Colorectal Cancer Recurrence Rates Research Articles

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study

BackgroundFluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. MethodsWe analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates.ResultsWe detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher’s exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1.ConclusionsThe two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

Comparison Accuracy of the Use Carcinoma Embryonic Antigen (CEA) and Lactate Dehidrogenase (LDH) Level to Predict Colorectal Carcinoma Recurrency in Abdul Moeloek Hospital Bandar Lampung

Background: Colorectal cancer is a malignancy that originates from the colon tissue, which consists of the colon and rectum. The incidence of colorectal cancer worldwide is the third largest and is the fourth leading cause of death, accounting for 11% of all cancers in human. In general, the development of colorectal cancer is an interaction between environmental factors and genetic factors. Environmental factors are divided into modifiable factors and non-modifiable factors. The recurrence rate of colorectal cancer is still very high, so it requires a precise and accurate early detection of the recurrency. Method: Comparing the accuracy of the Carcinoma Embryonic Antigen (CEA) tumor marker examination with Lactate Dehydrogenase (LDH) levels to detect colorectal cancer recurrency by using Spearman correlation analysis between two variables at Abdul Moeloek Hospital Bandar Lampung during the study period of October 2019 to September 2020. Results: Twenty one samples are obtained, 11 samples did not experience any recurrency and the other 10 samples had colorectal cancer recurrence. The mean CEA level was 139.64 U / mL and the mean LDH level was 353.10 U / L. The relationship between CEA levels and colorectal cancer recurrence was significant with a correlation coefficient of 0.663, while the relationship between LDH levels and colorectal cancer recurrence was insignificant with a correlation coefficient of 0.213. Conclusion: CEA is more accurate than LDH to predict the recurrency of colorectal cancer, so that in clinical practice CEA is better used to predict colorectal cancer recurrence.

Estimating Population-Based Recurrence Rates of Colorectal Cancer over Time in the United States.

Population-based metastatic recurrence rates for patients diagnosed with nonmetastatic colorectal cancer cannot be estimated directly from population-based cancer registries because recurrence information is not reported. We derived population-based colorectal cancer recurrence rates using disease-specific survival data based on our understanding of the colorectal cancer recurrence-death process. We used a statistical continuous-time multistate survival model to derive population-based annual colorectal cancer recurrence rates from 6 months to 10 years after colorectal cancer diagnosis using relative survival data from the Surveillance, Epidemiology, and End Results Program. The model was based on the assumption that, after 6 months of diagnosis, all colorectal cancer-related deaths occur only in patients who experience a metastatic recurrence first, and that the annual colorectal cancer-specific death rate among patients with recurrence was the same as in those diagnosed with de novo metastatic disease. We allowed recurrence rates to vary by post-diagnosis time, age, stage, and location for two diagnostic time periods. In patients diagnosed in 1975-1984, annual recurrence rates 6 months to 5 years after diagnosis ranged from 0.054 to 0.060 in stage II colon cancer, 0.094 to 0.105 in stage II rectal cancer, and 0.146 to 0.177 in stage III colorectal cancer, depending on age. We found a statistically significant decrease in colorectal cancer recurrence among patients diagnosed in 1994-2003 compared with those diagnosed in 1975-1984 for 6 months to 5 years after diagnosis (hazard ratios between 0.43 and 0.70). We derived population-based annual recurrence rates for up to 10 years after diagnosis using relative survival data. Our estimates can be used in decision-analytic models to facilitate analyses of colorectal cancer interventions that are more generalizable.

Primate-specific miR-944 activates p53-dependent tumor suppression in human colorectal cancers

As cancers with a high incidence rate, colorectal cancers are a main cause of cancer-related death. MicroRNAs are often deregulated in cancers. The primate-specific miR-944, located in a p63 intron, is known to be highly expressed in patients exhibiting low colorectal cancer recurrence rates. However, the biological functions of miR-944 in colorectal cancers remain unclear. In this study, we found that miR-944 was downregulated in colorectal cancer tissues, and inhibited cancer cell growth in a xenograft mouse model. The overexpression of miR-944 caused G1 phase arrest and increased p53 expression in cancer cells. p53 stability was enhanced by miR-944s targeting E3 ligases COP1 and MDM2. Overexpression of COP1 and MDM2 restored cell growth inhibition caused by miR-944. Taken together, our results suggest that miR-944 acts as a potential tumor suppressor in colorectal cancers through the ubiquitin-proteasome system.

