Management Of Colon Cancer Patients Research Articles

Albendazole inhibits colon cancer progression and therapy resistance by targeting ubiquitin ligase RNF20.

The repurposing of FDA-approved drugs for anti-cancer therapies is appealing due to their established safety profiles and pharmacokinetic properties and can be quickly moved into clinical trials. Cancer progression and resistance to conventional chemotherapy remain the key hurdles in improving the clinical management of colon cancer patients and associated mortality. High-throughput screening (HTS) was performed using an annotated library of 1,600 FDA-approved drugs to identify drugs with strong anti-CRC properties. The candidate drug exhibiting most promising inhibitory effects in in-vitro studies was tested for its efficacy using in-vivo models of CRC progression and chemoresistance and patient derived organoids (PTDOs). Albendazole, an anti-helminth drug, demonstrated the strongest inhibitory effects on the tumorigenic potentials of CRC cells, xenograft tumor growth and organoids from mice. Also, albendazole sensitized the chemoresistant CRC cells to 5-fluorouracil (5-FU) and oxaliplatin suggesting potential to treat chemoresistant CRC. Mechanistically, Albendazole treatment modulated the expression of RNF20, to promote apoptosis in CRC cells by delaying the G2/M phase and suppressing anti-apoptotic-Bcl2 family transcription. Albendazole, an FDA approved drug, carries strong therapeutic potential to treat colon cancers which are aggressive and potentially resistant to conventional chemotherapeutic agents. Our findings also lay the groundwork for further clinical testing.

Aluminium bioaccumulation in colon cancer, impinging on epithelial-mesenchymal-transition and cell death

We investigated the presence of aluminium (Al) in human colon cancer samples and its potential association with biological processes involved in cancer progression, such as epithelial to mesenchymal transition (EMT) and cell death. 25 consecutive colon samples were collected from patients undergoing colonic resection. Both neoplastic and normal mucosa were collected from each patient and subjected to histological, ultrastructural and immunohistochemical analyses. Moreover, colon samples from two Al-positive patients underwent multi-omic analyses, including whole genome sequencing and RNA sequencing (RNAseq). Morin staining, used to identify in situ aluminium bioaccumulation, showed the presence of Al in tumor areas of 24 % of patients. Transmission electron microscopy and energy-dispersive X-ray microanalysis confirmed the presence of Al specifically in intracytoplasmic electrondense nanodeposits adjacent to mitochondria of colon cancer cells. Immunohistochemical analyses for vimentin and nuclear β-catenin were performed to highlight the occurrence of the EMT phenomenon in association to Al bioaccumulation. Al-positive samples showed a significant increase in both the number of vimentin-positive and nuclear β-catenin-positive cancer cells compared to Al-negative samples. Moreover, Al-positive samples exhibited a significant decrease in the number of apoptotic cells, as well as the expression of the anti-apoptotic molecule BCL-2. Multi-omic analyses revealed a higher tumor mutational burden (TMB) in Al-positive colon cancers (n = 2) compared to a control cohort (n = 100). Additionally, somatic mutations in genes associated with EMT (GATA3) and apoptosis (TP53) were observed in Al-positive colon cancers. In conclusion, this study provides the first evidence of Al bioaccumulation in colon cancer and its potential role in modulating molecular pathways involved in cancer progression, such as EMT and apoptosis. Understanding the molecular mechanisms underlying Al toxicity might contribute to improve strategies for prevention, early detection, and targeted therapies for the management of colon cancer patients.

