Colon Carcinoma Patients Research Articles

Biomarker-stratified first-line treatment of right-sided metastatic colon cancer with interdisciplinary collaboration in the IVOPAK II trial.

Patients with right-sided metastatic colon carcinoma have a significantly worse prognosis than those with left-sided colorectal cancer (CRC), regardless of treatment. The aim of the prospective IVOPAK II study was to implement an interdisciplinary guideline-conform personalized CRC palliative therapy of metastatic colorectal carcinoma and to improve the overall survival (OS) by multidisciplinary approach via secondary metastatic resection. We present the efficacy data of first-line treatment and the benefit of interdisciplinary collaboration of right-sided metastatic colon carcinoma patients: n = 25. RAS mutation: n = 20 (80%): received systemic first-line treatment: FOLFIRI plus bevacizumab. All-RAS-wildtype: n = 5 (20%): received systemic first-line treatment: FOLFIRI plus cetuximab. Last date evaluation: 31 January 2024. Median age: 59.6 years (range 42-71), men/women: 14/11. Eastern Cooperative Oncology Group (ECOG) index: 0/1/2 : 11/10/4. Evaluable for response: n = 25. Complete response: n = 0, partial response: n = 14 (56%), stable disease: n = 8 (32%), progressive disease: n = 3 (12%), early tumor shrinkage: n = 13 (52%), estimates progression-free survival: 13 months (95% CI 8-17 months), estimated OS: 48 months (95% CI 25-71 months), median follow-up: 26 months (1-61 months), no evidence of disease: n = 4 (16%). A chemotherapy doublette regimen with FOLFIRI plus a biological as first-line treatment shows promising efficacy and secondary metastatic resection after interdisciplinary discussion was associated with a survival benefit in right-sided metastatic colon carcinoma.

Implications of Pretreatment Serum Carcinoembryonic Antigen Levels and Perineural Invasion with Staging, Prognosis, and Management in Stage I-III Colon Cancer after Surgery: A Retrospective Cohort Study in the SEER Database.

Pretreatment levels of serum carcinoembryonic antigen (CEA) and perineural invasion (PNI) are related to poor prognosis in colon cancer. We analyzed the CEA and PNI (defined as incorporation of carcinoembryonic antigen and perineural invasion (CP)-stage), which are included in the Tumor-Node-Metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC), and evaluated the survival prognosis of patients treated with surgery in I-III stage colon carcinoma. We employed a retrospective study for eligible colon carcinoma patients obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015. Kaplan-Meier curve and Multivariate Cox regression analysis were used to analyze different TNM-CP stages for the cancer-specific survival (CSS) probabilities in colon cancer. In our study, CEA levels and PNI were significant prognostic factors (p < 0.05), and the newly proposed CP-stage was an independent prognostic index in stage I-III colon carcinoma after surgery. Multivariate Cox regression analyses indicated that CP1-stage was related to a 63.9% increased risk of cancer-specific mortality (hazard ratio (HR): 1.639, 95% confidence interval (CI): 1.544-1.739, p < 0.001), compared with CP0-stage in colon cancer. In respective TNM stages, the CP0-stage had an advantage over the CP1-stage for CSS (p < 0.001). Moreover, CP1-stage patients with node-negative colon cancer were contacted with similar or worse survival in comparison to CP0-stage patients with node-positive. For postoperative patients with stage I-III colon cancer, our study indicated that the CP stage is a significant prognostic factor for CSS, which deserves more clinical attention. It's worth noting that including the CP stage in the AJCC TNM staging system of colon carcinoma is beneficial to the survival prediction and clinical treatment.

Abstract 5493: Digital spatial profiling of MC38 colon carcinoma following checkpoint inhibition

