Colon Cancer Patients Research Articles

LGR6 is a prognostic biomarker for less differentiated tumors in lymph nodes of colon cancer patients.

The aim was to investigate whether the stem cell marker LGR6 has prognostic value in colon cancer, alone or in combination with the prognostic biomarkers CEA and CXCL16. LGR6 mRNA levels were determined in 370 half lymph nodes of 121 colon cancer patients. Ability to predict relapse after curative surgery was estimated by Kaplan-Meier survival model and Cox regression analyses. Patients with high LGR6 levels [LGR6(+)] had a decreased mean survival time of 11 months at 5-year follow-up and 47 months at 12-year follow-up, respectively, with hazard ratios of 3.2 and 2.8. LGR6 mRNA analysis added prognostic value to CEA and CXCL16 mRNA analysis. In the poor prognosis groups CEA(+) and CXCL16(+), further division was achieved by LGR6 analysis. LGR6(+) patients had a very poor prognosis. LGR6 also identified a small number of CEA(-), TNM stage I patients who relapsed suggesting stem cell origin of these tumors. LGR6 and LGR5 levels correlated strongly in lymph nodes of stage I and IV patients but not in stage II patients, suggesting that these stem cell markers are differentially regulated. This study highlights LGR6 as a useful prognostic biomarker independently and in combination with CEA, CXCL16 or LGR5 identifying different risk groups.

Imaging in the era of risk-adapted treatment in colon cancer.

The treatment landscape for patients with colon cancer is continuously evolving. Risk-adapted treatment strategies, including neoadjuvant chemotherapy and immunotherapy, are slowly finding their way into clinical practice and guidelines. Radiologists are pivotal in guiding clinicians toward the most optimal treatment for each colon cancer patient. This review provides an overview of recent and upcoming advances in the diagnostic management of colon cancer and the radiologist's role in the multidisciplinary approach to treating colon cancer.

Conditional survival analysis and real-time prognosis prediction in stage III T3–T4 colon cancer patients after surgical resection: a SEER database analysis

BackgroundConditional survival (CS) takes into consideration the duration of survival post-surgery and can provide valuable additional insights. The aim of this study was to investigate the risk factors associated with reduced one-year postoperative conditional survival in patients diagnosed with stage III T3–T4 colon cancer and real-time prognosis prediction. Furthermore, we aim to develop pertinent nomograms and predictive models.MethodsClinical data and survival outcomes of patients diagnosed with stage III T3–T4 colon cancer were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, covering the period from 2010 to 2019. Patients were divided into training and validation cohorts at a ratio of 7:3. The training set consisted of a total of 11,386 patients for conditional overall survival (cOS) and 11,800 patients for conditional cancer-specific survival (cCSS), while the validation set comprised 4876 patients for cOS and 5055 patients for cCSS. Univariate and multivariate Cox regression analyses were employed to identify independent risk factors influencing one-year postoperative cOS and cCSS. Subsequently, predictive nomograms for cOS and cCSS at 2-year, 3-year, 4-year, and 5-year intervals were constructed based on the identified prognostic factors. The performance of these nomograms was rigorously assessed through metrics including the concordance index (C-index), calibration curves, and the area under curve (AUC) derived from the receiver operating characteristic (ROC) analysis. Clinical utility was further evaluated using decision curve analysis (DCA).ResultsA total of 18,190 patients diagnosed with stage III T3–T4 colon cancer were included in this study. Independent risk factors for one-year postoperative cOS and cCSS included age, pT stage, pN stage, pretreatment carcinoembryonic antigen (CEA) levels, receipt of chemotherapy, perineural invasion (PNI), presence of tumor deposits, the number of harvested lymph nodes, and marital status. Sex and tumor site were significantly associated with one-year postoperative cOS, while radiation therapy was notably associated with one-year postoperative cCSS. In the training cohort, the developed nomogram demonstrated a C-index of 0.701 (95% CI, 0.711–0.691) for predicting one-year postoperative cOS and 0.701 (95% CI, 0.713–0.689) for one-year postoperative cCSS. Following validation, the C-index remained robust at 0.707 (95% CI, 0.721–0.693) for one-year postoperative cOS and 0.700 (95% CI, 0.716–0.684) for one-year postoperative cCSS. ROC and calibration curves provided evidence of the model's stability and reliability. Furthermore, DCA underscored the nomogram’s superior clinical utility.ConclusionsOur study developed nomograms and predictive models for postoperative stage III survival in T3–T4 colon cancer with the aim of accurately estimating conditional survival. Survival bias in our analyses may lead to overestimation of survival outcomes, which may limit the applicability of our findings.

