complications were balanced after propensity score. Perioperative allogeneic blood transfusion is not correlated with recurrence of gastric cancer and colorectal cancer. Perioperative allogeneic blood transfusions are significantly associated with worse overall survival in gastric cancer and colorectal cancer, which may be attributable to unbalanced major postoperative complications after propensity score adjustment.

Contribution of Metabolic Parameters and Pericolic Fat Stranding on Preoperative 18F-FDG PET/CT in Predicting Post-operative Histopathology and Outcome in Colorectal Cancer.

We aimed to investigate the additional value of preoperative PET/CT and reveal relationships between metabolic parameters, pericolic fat stranding finding, postoperative histopathology, and overall survival in colorectal cancer (CRC). CRC patients who underwent preoperative PET/CT between January 2017-December 2021 were analyzed. Lymph nodes, organ metastases, and metabolic parameters were evaluated from PET/CT. The pericolic fat stranding was evaluated from CT component. Relationships between these factors and postoperative histopathological findings were statistically analyzed. Survival analyses were performed. Ninety-one patients (59 males, 32 females) were included in the study. All tumors showed high FDG uptake (mean SUVmax 19.5 ± 9.9). SUVmax of the tumor differed significantly at T3 and T4 stages (p = 0.041). A significant correlation was found between MTV, TLG values and the differentiation degree (p = 0.005, 0.003, respectively). PET/CT predicted the N stage with a high accuracy rate (80%). PET/CT found additional metastases that changed treatment decisions in one-third of patients. A relationship was found between tumor length, surgical margin, lymphovascular invasion and pericolic fat stranding. In multivariate analysis, differentiation degree (HR = 26.1, 95%CI 1.672-408.467), MTV (HR = 0.3, 95%CI 0.071-0.841), TLG (HR = 3.5, 95%CI 1.065-11.193), and lymphovascular invasion (HR = 0.2, 95%CI 0.026-0.853, p = 0.033) were independent factors affecting overall survival. Preoperative PET/CT contributes to CRC management by detecting additional metastases as well as predicting prognosis and postoperative findings such as T stage, N stage and tumor differentiation. The SUVmax may differentiate between T3 and T4 tumor. Reporting of pericolic fat stranding may contribute to the estimation of lymphatic invasion and positive surgical margin.

Effect of liver metastasis on the efficacy of immune checkpoint inhibitors in cancer patients: a systemic review and meta-analysis.

Liver metastasis is a frequent phenomenon in advanced tumor disease. Immune checkpoint inhibitors (ICIs) are a new class of therapeutics that can improve the prognosis of cancer patients. The purpose of this study is to elucidate the relationship between liver metastasis and survival outcomes of patients receiving ICIs treatment. We searched four main databases, including PubMed, EMBASE, Cochrane Library, and Web of Science. Overall survival (OS) and progression-free survival (PFS) were the survival outcomes of our concern. Hazard ratio (HR) with 95% confidence interval (CI) were used to evaluate the relationship between liver metastasis and OS/ PFS. Finally, 163 articles were included in the study. The pooled results showed that patients with liver metastasis receiving ICIs treatment had worse OS (HR=1.82, 95%CI:1.59-2.08) and PFS (HR=1.68, 95%CI:1.49-1.89) than patients without liver metastasis. The effect of liver metastasis on ICIs efficacy differed in different tumor types, and patients with urinary system tumors (renal cell carcinoma OS: HR=2.47, 95%CI:1.76-3.45; urothelial carcinoma OS: HR=2.37, 95%CI:2.03-2.76) had the worst prognosis, followed by patients with melanoma (OS: HR=2.04, 95%CI:1.68-2.49) or non-small cell lung cancer (OS: HR=1.81, 95%CI:1.72-1.91). ICIs efficacy in digestive system tumors (colorectal cancer OS: HR=1.35, 95%CI:1.07-1.71; gastric cancer/ esophagogastric cancer OS: HR=1.17, 95%CI:0.90-1.52) was less affected, and peritoneal metastasis and the number of metastases have a greater clinical significance than liver metastasis based on univariate data. For cancer patients receiving ICIs treatment, the occurrence of liver metastasis is associated with poor prognosis. Different cancer types and metastatic sites may hold a different prognostic effect on the efficacy of ICIs treatment in cancer patients.

MicroRNA-675-5p Overexpression Is an Independent Prognostic Molecular Biomarker of Short-Term Relapse and Poor Overall Survival in Colorectal Cancer.

Colorectal cancer (CRC) is the main cause of cancer-related deaths globally, highlighting the importance of accurate biomarkers for early detection and accurate prognosis. MicroRNAs (miRNAs) have emerged as effective cancer biomarkers. The aim of this study was to investigate the prognostic potential of miR-675-5p as a molecular prognostic biomarker in CRC. For this reason, a quantitative PCR assay was developed and applied to determine miR-675-5p expression in cDNAs from 218 primary CRC and 90 paired normal colorectal tissue samples. To assess the significance of miR-675-5p expression and its association with patient outcome, extensive biostatistical analysis was performed. miR-675-5p expression was found to be significantly downregulated in CRC tissue samples compared to that in adjacent normal colorectal tissues. Moreover, high miR-675-5p expression was associated with shorter disease-free (DFS) and overall survival (OS) in CRC patients, while it maintained its unfavorable prognostic value independently of other established prognostic factors. Furthermore, TNM stage stratification demonstrated that higher miR-675-5p levels were associated with shorter DFS and OS intervals, particularly in patients with CRC of TNM stage II or III. In conclusion, our findings suggest that miR-675-5p overexpression constitutes a promising molecular biomarker of unfavorable prognosis in CRC, independent of other established prognostic factors, including TNM staging.