Abstract Immunotherapy aims to bolster the immune response within the tumor microenvironment (TME). However, checkpoint inhibitors utilized in the treatment of colon carcinoma have demonstrated efficacy only in certain patients. To develop more effective therapeutics, strategies that navigate the heterogeneous nature of the TME must be employed. The MC38 tumor model, known for its immunologically active characteristics and responsiveness to certain immunotherapies, is widely used for preclinical drug development. Furthermore, elevated levels of pan-cytokeratin (PanCK) expression in tumors have shown an association with diminished survival rates among colon carcinoma patients. In this study, we used the GeoMx® DSP platform (NanoString Technologies) to investigate the spatial expression profile of PanCK in MC38 tumors and analyze the impact that PanCK expression exerts on anti-PD-1 induced gene expression in tumor and immune cells. To this end, C57BL/6J female mice were implanted with MC38 cells, enrolled into groups, and treated with anti-PD-1 antibody. Tumor growth was monitored by caliper measurements and anti-PD-1 produced minimal responses with a Day 22 median % Delta T/C value of 88%. For DSP analysis, tumors were collected 10 days post-treatment, formalin fixed for paraffin embedding, and then sectioned for PanCK and CD45 protein visualization. Regions of interest were drawn to create a matrix analysis that defined regions with high or low PanCK expression, that were proximal or distal to CD45+ immune rich regions of the tumor. A segmentation algorithm was applied to examine gene expression within each region using the GeoMx Mouse Whole Transcriptome Atlas. Cluster analysis revealed an enrichment of apoptosis and autophagy gene sets in tumor cells that were proximal to immune rich regions. In the CD45+ segment, immune cells adjacent to high PanCK-expressing cells contained 318 genes with significantly increased expression levels when compared to low PanCK-expressing cells, and only 11 genes with decreased expression levels. The upregulated genes were enriched for numerous biomarkers of T cell recruitment and activation, including cd3, cd8, cxcr3, ccl5, cxcl9, icos, and cd27. Next, we conducted a linear mixed model analysis to examine the impact of PanCK expression on anti-PD-1 induced gene regulation. Notably, an enrichment of genes that code for T cell exhaustion biomarkers was observed in immune cells near PanCK high expressing cells, including ctla4, slamf7, tigit, and lag3. In summary, the most pronounced transcriptomic changes occurred within immune cells situated near tumor cells displaying high PanCK expression and suggest that PanCK expression correlates directly with T cell recruitment and activation but also exhaustion. Furthermore, these data emphasize the significance of spatial analysis as a valuable component of preclinical research, as demonstrated in MC38 tumor model. Citation Format: Priyanka Singh, Daniel Saims, Sheri Barnes, David Draper. Digital spatial profiling of MC38 colon carcinoma following checkpoint inhibition [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 5493.

Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II–III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1–TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063–2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.

Problems of staging complicated forms of colon carcinoma in patients who were urgently operated in a general surgical hospital

The aim of the study: to analyze the results of surgical treatment and pathomorphological examination of preparations of patients who were urgently operated on for complicated forms of colon cancer, and to assess their influence on the correct staging of the tumor process in the postoperative period. Materials and methods. An analysis of data from pathomorphological studies of 71 (100 %) patients who underwent treatment at the surgical department for complicated forms of colon cancer was carried out. Results. Colon adenocarcinoma was detected in all 71 (100 %) patients (mucinous adenocarcinoma in 3 (4.23 %) patients, and the rest 68 (95.77 %) – unspecified adenocarcinoma). 44 (61.97 %) patients were diagnosed with moderately differentiated adenocarcinoma of the colon, 25 (35.21 %) – with poorly differentiated, and 2 (2.82 %) – with highly differentiated tumors. Conclusions. In the case of surgical interventions for complicated forms of colon cancer, lymphatic dissection in the minimum extent (D1) was performed in 54 (76.06 %) patients, and 17 (23.94 %) patients were operated on without removal of lymph nodes. The insufficient level of performing lymphatic dissections in patients with complicated forms of malignant pathology of the large intestine does not make it possible to assess the real picture of metastatic lesions of regional lymph nodes and to assign the correct stage of pN according to TNM 8 (in 17 (23.94 %) patients, no pathomorphological assessment was performed at all, and in 40 (56.34 %) patients, the number of examined lymph nodes were not indicated in the preparation). In the structure of staging of oncopathology, in 12 (16.90 %) patients, the stage of cancer was assign only according to the criterion of the degree of invasion (T) and in 5 (7.04 %) patients – only according to the data of instrumental examination and intraoperative revision (clinically), and was overestimated. Lack of a clear consistent assessment of the macroscopic, microscopic, immunohistochemical and molecular characteristics of the tumor process in 17 (23.94 %) patients leads to inaccuracies in the assessment of the stage of the tumor process, which in turn affects the prognosis for relapse and survival of the patient, and the tactic of postoperative treatment.