Adjuvant chemotherapy in stage 1 colon cancer: Patient characteristics and survival analysis from the national cancer database

BackgroundA subset of patients in ACS-NCDB with stage-1 colon cancer received adjuvant chemotherapy (AC), in contrast to national guidelines. This study aimed to define this population and evaluate associations between AC and survival. MethodsPatients with T1-2N0 colon cancer from 2004 to 2016 were separated into AC and non-AC groups. Adverse pathological features (APF) included T2, poor differentiation, lymphovascular invasion, positive margin, and inadequate lymph nodes (<12). Cox proportional hazard models were used to estimate prognostic factors for overall survival (OS). ResultsA total of 1745 of 139,857 patients (1.2 %) received AC. Receiving AC was associated with male sex (p = 0.02), uninsured (p < 0.01), low income (p = 0.02), or having ≥2 APFs (p < 0.001). In the total cohort, AC was associated with increased mortality (HR 1.14 [1.04–1.24] P < 0.01). On subset analysis, AC was associated with improved OS for patients with ≥2 APFs (log-rank P=<0.001), and decreased mortality when adjusted for covariates (HR 0.81 [0.69–0.95] P=<0.01). The most significant predictor of mortality was old age (HR 3.78 [3.67, 3.89] p ≤ 0.01), followed by higher Charlson Comorbidity Index (HR 1.73 [1.69, 1.76] (p ≤ 0.01), and higher APF score (HR 1.46 [1.42, 15.2] p ≤ 0.01). ConclusionAC was associated with decreased survival in the total cohort of stage 1 colon cancer patients, but was associated with improved survival for patients with multiple APFs.

LncRNA EBLN3P Accelerates Cell Proliferation and Invasion of Colon Cancer through Modulating the miR-519d-3p/ZFP91 Axis.

Purpose: The study aims to explore the roles and underlying mechanisms of long noncoding RNAs endogenous bornavirus-like nucleoprotein (lncRNA EBLN3P) in colon cancer, emphasizing the potential impact of these insights on advancing colon cancer treatment strategies. By shedding light on lncRNA EBLN3P's involvement, this research could contribute to the development of novel therapeutic approaches, enhancing the efficacy of interventions for colon cancer patients. Methods: We employed quantitative reverse transcription polymerase chain reaction to assess the levels of lncRNA EBLN3P, zinc finger protein (ZFP91), and miR-519d-3p, alongside CCK-8 and EdU assays for cell proliferation, flow cytometry for apoptosis, and Transwell and wound healing assays for migration and invasion. The in vivo function of lncRNA EBLN3P was investigated through a xenograft model, and protein levels were evaluated via Western blot analysis. Results: LncRNA EBLN3P was found to be upregulated in colon cancer tissues and cells, promoting cell proliferation and metastasis while inhibiting apoptosis. Downregulation of lncRNA EBLN3P reduced tumor size, volume, and weight in a mouse model. MiR-519d-3p, which negatively interacts with lncRNA EBLN3P, was found to be downregulated in colon cancer tissues and cell lines. Its upregulation hindered cancer cell proliferation and metastasis while enhancing apoptosis. ZFP91, a binding partner of miR-519d-3p, was upregulated in colon cancer and inversely related to miR-519d-3p levels. Rescue experiments indicated that the effects of lncRNA EBLN3P silencing could be reversed by miR-519d-3p suppression, but were mitigated by ZFP91 downregulation. Conclusion: LncRNA EBLN3P facilitates colon cancer progression via the miR-519d-3p/ZFP91 axis, presenting a novel understanding of lncRNA EBLN3P's role and offering potential therapeutic insights for colon cancer treatment. This study fills a critical gap by linking lncRNA EBLN3P with the miR-519d-3p/ZFP91 axis in the context of colon cancer, thereby broadening our understanding of the molecular mechanisms underlying colon cancer progression.