Diagnosis and management of colon cancer patients presenting in advanced stages of complications

Colorectal cancer is an important health problem with a significant impact on the individual and society. Malignancy (including colorectal cancer) is usually slightly symptomatic in its initial stages. This causes cancer to be discovered in some patients accidentally (either through screening tests in predisposed individuals or during routine investigations for other diseases), while in other patients the colorectal cancer is discovered in late stages, when the symptoms are much more intense due to complications. Unfortunately, such advanced cases of the disease have high rates of morbidity and mortality even with treatment. Current treatment methods are usually complex, interdisciplinary, causing significant suffering (physical, mental) to the individual, while the cost of treatment per patient seems to be extremely high. Until finding therapeutic methods that are effective and accessible to most patients with advanced colorectal cancer, several methods of prophylaxis and early diagnosis should be considered, to reduce as much as possible the devastating impact of this disease. The purpose of this review is to present literature data regarding the current methods of diagnosis and treatment of patients presenting to the doctor with colorectal cancer in advanced stages of complications.

A novel enterocyte-related 4-gene signature for predicting prognosis in colon adenocarcinoma.

Colon adenocarcinoma (COAD) is a fatal disease, and its cases are constantly increasing worldwide. Further, the therapeutic and management strategies for patients with COAD are still unsatisfactory due to the lack of accurate patient classification and prognostic models. Therefore, our study aims to identify prognostic markers in patients with COAD and construct a cell subtype-specific prognostic model with high accuracy and robustness. Single-cell transcriptomic data of six samples were retrieved from the Gene expression omnibus (GEO) database. The cluster annotation and cell-cell communication analysis identified enterocytes as a key player mediating signal communication networks. A four-gene signature prognostic model was constructed based on the enterocyte-related differentially expressed genes (ERDEGs) in patients with COAD of the Cancer Genome Atlas cohort. The prognostic model was validated on three external validation cohorts from the GEO database. The correlation between immune cell infiltration, immunotherapy response, drug sensitivity, and the four-gene signature prognostic model was investigated. Finally, immunohistochemistry (IHC) was performed to determine the expression of the four genes. We found that the proportion of epithelial cells was obviously large in COAD samples. Further analysis of epithelial cells showed that the activity of the enterocytes was highest in the cell-cell communication network. Based on enterocyte data, 30 ERDEGs were identified and a 4-gene prognostic model including CPM, CLCA4, ELOVL6, and ATP2A3 was developed and validated. The risk score derived from this model was considered as an independent variable factor to predict overall survival. The patients were divided into high- and low-risk groups based on the median riskscore value. The correlation between immune cell infiltration, immunotherapy response, immune status, clinical characteristics, drug sensitivity, and risk score was analyzed. IHC confirmed the expression of signature genes in tissues from normal individuals, patients with polyps, and COAD. In this study, we constructed and validated a novel four-gene signature prognostic model, which could effectively predict the response to immunotherapy and overall survival in patients with COAD. More importantly, this model provides useful insight into the management of colon cancer patients and aids in designing personalized therapy.

Accurate population-based model for individual prediction of colon cancer recurrence

Background Prediction models are useful tools in the clinical management of colon cancer patients, particularly when estimating the recurrence rate and, thus, the need for adjuvant treatment. However, the most used models (MSKCC, ACCENT) are based on several decades-old patient series from clinical trials, likely overestimating the current risk of recurrence, especially in low-risk groups, as outcomes have improved over time. The aim was to develop and validate an updated model for the prediction of recurrence within 5 years after surgery using routinely collected clinicopathologic variables. Material and methods A population-based cohort from the Swedish Colorectal Cancer Registry of 16,134 stage I–III colon cancer cases was used. A multivariable model was constructed using Cox proportional hazards regression. Three-quarters of the cases were used for model development and one quarter for internal validation. External validation was performed using 12,769 stage II–III patients from the Norwegian Colorectal Cancer Registry. The model was compared to previous nomograms. Results The nomogram consisted of eight variables: sex, sidedness, pT-substages, number of positive and found lymph nodes, emergency surgery, lymphovascular and perineural invasion. The area under the curve (AUC) was 0.78 in the model, 0.76 in internal validation, and 0.70 in external validation. The model calibrated well, especially in low-risk patients, and performed better than existing nomograms in the Swedish registry data. The new nomogram’s AUC was equal to that of the MSKCC but the calibration was better. Conclusion The nomogram based on recently operated patients from a population registry predicts recurrence risk more accurately than previous nomograms. It performs best in the low-risk groups where the risk-benefit ratio of adjuvant treatment is debatable and the need for an accurate prediction model is the largest.