The DEAD-box RNA helicase DDX5 (p68) and β-catenin: The crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer

Forkhead box M1 (FOXM1), a vital member of the Forkhead box family of transcription factors, helps in mediating oncogenesis. However, limited knowledge exists regarding the mechanistic insights into the FOXM1 gene regulation. DDX5 (p68), an archetypal member of the DEAD-box family of RNA helicases, shows multifaceted action in cancer progression by arbitrating RNA metabolism and transcriptionally coactivating transcription factors. Here, we report a novel mechanism of alliance between DDX5 (p68) and the Wnt/β-catenin pathway in regulating FOXM1 gene expression and driving colon carcinogenesis. Initial bioinformatic analyses highlighted elevated expression levels of FOXM1 and DDX5 (p68) in colorectal cancer datasets. Immunohistochemical assays confirmed that FOXM1 showed a positive correlation with DDX5 (p68) and β-catenin in both normal and colon carcinoma patient samples. Overexpression of DDX5 (p68) and β-catenin increased the protein and mRNA expression profiles of FOXM1, and the converse correlation occurred during downregulation. Mechanistically, overexpression and knockdown of DDX5 (p68) and β-catenin elevated and diminished FOXM1 promoter activity respectively. Additionally, Chromatin immunoprecipitation assay demonstrated the occupancy of DDX5 (p68) and β-catenin at the TCF4/LEF binding element (TBE) sites on the FOXM1 promoter. Thiostrepton delineated the effect of FOXM1 inhibition on cell proliferation and migration. Colony formation assay, migration assay, and cell cycle data reveal the importance of the DDX5 (p68)/β-catenin/FOXM1 axis in oncogenesis. Collectively, our study mechanistically highlights the regulation of FOXM1 gene expression by DDX5 (p68) and β-catenin in colorectal cancer.

Feasibility and effectiveness of a multimodal rehabilitation program (Fit4Chemo) in patients with stage 3 colon carcinoma prior to and during adjuvant chemotherapy

Background: In the Netherlands, 5,000 patients are diagnosed with colon carcinoma (CC) with lymph node metastases every year. These stage 3 CC patients require adjuvant chemotherapy after surgical resection to prevent recurrence or metastasis and thus to improve survivability. If the additional chemotherapy cannot be started in time or cannot be fully completed, 5-year survival rates drop from 75% to 39%. Due to high risk of complications (up to 60%) after colorectal surgery, postoperative recovery in patients is often delayed. As a result, only 50% of patients can start adjuvant chemotherapy in time, but another 50% of these patients need a dose reduction or discontinuation of adjuvant chemotherapy due to side effects. Research shows that functional recovery can be accelerated by optimizing a patient’s condition preoperatively through multimodal prehabilitation. By analogy, it can be hypothesized that a comparable multimodal rehabilitation program might lead into enhanced recovery after surgery, resulting in timely started adjuvant chemotherapy and higher compliance in patients with stage 3 CC.

Clinicopathological Parameters and Immunohistochemical Expression of EGFR in Colorectal Carcinoma: A Cross-sectional Study

Introduction: Colorectal Carcinoma (CRC) is the third most common type of cancer worldwide and is one of the leading causes of cancer-related death. Adenocarcinoma is the most common type. Histopathological examination is necessary to determine the type and extent of the tumour, which is essential for patient management and prognosis. Molecular markers play a major role in CRC, among which Epidermal Growth Factor Receptor (EGFR) has prognostic significance. Aim: The aim of this study was to evaluate the immunohistochemical expression of EGFR in cases of colonic carcinoma and analyse its relationship with various histological and clinical parameters. Materials and Methods: An observational (cross-sectional) study was conducted in the Department of Pathology, Sree Mookambika Institute of Medical Sciences, Kulasekharam, Kanyakumari district, Tamil Nadu, India. Data from colonic carcinoma patients confirmed by Haematoxylin and Eosin (H&amp;E) staining were collected over a three-year period from January 2019 to December 2021. A total of 58 cases were included. The characteristics studied included age, sex, Carcinoembryonic Antigen (CEA) levels, tumour site, size, degree of histological differentiation (well, moderate, poor), TNM staging, and lymph node status. The EGFR score was obtained by multiplying the grade (% positive cells) by the intensity, and a composite score ranging from 0 to 9 was obtained. This score was used to define low EGFR expression (&lt;6) or high EGFR expression (&gt;6). Analysis was performed using the Chi-square test in Statistical Package for the Social Sciences (SPSS) version 20.0. Results: Among the 58 patients included in the study, the most common age group affected by CRC was 61 to 70 years (28 cases; 48.3%), with a mean age of 63.32±14.36 years. The most common histological variant was low-grade adenocarcinoma (47 cases; 81.03%). EGFR reactivity was positive in 50 patients (86.20%). EGFR overexpression was significantly associated with histopathological type (low-grade adenocarcinoma) and tumour stage, with p-values of 0.03 and 0.001, respectively. Conclusion: Immunohistochemical overexpression of EGFR in CRC is associated with histopathological type and tumour staging in this study. This overexpression is associated with poor prognosis and can be used as a predictive marker for patients who yield positive results with chemotherapy.