A phenotypic screening approach to target p60AmotL2-expressing invasive cancer cells

BackgroundTumor cells have the ability to invade and form small clusters that protrude into adjacent tissues, a phenomenon that is frequently observed at the periphery of a tumor as it expands into healthy tissues. The presence of these clusters is linked to poor prognosis and has proven challenging to treat using conventional therapies. We previously reported that p60AmotL2 expression is localized to invasive colon and breast cancer cells. In vitro, p60AmotL2 promotes epithelial cell invasion by negatively impacting E-cadherin/AmotL2-related mechanotransduction.MethodsUsing epithelial cells transfected with inducible p60AmotL2, we employed a phenotypic drug screening approach to find compounds that specifically target invasive cells. The phenotypic screen was performed by treating cells for 72 h with a library of compounds with known antitumor activities in a dose-dependent manner. After assessing cell viability using CellTiter-Glo, drug sensitivity scores for each compound were calculated. Candidate hit compounds with a higher drug sensitivity score for p60AmotL2-expressing cells were then validated on lung and colon cell models, both in 2D and in 3D, and on colon cancer patient-derived organoids. Nascent RNA sequencing was performed after BET inhibition to analyse BET-dependent pathways in p60AmotL2-expressing cells.ResultsWe identified 60 compounds that selectively targeted p60AmotL2-expressing cells. Intriguingly, these compounds were classified into two major categories: Epidermal Growth Factor Receptor (EGFR) inhibitors and Bromodomain and Extra-Terminal motif (BET) inhibitors. The latter consistently demonstrated antitumor activity in human cancer cell models, as well as in organoids derived from colon cancer patients. BET inhibition led to a shift towards the upregulation of pro-apoptotic pathways specifically in p60AmotL2-expressing cells.ConclusionsBET inhibitors specifically target p60AmotL2-expressing invasive cancer cells, likely by exploiting differences in chromatin accessibility, leading to cell death. Additionally, our findings support the use of this phenotypic strategy to discover novel compounds that can exploit vulnerabilities and specifically target invasive cancer cells.

Abstract CT194: N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study

Abstract Introduction. Zelenirstat (PCLX-001) is a small molecule inhibitor of N-myristoylation, a process that involves addition of the fatty acid myristate to over 200 proteins by two N-myristoyltransferases (NMT1 and 2). These include Src family kinases and c-Abl. Inhibition of N-myristoylation by zelenirstat leads to the degradation of non-myristoylated proteins and cancer cell death. We conducted a phase I trial to evaluate the safety, tolerability, and maximally tolerated dose (MTD) of zelenirstat in patients with refractory cancer. Methods. Differential mass spectrometry was performed in NMT1 and NMT2 CRISPR/Cas9 KOs or zelenirstat-treated HAP1 cells to identify N-myristoylation-regulated proteins. Fully consented patients with advanced solid malignancies or refractory B-cell lymphomas were administered escalating doses of zelenirstat in 28-day cycles until progression or dose-limiting toxicity (DLT). Results. Proteomic analysis of cells with genetic or pharmacological NMT inhibition was performed to gain insights into NMT substrates and function. In addition to the rapid degradation of SFKs, which disrupts the pro-survival signaling of RTKs, we identified multiple respiratory complex I proteins as the most degraded, including NDUFAF4. NMT1 KO and zelenirstat treatment disrupted complex I leading to oxidative phosphorylation (OXPHOS) inhibition, which is essential for both cancer stem cell survival and metastasis. Continuous once-daily zelenirstat at 20 mg to 210 mg was well tolerated, with no dose-limiting toxicities in 24 patients up to and including 210 mg. Gastrointestinal DLTs were observed in the 280 mg cohort, establishing 210 mg as the MTD. Oral absorption was rapid, and pharmacokinetics were suitable for once daily dosing. Seven patients had stable disease as best response, including pancreatic, ovarian and colon cancer patients; one colon cancer patient with 5 prior lines of therapy continues 210 mg beyond 11 cycles with reduction in carcinoembryonic antigen (CEA) and tumor dimensions. Kaplan-Meier analysis revealed longer progression-free survival (log-rank p=0.033) and overall survival (p=0.026) in the patients treated at 210 mg (n=7) when compared with patients treated in lower dose cohorts (n=17). Conclusion. Zelenirstat has a unique dual impact on growth signaling and OXPHOS. Having previously demonstrated pre-clinical efficacy in hematologic cancers in vitro and in vivo, we now demonstrate the therapeutic potential of zelenirstat in patients with refractory advanced solid malignancies, warranting further clinical evaluation in these indications. Citation Format: Luc Gerard Berthiaume, Erwan Beauchamp, Jay Gamma, Rony Pain, Morris A. Kostiuk, Christopher R. Cromwell, Eman W. Moussa, Olivier Julien, Basil P. Hubbard, John Kuruvilla, Laurie H. Sehn, Jennifer Spratlin, Rahima Jamal, Randeep Sangha, John R. Mackey. N-myristoylation inhibitor zelenirstat: New mechanistic insights and efficacy signals from a first in human phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT194.