Hemicolectomy Does Not Provide Survival Benefit for Right-Sided Mucinous Colon Adenocarcinoma

BackgroundThe extent of bowel resection is widely debated in colon cancer surgery. Right hemicolectomy (RHC) and partial colectomy (PC) are the most common operation options for right-sided colon cancer (RCC). However, there are still no treatment guidelines or published studies to guide surgical options for mucinous adenocarcinoma (MAC) of RCC.MethodsPatients with MAC and non-specific adenocarcinoma (AC) of RCC who underwent RHC and PC from 2010 to 2015 in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. The general characteristics and survival were compared and analyzed.ResultsA total of 27,910 RCC patients were enrolled in this study, among them 3,413 were MAC. The results showed that race, carcinoembryonic antigen (CEA) level, perineural invasion (PNI), tumor size, tumor location, TNM stage, liver metastasis, chemotherapy were significantly different between MAC and AC groups. The MAC group had similar dissected lymph nodes, but more positive lymph nodes than the AC group. The overall survival (OS) of the MAC group was poorer than that of the AC group, but cancer-specific survival (CSS) was similar between the two groups. The RHC subgroup of the MAC group had more patients of age ≤60 years, larger tumor size, cecum/ascending colon location and dissected lymph nodes than the PC subgroup, but similar positive lymph nodes, perioperative mortality, OS and CSS as the PC subgroup. Moreover, the univariate and multivariable analyses for the survival of RCC patients with MAC showed that RHC might not be a superior predictor for OS and CSS compared with PC.ConclusionsRHC could not dissect more positive lymph nodes or provide long-term survival benefits for RCC patients with MAC compared with PC. This study could provide some evidence for surgery treatment selection for MAC of RCC, which has important clinical value in individual management of colon cancer patients.

Management of colon cancer patients: A comprehensive analysis of the absence of multidisciplinary team meetings in two French departments

The care management of colorectal cancers has evolved, particularly since the implementation of multidisciplinary team meetings (MDTm). The aim of this study was to identify factors associated with the non-presentation of colon cancer patients in MDTm (no-MDTm) and to assess the association between no-MDTm and the diagnostic and therapeutic care management, in two areas in France, in 2010. Patients over 18 years diagnosed for invasive colon cancer in Gironde and Tarn during 2010 were included from the cancer registries of these two departments. We used five indicators to evaluate the care management of colon cancer patients (about diagnosis, treatment and selection of patients for chemotherapy). No-MDTm patients were more likely to die early after diagnosis (OR=2.94, 95% CI=[1.52-5.66]). Elderly patients and those living in more disadvantaged areas were less often presented in MDTm (OR≥85years=2.10, 95% CI=[1.06-4.18]; OREDIQ4-Q5=1.96, 95% CI=[1.23-3.14]). After adjusting for patient-related variables (age, comorbidities, deprivation) and tumor (stage at diagnosis), we found that thoracic CT scan was less often performed among no-MDTm patients (OR=0.40, 95% CI=[0.24-0.65]). There was no association between the absence of MDTm and the therapeutic care management indicators. In conclusion, therapeutic care management was not associated with the absence of MDTm but with patient and tumor characteristics, including age, comorbidities and level of deprivation, that influence the non-presentation in MDTm.

Totally robotic modified complete mesocolic excision and central vascular ligation for right-sided colon cancer: technical feasibility and mid-term oncologic outcomes.