Profile of patients of colon cancers treated without any targeted therapies and comparison of treatment outcome between left- and right-sided tumors: A retrospective study from a tertiary cancer center in South India

Introduction: Left- and right-sided colon cancers differ in pathology, tumor biology, and response to therapies. In our country, most of the patients with carcinoma of colon, do not afford targeted therapies and are treated with chemotherapy only, for their metastatic diseases. Aims: The present study aimed to find out differences in terms of survival outcomes between right- and left-sided colon carcinoma patients who were treated without any targeted therapy or immunotherapy. Materials and Methods: Retrospectively, data of patients of carcinoma colon who were diagnosed and treated in between January 2010 and August 2017 were collected. The different clinicopathological and survival parameters were compared between right-sided and left-sided colon carcinoma patients using Kaplan–Meier models, unadjusted Cox regression models, and Cox models stratified by stage. Results: Mean disease-free survival (DFS) for Stage I, II, and III patients was 37.9 months, 33.7 months, and 28.9 months, respectively, and mean progression-free survival (PFS) in 1st line for metastatic disease was 8.1 months. Mean PFS for metastatic diseases in 1st line was not different significantly between left- and right-sided tumors (left vs. right: 8.1 months vs. 8.5 months, P = 0.72). For nonmetastatic disease, mean overall survival (OS) was significantly better in left-sided tumors (left vs. right: 46.2 months vs. 39.6 months, P = 0.019). Those with metastatic disease at presentation, OS did not vary with side (left vs. right: 24.5 months vs. 24.2 months, P = 0.89). Among the patients, who had undergone curative surgery, either upfront or after conversion chemotherapy, left-sided tumors were found to have higher mean DFS and OS (left vs. right, DFS: 31.2 months vs. 20.4 months, P = 0.006, hazard ratio [HR] = 0.54, 95% confidence interval [CI]: [0.38–0.77]; OS: 46.4 months vs. 39.6 months, HR = 0.51, 95% CI = [0.31–0.84], P = 0.008). Conclusion: Patients with left-sided nonmetastatic tumors or metastatic tumors that could undergo curative surgery had higher DFS and OS. Among the patients who did not undergo curative surgery, and were treated with chemotherapy alone, PFS and OS were similar for tumors of both sides. With only chemotherapy without any targeted agents for the metastatic disease, there was no difference in survival with the side.

Value of Geographical Information Systems in Analyzing Geographic Accessibility to Inform Radiotherapy Planning: A Systematic Review.

Vulnerable populations face geographical barriers in accessing radiotherapy (RT) facilities, resulting in heterogeneity of care received and cancer burden faced. We aimed to explore the current use of Geographical Information Systems (GIS) in access to RT and use these findings to create sustainable solutions against barriers for access in low- and middle-income countries. A systematic review using the PRISMA search strategy was done for studies using GIS to explore outcomes among patients with cancer. Included studies were reviewed and classified into three umbrella categories of how GIS has been used in studying access to RT. Forty articles were included in the final review. Thirty-eight articles were set in high-income countries and two in upper-middle-income countries. Included studies were published from 2000 to 2020, and were comprised of patients with all-cancers combined, breast, colon, skin, lung, prostate, ovarian, and rectal carcinoma patients. Studies were categorized under three groups on the basis of how they used GIS in their analyses: to describe geographic access to RT, to associate geographic access to RT with outcomes, and for RT planning. Most studies fell under multiple categories. Although this field is relative nascent, there is a wide array of functions possible through GIS for RT planning, including identifying high-risk populations, improving access in high-need areas, and providing valuable information for future resource allocation. GIS should be incorporated in future studies, especially set in low- and middle-income countries, which evaluate access to RT.

Identification of Hypoxia-Related Subtypes, Establishment of Prognostic Models, and Characteristics of Tumor Microenvironment Infiltration in Colon Cancer.