Adherence to surveillance guidelines after removal of colorectal adenomas: a large, community-based study

ObjectiveTo determine adherence to recommended surveillance intervals in clinical practice.Design2997 successive patients with a first adenoma diagnosis (57% male, mean age 59 years) from 10 hospitals, who underwent colonoscopy between...

Upregulation of nemo-like kinase is an independent prognostic factor in colorectal cancer.

To investigate the expression and oncogenic role of nemo-like kinase (NLK) in colorectal cancer. Expression of NLK protein was assessed by immunohistochemistry in tissue specimens from 56 cases of normal colorectal mucosa, 51 cases of colorectal adenoma, and 712 cases of colorectal cancer. In addition, NLK expression was knocked down using a lentivirus carrying NLK small hairpin RNA in colorectal cancer cells. Cell viability methylthiazoletetrazolium assays, colony formation assays, flow cytometry cell cycle assays, Transwell migration assays, and gene expression assays were performed to explore its role on proliferation and migration of colorectal cancer. Expression of NLK protein progressively increased in tissues from the normal mucosa through adenoma to various stages of colorectal cancer. Overexpression of NLK protein was associated with advanced tumor-lymph node-metastasis stages, poor differentiation, lymph node and distant metastases, and a higher recurrence rate of colorectal cancer (P < 0.05). Multivariate analyses showed that NLK expression was an independent prognostic factor to predict overall survival (hazard ratio 2.57, 95% confidence interval: 1.66-3.98; P < 0.001) and disease-free survival (hazard ratio 1.96, 95% confidence interval: 1.40-2.74: P < 0.001) of colorectal cancer patients. Furthermore, knockdown of NLK expression in colorectal cancer cell lines reduced cell viability, colony formation, and migration, and arrested tumor cells at the G0/G1 phase of the cell cycle. At the gene level, knockdown of NLK expression inhibited matrix metalloproteinase-2 expression in colorectal cancer cells. NLK overexpression is an independent prognostic factor in colorectal cancer and knockdown of NLK expression inhibits colorectal cancer progression and metastasis.

Abstract 2126: PIK3CA mutation status is not involved in the response of nonsteroidal anti-inflammatory drugs in colorectal cancer cell lines

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown a chemopreventive effect for colorectal cancer (CRC) in many epidemiological and large scale population studies. Moreover, regular use of NSAIDs has been recently associated with a reduction in the recurrence rate of CRC in patients previously diagnosed with colorectal tumors harboring PIK3CA mutations in two different retrospective analyses of large clinical cohorts. However, the mechanism by which PIK3CA mutations interacts with the mechanism of action of NSAIDs remains elusive. Our aim was to investigate the contribution of the most common alterations detected in PIK3CA to the sensitivity of NSAIDs in CRC cell line models. We have studied the cytotoxicity activity of two NSAIDs, Aspirin and Naproxen, in a panel of nine CRC cell lines by performing drug cytotoxicity assays. We have compared the sensitivity to Aspirin and Naproxen in cell lines grouped by the PIK3CA mutational status (wild-type versus mutant and by specific mutation hot-spots). Drug concentrations resulting in 50% growth inhibition (IC50) were determined by a curve-fitting analysis. In addition, two pairs of isogenic cell lines were used to analyze the contribution of PIK3CA mutations to drug sensitivity. One pair of each cell line contain only the mutant allele and the other the wild-type copy. The DLD-1 and HCT-116 cell line models containing only the wild-type allele were named 123 and 127, respectively. The DLD-1 and HCT-116 harboring the p.H1047R (exon 20) and p.E545K (exon 9) mutation were named 125 and 129, respectively. Moreover, modulation of classical biomarkers of the effect of NSAIDs, COX-2 and Prostaglandin E2 (PGE2) levels, was studied by qRT-PCR in treated and untreated cell lines. The ß-actin housekeeping gene was used to normalize samples and relative quantification of COX-2 and PGE2 RNA was done by the ΔΔCt approach. PIK3CA mutant cell lines showed no significant differences in IC50 compared to wild-type cells lines. This lack of contribution of the PIK3CA mutations to the cytotoxic effect of NSAIDs was further validated in the isogenic cell line pairs. Also, in the isogenic cell lines pairs, we found a reduced expression of COX-2 and an increased expression of PGE2 when the cell lines were treated with Aspirin or Naproxen as expected based on the known effects of NSAIDs, and thus corroborating their mechanistic effect. Therefore, we conclude that PIK3CA alterations are not correlated with sensitivity to NSAIDs. Our preclinical results do not support the epidemiological observations that PIK3CA tumors are more sensitive to NSADIS. Further in vitro and in vivo analyses to continue elucidating the contribution of the PI3K pathway to the effect of NSAIDs in CRC models are warranted. Citation Format: Ester Borras-Flores, Kara Calhoun, Gita Bhatia, Hong Wu, Eduardo Vilar-Sanchez. PIK3CA mutation status is not involved in the response of nonsteroidal anti-inflammatory drugs in colorectal cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2126. doi:10.1158/1538-7445.AM2014-2126