Recently, an operative strategy involving complete mesocolic excision (CME) and central vascular ligation (CVL) for colonic cancer has been introduced. We aimed to describe our initial experience and assess the long-term outcomes of robotic modified CME (mCME) and CVL (mCME+CVL) for right-sided colon cancer. Of the 677 patients with histologically confirmed, right-sided colon adenocarcinoma who underwent curative mCME+CVL between February 2008 and October 2016, 43 who were treated entirely using the robotic approach were included in this retrospective study. Survival rates were determined using the Kaplan-Meier method, and P values of < 0.05 indicated statistically significant differences. The total operation and docking times were 293 (180-644) min and 5 (3-19) min, respectively, with an estimated blood loss of 50 (10-400) mL. The time to soft diet was 4 (1-16) days and the length of hospitalization was 8 (4-48) days. Based on the Clavien-Dindo classification, grade I, II, IIIa, IIIb, and IV complications were noted in 3 (7.0%), 5 (11.7%), 2 (4.7%), 1 (2.3%), and 0 (0%) patients, respectively. The proximal and distal resection margins were 14 (4-54) and 19 (4-48) cm, respectively, and 29 (6-157) lymph nodes were harvested per patient. The patients were followed-up for a median of 55 (2-109) months, during which the overall survival rate, median disease-free period, disease-free survival rate, and tumor recurrence rate were 93.6%, 38 (2-109) months, 81.1%, and 16.3% (7 patients), respectively. Robotic mCME and CVL for right-sided colon cancer was feasible and safe. It can be added to the surgeon's toolbox as an optional strategy for the management of colon cancer patients.

Recurrence-Associated Long Non-coding RNA Signature for Determining the Risk of Recurrence in Patients with Colon Cancer

Patients with colon cancer are often faced a high risk of disease recurrence within 5 years of treatment that is the major cause of cancer mortality. Reliable molecular markers were required to improve the most effective personalized therapy. Here, we identified a recurrence-associated six-lncRNA (long non-coding RNA) signature (LINC0184, AC105243.1, LOC101928168, ILF3-AS1, MIR31HG, and AC006329.1) that can effectively distinguish between high and low risk of cancer recurrence from 389 patients of a discovery dataset, and validated its robust performance in four independent datasets comprising a total of 906 colon cancer patients. We found that the six-lncRNA signature was an independent predictive factor of disease recurrence in multivariate analysis and was superior to the performance of clinical factors and known gene signature. Furthermore, in silico functional analysis showed that the six-lncRNA-signature-associated coding genes are significantly enriched in proliferation and angiogenesis, cell death, as well as critical cancer pathways that could play important roles in colon cancer recurrence. Together, the six-lncRNA signature holds great potential for recurrence risk assessment and personalized management of colon cancer patients.

ColotypeR: A tool to classify colon cancers by consensus molecular subtype and subtype-specific risk of recurrence.

632 Background: Colon cancer is highly heterogeneous in prognosis and response to treatment. The consensus molecular subtypes (CMS1-4, and mixed) partition colon cancers into distinct groups. CMS4 tumors, a mesenchymal subtype, have the worst prognosis and poor response to standard chemotherapies. There is a critical need for accurate molecular subtyping, and subtype-specific management. Methods: Affymetrix microarrays colon cancer datasets (N = 813; GSE39582, GSE14333) were partitioned into training (AT; N = 370) and validation sets (AV; N = 443) balanced for clinical traits. A novel multistate gene methodology was used to predict CMS, and prognosticate subtype-specific relapse-free survival (RFS) in the training set. Accuracy of CMS prediction and prognostic significance was validated in the AV and TCGA colon cancer (COAD; N = 458) sets. Results: In the training set, a 20-gene panel (ColotypeR-CMS) predicts CMS subtype. Mean accuracy for CMS1-4 prediction was 0.87 in AV and 0.81 in COAD. In AV, 5-year RFS is 0.52 (95%CI 0.43 – 0.63) in the predicted CMS4, and 0.70 (95%CI 0.65 – 0.77) in the non-CMS4 samples. The risk of relapse for non-CMS4 samples was refined by a genomic score (ColotypeR-Risk) computed using expression of 25 genes in the training set. ColotypeR-Risk was prognostic of RFS (p = 0.0004) among the AV non-CMS4 samples, and also prognostic (p = 0.0001) among the stage II non-CMS4 AV samples not treated with chemotherapy. The prognostic significance of ColotypeR-Risk among non-CMS4 samples is independent of tumor location (right or left) and CMS subtype (CMS1-3 or mixed). ColotypeR-Risk was also prognostic of RFS in non-CMS4 samples in COAD (p = 0.005). Conclusions: ColotypeR identifies the consensus molecular subtypes (CMS1, CMS2, CMS3, CMS4, or mixed), and assesses subtype-specific risk of recurrence of colon cancer. ColotypeR identifies prognostic risk and molecular features that could help guide the management of colon cancer patients.