Abstract LB320: Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis

Abstract Cancer associated fibroblasts (CAFs) express a variety of cytokines and factors that activate and contribute to pathways that favor tumorigenesis. CAFs disrupt normal cellular functions, such as cell cycle regulation and cell death including apoptosis, or signal certain types of cells to abnormally activate pro-tumor activities. In addition, when it is abnormally activated, it is characterized by increased collagen deposition and more contractility. Likewise, This pattern of abnormal activation is often observed in keloid disease. Keloid constitutes an abnormal fibroproliferative wound healing response with excessive collagen deposition causing abnormal wound healing. To better understand the CAF subtypes with abnormal activation and cancer-promoting properties and the subtypes of keloid fibroblasts with similar activation properties, it is essential to find the master transcription factors (TFs) that determine their identity. To identify functionally important TFs in abnormal CAFs and keloid fibroblasts, we analyzed H3K27ac ChIP-seq of CAFs and keloid fibroblasts and observed that Runx2 significantly enriched the two types of abnormal fibroblasts.To investigate the biological function of Runx2 , we established CAFs from colon cancer patients and performed ShRNA-mediated knockdown of the RUNX2 gene. We confirmed that knockdown of RUNX2 in CAFs suppressed the migration or invasion of cancer cells. Additionally, using a gel contraction assay, we confirmed that fibroblast contractility was significantly reduced by RUNX2 knockdown. Similarly, in keloid fibroblasts, it was confirmed that the migration and gel contraception abilities of fibroblasts were significantly reduced following knockdown of RUNX2 [A1] gene. Last but not least, expression of ECM elements, such as collagens and fibronectin, were significantly as a result of the knockdown of the RUNX2 gene in both abnormally activated fibroblasts. To conclude, we believe that Runx2 acts as a key TF that maintains the contractility and ECM remodeling ability of abnormally activated fibroblasts. Our findings indicate that Runx2 is a attractive therapeutic target not only for pro-tumorigenesis in the cancer microenvironment, but also for keloid fibroblasts. Citation Format: Keun-Woo Lee, Insuk Sohn, Seok-Hyung Kim, So-Young Yeo. Runx2 as a key transcription factor regulating contractility and extracellular matrix remodeling in abnormally activated fibroblasts: Implications for tumorigenesis and keloid pathogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB320.

Chemotherapeutic potential of betanin/capecitabine combination targeting colon cancer: experimental and bioinformatic studies exploring NFκB and cyclin D1 interplay.

Introduction: Betanin (C₂₄H₂₆N₂O₁₃) is safe to use as food additives approved by the FDA with anti-inflammatory and anticancer effects in many types of cancer cell lines. The current experiment was designed to test the chemotherapeutic effect of the combination of betanin with the standard chemotherapeutic agent, capecitabine, against chemically induced colon cancer in mice. Methods: Bioinformatic approach was designed to get information about the possible mechanisms through which the drugs may control cancer development. Five groups of mice were assigned as, (i) saline, (ii) colon cancer, (iii) betanin, (iv) capecitabine and (v) betanin/capecitabine. Drugs were given orally for a period of six weeks. Colon tissues were separated and used for biological assays and histopathology. Results: In addition, the mRNA expression of TNF-α (4.58-fold), NFκB (5.33-fold), IL-1β (4.99-fold), cyclin D1 (4.07-fold), and IL-6 (3.55-fold) and protein levels showed several folds increases versus the saline group. Tumor histopathology scores in the colon cancer group (including cryptic distortion and hyperplasia) and immunostaining for NFκB (2.94-fold) were high while periodic-acid Schiff staining demonstrated poor mucin content (33% of the saline group). These pathologic manifestations were reduced remarkably in betanin/capecitabine group. Conclusion: Collectively, our findings demonstrated the usefulness of betanin/capecitabine combination in targeting colon cancer and highlighted that betanin is a promising adjuvant therapy to capecitabine in treating colon cancer patients.