Background: Immunotherapy is a treatment that can significantly improve the prognosis of patients with colon cancer, but the response to immunotherapy is different in patients with colon cancer because of the heterogeneity of colon carcinoma and the complex nature of the tumor microenvironment (TME). In the precision therapy mode, finding predictive biomarkers that can accurately identify immunotherapy-sensitive types of colon cancer is essential. Hypoxia plays an important role in tumor proliferation, apoptosis, angiogenesis, invasion and metastasis, energy metabolism, and chemotherapy and immunotherapy resistance. Thus, understanding the mechanism of hypoxia-related genes (HRGs) in colon cancer progression and constructing hypoxia-related signatures will help enrich our treatment strategies and improve patient prognosis. Methods: We obtained the gene expression data and corresponding clinical information of 1,025 colon carcinoma patients from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. We identified two distinct hypoxia subtypes (subtype A and subtype B) according to unsupervised clustering analysis and assessed the clinical parameters, prognosis, and TME cell-infiltrating characteristics of patients in the two subtypes. We identified 1,132 differentially expressed genes (DEGs) between the two hypoxia subtypes, and all patients were randomly divided into the training group (n = 513) and testing groups (n = 512). Following univariate Cox regression with DEGs, we construct the prognostic model (HRG-score) including six genes (S1PR3, ETV5, CD36, FOXC1, CXCL10, and MMP12) through the LASSO–multivariate cox method in the training group. We comprehensively evaluated the sensitivity and applicability of the HRG-score model from the training group and the testing group, respectively. We explored the correlation between HRG-score and clinical parameters, tumor microenvironment, cancer stem cells (CSCs), and MMR status. In order to evaluate the value of the risk model in clinical application, we further analyzed the sensitivity of chemotherapeutics and immunotherapy between the low-risk group and high-risk group and constructed a nomogram for improving the clinical application of the HRG-score. Result: Subtype A was significantly enriched in metabolism-related pathways, and subtype B was significantly enriched in immune activation and several tumor-associated pathways. The level of immune cell infiltration and immune checkpoint-related genes, stromal score, estimate score, and immune dysfunction and exclusion (TIDE) prediction score was significantly different in subtype A and subtype B. The level of immune checkpoint-related genes and TIDE score was significantly lower in subtype A than that in subtype B, indicating that subtype A might benefit from immune checkpoint inhibitors. Finally, an HRG-score signature for predicting prognosis was constructed through the training group, and the predictive capability was validated through the testing group. The survival analysis and correlation analysis of clinical parameters revealed that the prognosis of patients in the high-risk group was significantly worse than that in the low-risk group. There were also significant differences in immune status, mismatch repair status (MMR), and cancer stem cell index (CSC), between the two risk groups. The correlation analysis of risk scores with IC50 and IPS showed that patients in the low-risk group had a higher benefit from chemotherapy and immunotherapy than those in the high-risk group, and the external validation IMvigor210 demonstrated that patients with low risk were more sensitive to immunotherapy. Conclusion: We identified two novel molecular subgroups based on HRGs and constructed an HRG-score model consisting of six genes, which can help us to better understand the mechanisms of hypoxia-related genes in the progression of colon cancer and identify patients susceptible to chemotherapy or immunotherapy, so as to achieve precision therapy for colon cancer.

COL11A1 is Downregulated by miR-339-5p and Promotes Colon Carcinoma Progression.

The roles of COL11A1 in cancer have been increasingly considered, but the understandings of the effects of COL11A1 on colon carcinoma progress are much limited yet. qRT-PCR and Western blot were utilized to evaluate COL11A1 expression at mRNA and protein levels, respectively, in colon carcinoma cell lines. Afterward, the tumorigenesis biological effects of COL11A1 were examined by CCK-8, colony formation, Transwell, and wound healing methods. Moreover, upstream miRNAs containing the binding sites with COL11A1 were predicted by the bioinformatics methods. The interplay between COL11A1 and miR-339-5p was identified by a dual-luciferase assay. COL11A1 expression was prominently upregulated in colon carcinoma cell lines relative to that in normal human colon mucosal epithelial cell lines, and it was related to tumor stages. The outcomes of in-vitro experiments suggested that interfering with COL11A1 remarkably repressed the malignant behaviors of SW480 and SW620 cells. MiR-339-5p was markedly lowly expressed in colon carcinoma cell lines. Furthermore, miR-339-5p directly targeted and negatively regulated COL11A1 expression. COL11A1 upregulation promoted colon carcinoma cell functions, while overexpressing miR-339-5p evidently attenuated the promotion. These results proved the modulation of the miR-339-5p/COL11A1 axis in colon carcinoma cells, and miR-339-5p repressed colon carcinoma progression via COL11A1 downregulation. These results offer new underlying targets for the accurate therapy of colon carcinoma patients.

Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1.