Isolated Tumor Cells in Regional Lymph Nodes as Relapse Predictors in Stage I and II Colorectal Cancer

Lymph node (LN) involvement is the most important prognostic factor in colorectal cancer (CRC), and pN-positive status identifies patients who require adjuvant chemotherapy. Approximately 15% to 20% of patients without nodal metastases (pN0) develop recurrent disease. In this study, we tested the prognostic significance of isolated tumor cells (ITCs) in LNs of patients with pN0 CRC (stages I and II). ITCs in LNs regional to CRC were assessed in 312 consecutive patients with pN0 CRC who were followed up clinically and/or endoscopically for at least 6 months after surgery (mean, 67 months; median, 64 months; range, 8 to 102 months). LNs were dissected from gross surgical specimens according to a standardized protocol (with a mean of 17 LNs per patient; range, five to 107 LNs). In all, 5,313 pN0 LNs were collected and assessed by using cytokeratin immunostaining in two serial histology sections from each LN, which amounting to a total of 10,626 specimens. The correlation between ITC status and cancer recurrence was tested by using univariate and multivariate statistics. ITCs were documented in 185 of 312 patients (59%). CRC relapsed in 31 of 312 patients (10%), and 25 of 31 recurrences (81%) were documented among ITC-positive patients. CRC recurrence rates among ITC-positive and ITC-negative patients were 14% (25 of 185 patients) and 4.7% (six of 127 patients), respectively. In both univariate and multivariate analyses, ITC status was the only variable significantly associated with cancer relapse (Cox model; hazard ratio, 3.00; 95% CI, 1.23 to 7.32; P = .013). In patients with pN0 CRC, cancer relapse was significantly associated with ITCs in regional LNs. ITCs should be considered among the clinicobiologic variables that identify high-risk patients who can benefit from adjuvant chemotherapy.

EphB2: a signature of colorectal cancer stem cells to predict relapse

Colorectal cancer is one of the most commonly diagnosed cancers and is the second leading cause of death from cancer. Currently, the conventional treatment in clinics is surgery combined with chemotherapy or radiation therapy. Although new drugs have been developed, relapse and metastasis occur in nearly half of colorectal cancer patients. As most other types of cancer, the recurrence rate of colorectal cancer is negatively correlated with the disease stage at diagnosis. Therefore, early diagnosis becomes an important approach to improve the treatment outcome. Consistent with this idea, prediction of the disease progression and recurrence has significant implications for the choices and outcome of treatment. With the rapid development of molecular biology, biochemistry and oncology in the past decade, scientists have taken great efforts identifying gene and/or biochemical markers that are associated with tumorigenesis, and several screening approaches have been developed and used in clinic. These applications have greatly benefited the early detection and remarkably reduced cancer deaths. Recently, Batlle group from Spain identified EphB2 as an intestinal stem cell (ISC) marker gene that can be used to identify colorectal cancer stem cells and predict colorectal cancer relapse (Merlos-Suarez et al., 2011). ISCs reside at the base of mucosal invaginations (crypt). Their progeny transient amplifying cells move upward as they proliferate through mitosis until get close to intestinal lumen, where cells undergo cell cycle arrest and terminal differentiation. ISCs are essential for the tissue regeneration in intestine. However, they also exhibit relatively high efficiency to develop colorectal tumors upon mutations of genes in Wnt signaling pathway, which are suggested to activate intestinal tumorigenesis. EphB2 is a receptor tyrosine kinase that is regulated by Wnt pathway. Targeted deletion of EphB2, EphB3 or their ligand ephrin-B1 in mouse caused intestinal cell compart

Transfusion is associated with increased colorectal cancer recurrence rates

ANZ Journal of SurgeryVolume 79, Issue 10 p. 762-763 Transfusion is associated with increased colorectal cancer recurrence rates Roger Browning MBChB, FANZCA, Staff Specialist, Roger Browning MBChB, FANZCA, Staff Specialist Department of Anaesthesia and Pain MedicineKing Edward Memorial Hospital for WomenWestern Australia, AustraliaSearch for more papers by this author Roger Browning MBChB, FANZCA, Staff Specialist, Roger Browning MBChB, FANZCA, Staff Specialist Department of Anaesthesia and Pain MedicineKing Edward Memorial Hospital for WomenWestern Australia, AustraliaSearch for more papers by this author First published: 28 October 2009 https://doi.org/10.1111/j.1445-2197.2009.05072.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume79, Issue10October 2009Pages 762-763 RelatedInformation