The safety and effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy in patients with pathological T3-4 locally advanced colon cancer

The safety and effectiveness of prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) in pathological T3-4 locally advanced (pT3N+M0 and pT4NxM0) colon cancer (CC) patients with radical resection need further study. Clinical and pathological information of pT3-4 locally advanced CC patients who received radical surgery in our hospital from January 2018 to December 2020 were analyzed. The prognosis of patients was estimated using Cox proportional hazards regression analysis and Kaplan-Meier method. Among 927 patients, 10.4% (96/927) received prophylactic HIPEC based on 5-FU, 4.6% (43/927) received prophylactic HIPEC based on lobaplatin, 85.0% (788/927) received conventional therapy. The incidence of metachronous peritoneal carcinomatosis (mPC) was 9.4%. Complications occurred in 32 patients (4.1%) in the conventional therapy group, 6 patients (6.3%) in the prophylactic HIPEC group based on 5-FU and 3 patients (7.0%) in the prophylactic HIPEC group based on lobaplatin within 30 days after surgery (5-FU vs. conventional therapy group, p=0.464; Lobaplatin vs. conventional therapy group, p=0.591). Multivariate Cox regression analysis revealed that prophylactic HIPEC based on either 5-FU or lobaplatin regimen could not effectively improve mPC-free survival (5-FU: p=0.020, HR=1.927, 95% CI, 1.111-3.343; Lobaplatin: p=0.167, HR=0.247, 95% CI, 0.034-1.796), overall survival (5-FU: p=0.361, HR=1.360, 95% CI, 0.703-2.634; Lobaplatin: p=0.780, HR=0.816, 95% CI, 0.195-3.416) and disease-free survival (5-FU: p=0.525, HR=1.149, 95% CI, 0.749-1.760; Lobaplatin: p=0.117, HR=0.488, 95% CI, 0.199-1.198). Early prophylactic HIPEC based on 5-FU or lobaplatin subsequent to radical resection for patients with pT3-4 locally advanced CC is safe, but not effective in reducing the risk for mPC.

Anti-Anisakis antibodies in colon cancer patients and their relationship with γδ T-cells

Many pathogens are related to carcinogenesis. Chronic inflammation, as a result of persistent infection, leads to DNA damage, higher expression of oncogenes, decreased apoptosis and immunosuppression, which are some of the reasons for cancer induction. Among parasites, Schistosoma, Opistorchis and Clonorchis are recognised as infectious agents which contribute to cancer. A relationship between Anisakis and cancer was hypothesised because cellular responses to Anisakis products could result in inflammation and DNA damage. Previous research has shown a decrease in CD8+ γδ T-cells and an increase in αβ and γδ T-cell apoptosis in colon cancer (CC) samples. Ninety-two CC patients and 60 healthy subjects were recruited. γδ and αβ T-cells were analysed, and their apoptosis was evaluated. Anti-Anisakis antibodies were tested in sera from CC patients and controls. Anti-Anisakis IgG, IgM, IgA and IgE antibodies were significantly higher in CC patients. A significant increase in anti-Anisakis IgA levels was observed in patients with angiolymphatic invasion. The number of all γδ T-cells, as well as CD3+ CD4+ αβ T-cells, was significantly lower in CC patients. The apoptosis of all T-cells was significantly increased in patients with CC. We observed a significantly higher percentage of anti-Anisakis IgE positive patients having a deficit of CD3+ γδ T-cells. Our results suggest a relationship between Anisakis and CC.

Spouses of patients treated for colon cancer: identification of key caregiver skills using the Delphi method.

Spouses are often the front-line caregivers for colon cancer patients. Providing this support requires a particular set of coping skills. Our objective was to identify key skills that healthcare and medico-social sector professionals could assess in routine practice that would allow them to propose appropriate support to spouses who are accompanying colon cancer patients in their care pathway. An online two-round Delphi study was conducted among French colon cancer patients, spouses and professionals. The content of the Delphi study was developed from a previously published qualitative study. In the first round of the study, 63% of the participants were professionals (n = 40), 19% spouses (n = 12) and 17% patients (n = 11). In the second round, they were respectively 55% (n = 22), 22% (n = 9) and 22% (n = 9). Twenty-seven of the 75 proposed skills were consensually identified as key skills. Nine were related to emotional and psychological well-being, six to social relations, four to organisation, five to health and three to domestic domains. The three most consensual skills (≥ 90% agreement) for spouses were (1) helping the tired patient in everyday life, (2) stimulating the patient to prevent him/her from giving up and (3) limiting one's amount of personal time to care for the patient. The study identified the key skills needed by spouses of patients being treated for colon cancer. Better awareness of these skills among professionals would enable them to offer tailored support to help patients and spouses maintain their physical and emotional well-being.