Circular-RNA friend leukemia virus integration 1 (circ-FLI1; hsa_circ_0000370) is a noninvasive biomarker for the diagnosis of colon carcinoma (CC). Herein, we intended to investigate its functions and competing endogenous RNA (ceRNA) mechanisms in CC cells. In terms of expression status, circ-FLI1 was abnormally upregulated in CC patients’ tumors and cells, paralleled with DKC1 upregulation and miR-197-3p downregulation. Most strikingly, there was a direct target relationship between miR-197-3p and circ-FLI1 or DKC1 based on the starbase database, dual-luciferase reporter assay, and RNA immunoprecipitation. Functionally, the colony formation assay, MTS method, fluorescence-activated cell sorting method, cell cycle and apoptosis assays, and transwell assays were performed, and the results revealed that interfering circ-FLI1 and re-expressing miR-197-3p could restrict colony formation, cell viability, cell cycle progression, and migration/invasion of CC cells with apoptosis rate elevation; besides, they promoted oxaliplatin (L-OHP)-induced cell viability inhibition. Furthermore, there were counteractive effects between circ-FLI1 silencing and miR-197-3p depletion, miR-197-3p overexpression and DKC1 restoration on regulating CC cell functions and L-OHP resistance. With a xenograft tumor model, the anti-growth role of circ-FLI1 silencing was also found in vivo with or without L-OHP treatment. Collectively, we demonstrated that circ-FLI1 might confer L-OHP resistance and malignant progression of CC presumably through the circ-FLI1/miR-197-3p/DKC1 ceRNA axis.

Potential Role of 8-Hydroxyguanosine and some Pro Inflammatory Cytokines as Biomarkers in Colorectal Cancer Iraqi Patients

8-hydroxyguanosine (8-OHdG) is considered as an indicator of the oxidative stress. Pro inflammatory cytokines are critical parts of the pathophysiological processes to which treatment can be applied. The aim of this study was to evaluate 8-OHdG and pro inflammatory cytokines concentration in colon carcinoma patients. Blood samples were taken before treatment from 50 incident cases with colon cancer (stage III) admitted for health examination at the Nanakali Hospital in Erbil city with 45 healthy samples of controls with age range between 38-69 years for both groups. All studied parameters were estimated by ELISA. Participants at this study were 95 Participants ranged in age from 38 to 69 years, 50 Participants had been newly diagnosed with colorectal cancer (without treatment) with 45 individuals were healthy used as controls. The data showed a non-significant elevation by comparing the normal participants with colorectal cancer cases for (8-OHdG) by P-value 0.054 and a significant elevation for Tumor necrosis factor alpha (TNF-α) by P-value 0.019 and interleukin-6 (IL6) by P-value &lt;0.0001. While the data showed a significant depletion by P-value &lt;0.0001 for SOD and POX. The findings of the current study reveal that 8-OHdG refers to the local oxidative stress in colorectal cancer and TNF-α is accountable for increasing the concentrations of IL6, which is linked with inflammation process in the surrounding of cancer cell.

Alterations of circulating lymphocyte subsets in patients with colorectal carcinoma

IntroductionCellular immune response to cancer is known to be of great importance for tumor control. Moreover, solid tumors influence circulating lymphocytes, which has been shown for several types of cancer. In our prospective study we elucidate changes in lymphocyte subsets in patients with colorectal carcinoma compared to healthy volunteers.MethodsFlow cytometry was performed at diagnosis of colon carcinoma to analyze B cells, T cells and NK cells including various subtypes of each group. Univariate and multivariate analyses including age, gender, tumor stage, sidedness and microsatellite instability status (MSI) were performed.ResultsForty-seven patients and 50 healthy volunteers were included. Median age was 65 years in patients and 43 years in the control group. Univariate analysis revealed lower total lymphocyte counts, lower CD4 + cells, CD8 + cells, B cells and NKs including various of their subsets in patients. In multivariate analysis patients had inferior values of B cells, CD4 + cells and NK cells and various subsets, regardless of age and gender. Naïve, central memory and HLADR + CD8 + cells showed an increase in patients whereas all other altered subsets declined. MSI status had no influence on circulating lymphocytes except for higher effector memory CD8 + cells in MSI-high patients. Localization in the left hemicolon led to higher values of total cytotoxic T cells and various T cell subsets.ConclusionWe found significant changes in circulating lymphocyte subsets in colon carcinoma patients, independent of physiological alterations due to gender or age. For some lymphocyte subsets significant differences according to tumor localization or MSI-status could be seen.