Identification of potential long non-coding RNA biomarkers associated with the progression of colon cancer.

Increasing evidence has suggested that dysregulated lncRNA expression played important roles in the development and progression of human cancers. Although prognostic roles of lncRNAs have been recognized for colon cancer (CC) patients, the search for novel lncRNA biomarkers potentially involved in CC progression is an urgent and still largely unmet medical need. In this study, we evaluated the lncRNA expression changes during the progression of CC by analyzing two cohorts of previously published expression profiles of CC patients and identified hundreds of differentially expressed lncRNAs. Then we identified eight lncRNAs that closely associated with the progression of CC patients from a large number of significantly altered lncRNAs using random forest supervised classification algorithm. Finally, an SVM-based lncRNA risk classifier was developed to discriminate high-risk CC patients from persons with early-stage and validated in both the training dataset and testing dataset by survival analysis and five-fold cross-validation strategy. Our pathway enrichment analysis based on protein-coding genes that are co-expressed with lncRNAs, suggested that variation in expression of eight lncRNAs biomarkers might affect critical pathways involved in CC progression. With further validation, these eight lncRNAs might have significant implications for the clinical management of CC patients with early stage and improve our understanding of cancer progression.

Therapeutic Management of Colon Cancer

Colorectal cancer is a major public health problem worldwide, and a major cause of mortality and morbidity. Correct pretherapeutic staging has the role of guiding the management of colon cancer patients. The diagnosis is guided by the clinical symptoms. Chemotherapy is an important part of colon cancer treatment. Chemotherapy regimens are adapted to tumor stage and patient status and have various side effects and variable survival outcomes. International guidelines recommend different treatments depending on the presence or absence of metastases. The primary goal of treatment in nonmetastatic colon cancer is surgical removal of the tumor which could be the first step of the complex therapy or preceded by neoadjuvant therapy, depending on pretherapeutic staging. In resectable nonmetastatic tumors the preferred surgical procedure is colectomy with en bloc removal of regional lymph nodes. The extent of colectomy should be based on tumor location. The management of metastatic colon cancer also targets the therapeutic approach of the metastatic disease. Therapy is standardized and applied according to tumor stage. Surveillance has a major role in therapeutic success, reason why a time schedule and a protocol adapted to the primary lesion are essential. The goal of implementing the recommendations of international guidelines for the treatment of colon cancer is to provide a uniform treatment for this disease in view of improving overall survival of patients.

Diagnostic and prognostic utility of methylation and protein expression patterns of myopodin in colon cancer