Clinical, pathological, and adjuvant chemotherapy use differences among microsatellite unstable and microsatellite stable colon cancers

BackgroundColon cancers are categorized into mismatch repair deficient/microsatellite unstable (MSI-H) and mismatch repair proficient/microsatellite stable (MSS) cancers. This study aims to compare the disease characteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups. MethodsMSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Cancer Database. We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages. Within MSI-H and MSS groups, we conducted a landmark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival. ResultsOf the 542,368 patients that met inclusion criteria, 120,751 (22%) had mismatch repair results available—out of these 96,928 (80%) had MSS colon cancers while 23,823 (19.7%) had MSI-H cancers. MSI-H disease had a bimodal age distribution (<40 years = 22%; ≥75 years = 26%) and was frequent among females (22%) and non-Hispanic Whites (20%). Among those < 65 years, 15% of low-risk stage 2 MSI-H patients and 40% of high-risk stage 2 MSI-H patients received adjuvant chemotherapy. More than two-thirds of stage 3 patients <65 years received adjuvant chemotherapy in both groups. After conducting propensity-score matching for age, gender, and co-morbidities, we found that adjuvant chemotherapy use had a trend towards lower overall survival (OS) in low-risk stage 2 MSI-H (HR = 1.8 [95% CI, 0.8–4.02]) and high-risk stage 2 MSI-H (HR = 1.42 [95% CI, 0.96–2.12]) groups. Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease. ConclusionsMSI-H colon cancer had bimodal age distribution. Among stage 2 MSI-H patients <65 years, a notable proportion received adjuvant chemotherapy. Among MSI-H stage 2 patients, adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients, irrespective of MSI status.

LncRNA ANRIL Promotes Glucose Metabolism and Proliferation of Colon Cancer in a High-Glucose Environment and is Associated with Worse Outcome in Diabetic Colon Cancer Patients.

The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. Epigenetic changes, such as deregulation of long non-coding RNA (lncRNA) and microRNA (miR), have been linked to the advancement of CC; however, the effects of high glucose levels on their deregulation and, in turn, colon cancer remain unexplored. Fifty patients had a dual diagnosis of CC and T2DM, and 60 patients with CC without diabetes mellitus were included in the study. qRT-PCR was used to examine the expression of lncRNA ANRIL and miR-186-5p in tissue samples. ANRIL, miR-186-5p, and their downstream target genes HIF-1α, PFK, HK, Bcl-2, and Bax were also determined in CC cell lines under various glucose conditions. Glucose uptake, lactate production and cells proliferation were estimated in CC cell lines. A significant upregulation of ANRIL expression levels (p<0.001) and a significant downregulation of miR-186-5p expression (p<0.001) in diabetic colon cancer specimens compared to those in non-diabetic colon cancer group were observed. MiR-186-5p expression levels were inversely correlated with ANRIL expression levels, blood glucose levels and HbA1c%. Concerning in vitro model, a significant upregulation of ANRIL, downregulation of miR-186-5p, upregulation of HIF-1α, glycolytic enzymes and activation of antiapoptotic pathway was detected in higher glucose concentrations than lower one. There was a significant increase of glucose uptake, lactate accumulation and proliferation of the Caco2 and SW620 cell lines in a dose dependent manner of glucose concentrations. Moreover, a significant positive correlation between glucose uptake and ANRIL expression was shown. A high-glucose environment can increase the tumor-promoting effect of ANRIL. ANRIL can promote glucose metabolism and colon cancer proliferation by downregulating miR-186-5p with subsequent upregulation of glycolysis enzymes expression and inhibition of apoptosis.

Development and Validation of a Prognostic Model based on 11 E3-related Genes for Colon Cancer Patients.