Preoperative intravenous iron treatment reduces postoperative complications and postoperative anemia in preoperatively anemic patients with colon carcinoma

PurposeAnemia is common among patients with colorectal cancer and is associated with an increased risk of complications and poorer survival rate. The main objective of our study was to determine the effect of preoperative intravenous iron supplementation therapy on the need for red blood cell transfusions, other postoperative complications, and length of hospital stay in colon cancer patients undergoing colon resection.MethodsIn this retrospective cohort study, data were collected from medical records of all 549 colon carcinoma patients who underwent a colon resection in Helsinki University Hospital during the years 2017 and 2018. The patients were divided into two cohorts: one with anemic patients treated with preoperative intravenous iron supplementation therapy (180 patients) and one with anemic patients without preoperative intravenous iron supplementation therapy (138 patients). Non-anemic patients and patients requiring emergency surgery were excluded (231 patients).ResultsPatients treated with intravenous iron had less postoperative complications (33.9% vs. 45.9%, p = 0.045) and a lower prevalence of anemia at 1 month after surgery (38.7% vs. 65.3%, p < 0.01) when compared with patients without preoperative iv iron treatment. No difference was found in the amount of red blood cell transfusions, length of stay, or mortality between the groups.ConclusionThis is the first study demonstrating a significant decrease in postoperative complications in anemic colon cancer patients receiving preoperative intravenous iron supplementation therapy. This treatment also diminishes the rate of postoperative anemia, which is often associated with a facilitated recovery.

P056 Crohn’s Disease associated fibrosis modulates the expression of collagen receptors

Abstract Background Crohn’s Disease (CD) patients often develop stenotic complications as immunomodulatory treatments do not prevent the fibrogenic response in the affected tissues, where a dysregulated activation of stromal cells provokes an excessive deposition of extracellular matrix (ECM). Recent evidences support the notion that local cells can sense the consequent alterations in tissue structure and rigidity through receptors that respond to some ECM components, and this may perpetuate the fibrogenic process even in the absence of inflammation. We aim to analyse the relevance of these signalling pathways in the fibrotic process associated to CD. Methods We obtained fibrotic ileal tissues from CD patients and healthy ileal samples from colon carcinoma patients (control), and analysed the expression (RT-PCR, IHQ) of collagen receptors (integrins, discoidin domain receptors/DDR) and of markers for some stromal cells (fibroblasts, endothelial cells). The relationship between these sets of data was analysed by Pearson’s correlation and the results organized as a correlation matrix. The expression of collagen receptors was also analysed in endothelial cells (HUVEC) treated with TGFβ 2 (1ng/ml, 48h). Results Ileal samples from CD patients present a differential gene expression of collagen receptors (Fig 1), with increased levels of ITGA10, ITGA11 and DDR2, and reduced expression of DDR1. In CD tissues, the expression of ITGA11 and DDR1 showed a significant correlation, positive and negative respectively, with that of endothelial markers (Fig 2). These correlations do not occur in control tissues. Integrin-α11 was detected in endothelial cells of submucosal vessels (IHQ). In HUVEC, TGFβ 2 increased the expression of ITGA11 (8.1±0.7 fold induction, p&amp;lt;0.01) and reduced that of DDR1 (0.74±0.06 fold induction, p&amp;lt;0.01), without affecting that of the other collagen receptors. Conclusion Intestinal tissues from CD patients affected by fibrosis present an altered pattern of expression of collagen receptors, which suggests a regulatory role of the ECM in the fibrotic response, while the correlation analysis and the changes induced by the fibrotic cytokine TGFβ in endothelial cells insinuates a particular relevance of these stromal cells in this process.

A nine-gene signature to improve prognosis prediction of colon carcinoma

ABSTRACT This study aims to establish a gene model that can robustly and effectively predict the prognosis of colon carcinoma patients via bioinformatics. Data along with clinical information in GSE39582 Series Matrix were firstly downloaded from Gene Expression Omnibus (GEO) database. Next, differentially expressed genes (DEGs) were obtained through “edgeR” analysis. Finally, a risk predication model was established through a series of regression analyses, and then prognostic performance of the model was comprehensively evaluated though Kaplan-Meier and receiver operating characteristic (ROC) analysis. Gene set enrichment analysis (GSEA) was further performed. Totally, 846 DEGs were obtained by analyzing the gene expression data in GSE39582 dataset. A 9-gene signature-based risk predication model was established via regression analyses, and the model-based risk score was formulated as: Riskscore = (−0.1214) * TNFRSF11A + (−0.2617) * TMEM97 + (−0.1041) * LGR5 + 0.0973 * KLK10 + 0.1655 * HOXB8 + 0.227 * FKBP10 + (−0.1312) * CXCL13 + (−0.1316) * CXCL10 + 0.2593 * CD36. Kaplan-Meier curve showed that colon carcinoma patients in the high-risk group had a lower survival rate. GSEA showed that high-risk group and low-risk group displayed significant difference in biological pathways including ECM RECEPTOR INTERACTION. Besides, correlation analysis between the riskscore of the model and clinical features of patients revealed that the model could effectively predict the prognosis of patients in different ages (age>65, age<65) and stages (tumor_stage I/II, tumor_stage III/IV, T3&T4, N0&N1, N2&N3, M0). This study provides a robust model for the prognosis prediction of colon carcinoma, and lays a basis for researching the molecular mechanism underlying the development of colon carcinoma.