Myopodin is an actin-binding protein believed to play a tumor suppressor role in several solid neoplasias. We evaluated the potential differential myopodin methylation and expression and their clinical relevance in colon cancer. The epigenetic silencing of myopodin by hypermethylation was tested in colon cancer cells (n = 5) before and after azacitidine treatment. Myopodin methylation status was evaluated by methylation-specific PCR in colon cancer cells and colorectal tissues (n = 210) grouped in a training set (n = 62) and two independent validation series (n = 100 and n = 48) collected at independent clinical settings. Myopodin expression patterns were analyzed by immunohistochemistry on tissue arrays. Myopodin hypermethylation correlated with gene and protein expression loss, being increased in vitro by azacitidine. Myopodin was frequently methylated in colon cancer cells (four out of five). Methylation rates were 90.3%, 70.0%, and 47.8% in the training and validation sets, respectively. Myopodin methylation rendered a diagnostic accuracy of 83.9% (p < 0.0005). Cytoplasmic myopodin expression was significantly higher in non-neoplastic biopsies compared to colon tumors (p < 0.0005). Loss of myopodin expression correlated with increasing tumor stage (p = 0.011), methylation (p = 0.005), and poor overall survival (p = 0.003). In the first validation set (n = 100), myopodin methylation predicted disease-free (p = 0.046) and overall survival (p = 0.031). In the second validation cohort, myopodin methylation and protein expression patterns predicted disease-specific (p = 0.012 and p = 0.001, respectively) and overall survival (p = 0.009 and p = 0.043, respectively). Thus, myopodin was revealed to be epigenetically modified in colon cancer. The diagnostic and prognostic clinical utility of myopodin methylation and expression patterns suggest considering their assessment for the clinical management of colon cancer patients.

Anti-Angiotensin and Hypoglycemic Treatments Suppress Liver Metastasis of Colon Cancer Cells

The effect of diabetic conditions on liver metastasis was examined using CT26 mouse colon cancer cells. CT26 cells produced angiotensin (A)-I and A-II from angiotensinogen; the production was abrogated by inhibitors of renin and chymase. Renin expression and A-II production increased with an increase in the concentration of glucose in the medium. In a streptozotocin-induced BALB/c mouse diabetes model that was fed a high-calorie diet, the blood sugar level increased and was associated with an increasing size and number of CT26 liver metastases. In this diabetic mouse model, liver metastasis of CT26 cells was suppressed by anti-angiotensin treatment with a chymase inhibitor, a renin inhibitor, and an A-II receptor blocker. Moreover, concurrent hypoglycemic and anti-angiotensin treatments showed a synergistic inhibitory effect on CT26 cell liver metastasis. These results suggest that angiotensin activation ability associated with diabetic conditions enhances liver metastasis of colon cancer. Therefore, treatment with anti-angiotensin and hypoglycemic agents might be relevant for baseline management of colon cancer patients with the diabetic condition for the prevention of liver metastasis. This scheme needs to be examined in a clinical setting.

Quality control issues in the management of colon cancer patients

Quality assurance in colon cancer demands a multidisciplinary effort involving general practitioners, surgeons, radiologists, gastroenterologists, medical oncologists, and pathologists, among others. Maximal improvements in survival will result when colon cancer screening, diagnosis, staging, treatment and surveillance are optimized. We seek to identify those issues most relevant to the quality of care we provide our colon cancer patients.

Osteopontin and colon cancer progression.

Human colon cancer affects nearly 150,000 patients and results in 60,000 deaths in the United States per year. Despite significant advances in the management of the colon cancer patient, little change in survival rates has been appreciated over the past 50 years. The primary cause of death relates to the development of distant metastases to organs such as the liver and lungs. Colon cancer represents an important disease to study in order to better understand tumor progression and metastasis primarily because there is almost a stepwise advancement of the disease that is marked by measurable genetic and associated phenotypic alterations. Metastasis appears to be the end product of the development of 'Herculean' cell clones capable of independent growth, invasion, adhesion, avoidance of apoptosis, and angiogenesis. Although significant progress has been made in understanding the sequential genetic events leading to the development of cancer, the precise genes and the associated molecular pathways underlying the development of metastatic potential are still poorly understood. Moreover, our enhanced genetic knowledge has had relatively little trickle down effect on our clinical management of this deadly disease. For this reason, we undertook a comprehensive study to develop a molecular encyclopedia of new tumor markers and markers of tumor progression, some of which will hopefully prove useful in the clinical management of colon cancer patients by means of their capacity to detect and predict the stage and disease burden. This review will focus on the application of gene expression profiling technology to the problem of identifying new tumor markers and progression markers, and the discovery of osteopontin as the leading candidate clinical marker derived from a screen of approximately 12,000 named genes.