Colon cancer is a common tumor in the gastrointestinal tract with a poor prognosis. According to research reports, ubiquitin-dependent modification systems have been found to play a crucial role in the development and advancement of different types of malignant tumors, including colon cancer. However, further investigation is required to fully understand the mechanism of ubiquitination in colon cancer. We collected the RNA expression matrix of the E3 ubiquitin ligase-related genes (E3RGs) from the patients with colon adenocarcinoma (COAD) using The Cancer Genome Atlas program (TCGA). The "limma" package was used to obtain differentially expressed E3RGs between COAD and adjacent normal tissues. Then, univariate COX regression and least absolute shrinkage and selection operator (LASSO) analysis were performed to construct the prognostic signature and nomogram model. Afterward, we used the original copy number variation data of COAD to find potential somatic mutation and employed the "pRRophetic" package to investigate the disparity in the effectiveness of chemotherapy drugs between high and low-risk groups. The RT-qPCR was also implied to detect mRNA expression levels in tumor tissues. A total of 137 differentially expressed E3RG3 were screened and 11 genes (CORO2B, KCTD9, RNF32, BACH2, RBCK1, DPH7, WDR78, UCHL1, TRIM58, WDR72, and ZBTB18) were identified for the construction of prognostic signatures. The Kaplan-Meier curve showed a worse prognosis for patients with high risk both in the training and test cohorts (P = 1.037e-05, P = 5.704e-03), and the area under the curve (AUC) was 0.728 and 0.892 in the training and test cohorts, respectively. Based on the stratified analysis, this 11- E3RGs signature was a novel and attractive prognostic model independent of several clinicopathological parameters (age, sex, stage, TNM) in COAD. The DEGs were subjected to GO and KEGG analysis, which identified pathways associated with cancer progression. These pathways included the cAMP signaling pathway, calcium signaling pathway, Wnt signaling pathway, signaling pathways regulating stem cell pluripotency, and proteoglycans in cancer. Additionally, immune infiltration analysis revealed significant differences in the infiltration of macrophages M0, T cells follicular helper, and plasma cells between the two groups. We developed a novel independent risk model consisting of 11 E3RGs and verified the effectiveness of this model in test cohorts, providing important insights into survival prediction in COAD and several promising targets for COAD therapy.

Constructing and validating a risk model based on neutrophil-related genes for evaluating prognosis and guiding immunotherapy in colon cancer.

Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients. We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues. We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy. The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy.

Further Distance From Treating Facility is Associated With Advanced Colon Cancer at Presentation and Increased Mortality.

Colon cancer outcomes in the United States have improved over the last thirty years. However, there remain significant outcome disparities, especially in rural regions. It is unclear if distance to the treating facility has an independent effect on colon cancer mortality and outcomes. We sought to evaluate whether distance from a treating facility impacts stage at diagnosis and mortality. The National Cancer Database (NCDB) was utilized to identify a cohort of adult patients with colon cancer between the years 2013 and 2017 in all regions of the United States. Outcomes measured included colon cancer TNM stage, time to surgery, time to chemotherapy, and overall survival. A total of n = 356,189 patients met inclusion criteria. When controlling for race, education status, insurance status, comorbidities, and income, distance from the treating facility was a significant predictor of stage at presentation with more advanced clinical TNM stage as distance increased (AORs 1.12-1.62, P < .001 for all groups). Longer distance significantly increased the time to surgery (between 5.06 and 14.46days, P < .001) and overall mortality (HR 1.11-1.28, P < .001). Median survival was 82.4months for the closest group, versus 75.1months for the farthest group (P < .001). Increased distance from the treating facility resulted in a significantly higher stage at presentation, increased time to surgery, and increased mortality. These results suggest that there are significant disparities in access to cancer care for patients who live in rural areas. Targeted interventions by treating facilities are needed to improve screening and timely treatment for rural colon cancer patients.

Promoting post-traumatic growth in cancer patients: a randomized controlled trial of guided written disclosure.