Clinical Significance and Oncogenic Activity of GRWD1 Overexpression in the Development of Colon Carcinoma.

ObjectiveGRWD1 (glutamate-rich WD40 repeat containing 1) is a multifunctional protein involved in multiple cellular regulatory pathways, particularly those associated with cell growth control. GRWD1 is represented as a potential oncogene in several cancers, however, the function and mechanism of GRWD1 in the development of colon cancer are still unknown.Materials and MethodsIHC was used to detect the expression of GRWD1 in colon carcinoma tissues. CCK-8, colony formation, and EdU were used to measure the cell proliferation after GRWD1 knockdown and overexpression. The distribution of the cell cycle was analyzed by flow cytometry. The effect of GRWD1 knockdown on migration and invasion was analyzed by wound healing and transwell assays.ResultsOverexpression of GRWD1 in colon carcinoma tissues was associated with pathological grading, tumor size, N stage, TNM stage, and poor survival. GRWD1 had high sensitivity and specificity in distinguishing colon cancer from noncancerous tissues, and might be served as an independent prognosis in colon carcinoma patients. Knockdown of GRWD1 significantly inhibited the cell proliferation and colony formation, and induced cell cycle arrest and more drug susceptibility, and suppressed the migration and invasion. GRWD1 exhibited these oncogenic activities might be associated with its regulation on the expression of PCNA and Ki67, Cyclin A2 and Cyclin B1, ABCC1 and GSTP1, MTA1 and MTA2.ConclusionGRWD1 may play an oncogenic activity in the development of colon carcinoma and its overexpression was associated with malignant characteristics and poor survival outcome of colon carcinoma. GRWD1 might be a potential target for future therapy.

Psychological Disorders, Cognitive Impairment, and Quality of Life with Chemotherapy-induced Neuropathy in Colon and Rectal Carcinoma Patients

Purpose: To evaluate mental health, cognitive function, and living quality of colon and rectal carcinoma patients with oxaliplatin-induced neurotoxicity. Methods: Fifty recurrence-free colorectal cancer (CRC) patients with oxaliplatin chemotherapy while 50 control patients without oxaliplatin chemotherapy were enrolled in this study. Subjective and objective aspects of oxaliplatin chemotherapy symptoms were assessed with oxaliplatin neurotoxicity classification. Psychological assessment was measured via the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS). Cognitive function was measured via Montreal Cognitive Assessment (MoCA). Quality of Life (QOL) was assessed using the World Health Organization’s Quality of Life (WHOQOL-BREF) shortened instrument. Results: Of the patients with oxaliplatin chemotherapy, 41 patients had depression and 42 patients had anxiety. Patients with oxaliplatin chemotherapy scored higher on average on both the SDS (64.36 ± 7.22) and SAS (67.49 ± 9.41) compared to those without oxaliplatin chemotherapy (SDS, 57.86 ± 5.27, p=0.006; SAS, 61.57 ± 10.06, p = 0.004). Patients with oxaliplatin chemotherapy, on average, scored lower on the MoCA (23.46 ± 3.17) compared to patients without oxaliplatin chemotherapy (27.49 ± 2.03, p &lt; 0.05). In addition, patients with oxaliplatin chemotherapy scored significantly lower on measures of physical health (18.9 ± 7.8 vs. 37.8 ± 6.2, p&lt;0.05), psychological health (19.3 ± 8.2vs. 39.8 ± 8.1, p&lt;0.05), and social relationship (50.2 ± 10.1 vs. 70.6 ± 10.5, p&lt;0.05) compared to patients without oxaliplatin chemotherapy. Multivariate linear regression analysis demonstrated that anxiety and cognitive impairment performance significantly predicted for global Quality of Life (QOL). Conclusions: colorectal cancer (CRC)patients with oxaliplatin chemotherapy experience mood disorders, cognitive impairment, and reduced Quality of Life (QOL). The clinical symptoms severity of oxaliplatin cemotherapy plays an important role in mood change and cognitive function. Decreased Quality of Life (QOL) was associated with anxiety and cognitive impairment.