Prognostic significance of increased preoperative red cell distribution width (RDW) and changes in RDW for colorectal cancer.

Increased preoperative red cell distribution width (RDW) is associated with poor prognosis in several cancers, but the relationships between preoperative RDW and changes in RDW (ΔRDW) and colorectal cancer (CRC) prognosis remain unclear. Our study aimed to demonstrate the prognostic significance of increased preoperative RDW and ΔRDW for CRC. In this retrospective analysis, we enrolled 833 patients who underwent CRC surgery between 2015 and 2019 at the Affiliated Hospital of Xuzhou Medical University, China. ΔRDW in our study was defined as RDW at 1 month after discharge minus preoperative RDW. According to receiver operating characteristic (ROC) curve analysis, we used cut-off values of 13.5% for RDW, 0.9% for ΔRDW. The cumulative survival rate was determined using the Kaplan-Meier method, and significant differences were evaluated by the log-rank test. Multivariable Cox regression model was applied to clarify the independent risk factors for overall survival (OS), which were used to construct a nomogram prediction model. The competing risk method was also applied, and we analyzed only patients with early-stage disease (stage 0-II) for sensitivity analysis. Multivariable Cox regression analysis demonstrated that age, RDW, ΔRDW, postoperative adjuvant chemotherapy, CEA, CA19-9, ASA, TNM stage, and pathological type were independent factors for OS in CRC patients (all p < 0.05). These prognostic factors were used to establish and verify the OS nomogram. Poorer OS was linked to higher RDW (HR = 1.52; 95% CI, 1.11-2.08; p < 0.01) and ΔRDW (HR = 1.65; 95% CI, 1.19-2.28; p < 0.01) in all-stage patients, and was only linked to higher RDW in early-stage patients. In competing risk model, H-RDW and H-ΔRDW were confirmed to be independent risk factors for CSS in CRC patients. High preoperative RDW and ΔRDW are both risk factors for OS and CSS in CRC.

GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer.

GPR176 belongs to the G protein-coupled receptor superfamily, which responds to external stimuli and regulates cancer progression, but its role in colorectal cancer (CRC) remains unclear. In the present study, expression analyses of GPR176 are performed in patients with colorectal cancer. Genetic mouse models of CRC coupled with Gpr176-deficiency are investigated, and in vivo and in vitro treatments are conducted. A positive correlation between GPR176 upregulation and the proliferation and poor overall survival of CRC is demonstrated. GPR176 is confirmed to activate the cAMP/PKA signaling pathway and modulate mitophagy, promoting CRC oncogenesis and development. Mechanistically, the G protein GNAS is recruited intracellularly to transduce and amplify extracellular signals from GPR176. A homolog model tool confirmed that GPR176 recruits GNAS intracellularly via its transmembrane helix 3-intracellular loop 2 domain. The GPR176/GNAS complex inhibits mitophagy via the cAMP/PKA/BNIP3L axis, thereby promoting the tumorigenesis and progression of CRC.

An unusual case of long-term survival with excellent quality of life after surgery of rectal cancer with metastasis to the liver, lung, and scalp

Abstract With improvements in therapies for colorectal cancer, patient survival can be extended remarkably. Multiple treatment modalities can be combined, and collaboration among different departments is important. A patient presented with rectal cancer with metastases to the liver, lungs, and scalp, which were excised completely. The scalp lesion recurred twice, and the final procedure was a free flap reconstruction after wide excision. Since then, there has been no recurrence, and the patient has had an excellent quality of life after 8 years of follow-up. The overall survival of colorectal cancer is increasing owing to improvements in surgery, chemotherapy, and targeted therapy. Aggressive treatment is helpful in patients with metastatic colorectal cancer.

Identification of prognostic immune-related lncRNA signature predicting the overall survival for colorectal cancer

Long non-coding RNA (lncRNA) is an important regulator of gene expression and serves a fundamental role in immune regulation. The present study aimed to develop a novel immune-related lncRNA signature to assess the prognosis of patients with colorectal cancer (CRC). Transcriptome data and clinical information of patients with CRC were downloaded from The Cancer Genome Atlas (TCGA) and UCSC Xena platforms. Immune-related mRNAs were extracted from the Molecular Signatures Database (MSigDB), and the immune-related lncRNAs were identified based on correlation analysis. Then, univariate, Lasso and multivariate Cox regression were applied to construct an immune-related lncRNA signature, and CRC patients were divided into high- and low-risk groups according to the median risk score. Finally, we evaluated the signature from the perspectives of clinical outcome, clinicopathological parameters, tumor-infiltrating immune cells (TIICs), immune status, tumor mutation burden (TMB) and immunotherapy responsiveness. In total, 272 immune-related lncRNAs were identified, five of which were applied to construct an immune-related lncRNA signature. The signature divided patients with CRC into low- and high-risk groups, the prognosis of patients in the high-risk group were significantly poorer than those in low-risk group, and the results were further confirmed in external validation cohort. Furthermore, the high-risk group showed aggressive clinicopathological characteristics, specific TIIC and immune function status, and low sensitivity to immunotherapy. The immune-related lncRNA signature could be exploited as a promising biomarker for predicting the prognosis and immune status of patients with CRC.

Effect of the MiR-99b and MiR-135b on peritoneal carcinomatosis and liver metastasis in colorectal cancer

AimThis study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival. Materials and methodsChanges in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis. ResultsThe expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p < 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p < 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p = 0.045, p = 0.006, and p = 0.012, respectively). ConclusionWhile the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.