BackgroundCancer is a life-threatening disease that triggers not only vulnerability to distressing symptoms but also a meaning-making process that may lead to post-traumatic growth. As people often struggle to integrate cancer illness into their meaning system to reach an adaptive meaning, psychological interventions focused on a reappraisal of the illness experience can facilitate this process. This multicenter randomized controlled trial (RCT) was primarily aimed at assessing the efficacy of a writing intervention known as a guided disclosure protocol (GDP), compared to a generic writing intervention, in promoting post-traumatic growth in stage I-III breast and colon cancer patients at the end of their adjuvant chemotherapy.MethodsBetween January 2016 and August 2020 recruitment of eligible subjects took place during follow-up clinical consultations. Assessment occurred at baseline (T0), after the intervention (T1, 3 months from baseline), and at 6 months from baseline (T2). Both interventions consisted of three 20-min writing sessions to be performed once every two weeks. Change in post-traumatic growth was assessed using the Posttraumatic Growth Inventory, meaning with the Constructed Meaning Scale, and psychological distress with the Impact of Event Scale and the Hospital Anxiety and Depression Scale.ResultsIn the five participating centers, 102 eligible patients were randomized and 72 participants completed follow-up evaluation. Most patients were women (79.4%), had breast cancer (68.6%), and stage I (27.5%), or stage II (44.1%) disease. Mean differences did not reach statistical significance for any of the dependent variables. However, an effect of the GDP, although not statistically relevant, was observed after the intervention in terms of enhanced post-traumatic growth and increased distress measured with the Impact of Event Scale.ConclusionThis is the first RCT investigating the efficacy of a GDP in cancer patients having post-traumatic growth as the primary aim. Though GDP is a promising intervention in promoting post-traumatic growth, the lack of statistical significance of our findings may be due to the study being underpowered, hence this trial should be replicated with an adequate sample size, paying attention to supporting recruitment.Clinical trial registration: ClinicalTrials.gov, identifier: 2015/0024360.

Defining the Role of Social Vulnerability in Treatment and Survival in Localized Colon Cancer: A Retrospective Cohort Study.

To determine whether variations in Social Vulnerability Index (SVI) are associated with disparities in colon cancer surgery and mortality. Colon cancer mortality is influenced by health care access, which is affected by individual and community-level factors. Prior studies have not used the SVI to compare surgical access and survival in localized colon cancer patients. Further, it is unclear if those above 65 years are more vulnerable to variations in SVI. We queried the Texas and California Cancer Registries from 2004-2017 to identify patients with localized colonic adenocarcinoma and categorized patients into <65 and ≥65 years. Our outcomes were survival and access to surgical intervention. The independent variable was census tract social vulnerability index, with higher scores indicating more social vulnerability. We used multivariable logistic regression and Cox proportional hazards for analysis. We included 73,923 patients with a mean age of 68.6 years (SD 13.0), mean SVI of 47.2 (SD 27.6), and 51.1% male. After adjustment, increasing SVI was associated with reduced odds of undergoing surgery (OR 0.996; 95% CI 0.995-0.997; P < 0.0001 and increased mortality (HR 1.002; 95% CI 1.001-1.002; P < 0.0001). Patients < 65 years were more sensitive to variation in SVI. Increased social vulnerability was associated with reduced odds of receiving surgery for early-stage colon cancer as well as increased mortality. These findings amplify the need for policy changes at the local, state, and federal level to address community-level vulnerability to improve access to surgical care and reduce mortality.

Association of the immediate perioperative dynamics of circulating DNA levels and neutrophil extracellular traps formation in cancer patients.

Elevated circulating DNA (cirDNA) concentrations were found to be associated with trauma or tissue damage which suggests involvement of inflammation or cell death in post-operative cirDNA release. We carried out the first prospective, multicenter study of the dynamics of cirDNA and neutrophil extracellular trap (NETs) markers during the perioperative period from 24 h before surgery up to 72 h after curative surgery in cancer patients. We examined the plasma levels of two NETs protein markers [myeloperoxidase (MPO) and neutrophil elastase (NE)], as well as levels of cirDNA of nuclear (cir-nDNA) and mitochondrial (cir-mtDNA) origin in 29 colon, prostate, and breast cancer patients and in 114 healthy individuals (HI). The synergistic analytical information provided by these markers revealed that: (i) NETs formation contributes to post-surgery conditions; (ii) post-surgery cir-nDNA levels were highly associated with NE and MPO in colon cancer [r=0.60 (P<0.001) and r=0.53 (P<0.01), respectively], but not in prostate and breast cancer; (iii) each tumor type shows a specific pattern of cir-nDNA and NETs marker dynamics, but overall the pre- and post-surgery median values of cir-nDNA, NE, and MPO were significantly higher in cancer patients than in HI. Taken as a whole, our work reveals the association of NETs formation with the elevated cir-nDNA release during a cancer patient's perioperative period, depending on surgical procedure or cancer type. By contrast, cir-mtDNA is poorly associated with NETs formation in the studied perioperative period, which would appear to indicate a different mechanism of release or suggest mitochondrial dysfunction.