Diagnostic significance of cytokeratin 19 and 20 expression on micrometastasis of colorectal cancer

To inquire into the diagnostic significance of cytokeratin 19(CK19) and cytokeratin 20(CK20) expression on hematogenous micrometastasis of colorectal cancer. Forty-four patients with colorectal cancer were collected as colorectal cancer groups, and another 18 patients treated with abdominal surgical operations because of benign diseases were collected as benign disease group. Blood of all the patients was harvested from their portal and peripheral veins, and CK19 and CK20 levels in the blood were determined by RT-PCR. There were no positive expression of CK19 and CK20 in the portal and peripheral blood of all the patients in benign disease group. Of the colorectal cancer group, 34 patients(77.3%) appeared positive expressions of CK19 and/or CK20 in portal and peripheral blood, and there was significant difference in the expressions of CK19 and CK20 between the two groups(P<0.05). Within the colorectal cancer group, the positive expression rates of CK19 and CK20 in peripheral blood were 36.4% and 52.3%, and the rates in portal blood were 59.1% and 72.7%. The rates of portal blood were significantly higher than those of peripheral blood(P<0.05). The positive expression rate in patients at stage III( was significantly higher than that in patients at stage I( orII( (P<0.05). The postoperative metastasis and recurrence rate of colorectal cancer in patients with positive expression of CK19 and CK20 in peripheral blood was 61.5%, which was significantly higher than that(25.0%) in patients with positive expression in portal blood only(P<0.05). In patients with colorectal cancer, the expressions of CK19 and CK20, which are determined by RT-PCR in blood from portal and peripheral veins, are the sensitive and specific indexes for diagnosing hematogenous micrometastasis of the cancer.

Feasibility and Morbidity of Combined Hyperthermia and Radiochemotherapy in Recurrent Rectal Cancer – Preliminary Results

Background: The local recurrence rate of colorectal cancer has been significantly reduced due to the use of combined radiochemotherapy. Despite this improvement regarding locally advanced tumour recurrences, the treatment strategy for pre-treated patients remains difficult and unresolved. Patients and Methods: We analysed treatment and follow-up data of 14 patients with local recurrence of rectal cancer who were treated with radiation therapy (RT), chemotherapy (CT) and regional hyperthermia (RHT) from November 1997 to December 2001. Nine of these patients had received irradiation and CT (= pre-treated patients) in the past. For this group, 30.6–39.6 Gy RT, 5-fluorouracil (5-FU) as a continuous infusion over 5 days per week (350 mg/m²/24 h) combined with RHT twice a week was given. The 5 remaining patients (= not pre-treated) received conformal irradiation of 45 Gy with a boost between 9 and 14.4 Gy, combined with continuous infusion of 5-FU on days 1–4, and 29–33 (500 mg/m²/ 24 h), and RHT twice a week. Response to therapy was evaluated by means of computed tomography (CT) or magnetic resonance imaging (MRI) and by clinical follow-up. Results: Among 13 evaluated cases, the overall objective response rate was 54% (5 complete responses, 2 partial responses). At mean follow-up of 13.9 months (range 5–32 months) 7 patients were alive. Conclusion: The therapeutic regimen appears to be active in the treatment of local recurrences of rectal cancer. Larger-scaled studies are needed to evaluate the potency of hyperthermia in this therapeutic strategy.

Blood Transfusion-Induced Immunomodulation

Blood Transfusion-Induced Immunomodulation

Randomised controlled trial comparing transfusion of leucocyte-depleted or buffy-coat-depleted blood in surgery for colorectal cancer

SummaryIn retrospective studies, perioperative blood transfusions were associated with poor prognosis after surgery for cancer and were a major independent risk factor for postoperative bacterial infection. Leucocyte-depleted, in contrast to buffy-coat-depleted, blood has no immunosuppressive effects in transplantation and so might lack detrimental effects on cancer prognosis and postoperative infections.We studied this hypothesis in a controlled trial by randomly allocating patients to receive either leucocyte-depleted red cells or packed cells without buffy coat when blood was needed. Between 1987 and 1990, 871 eligible patients with colorectal cancer, including 697 patients operated upon with curative intent, were randomised in the 16 participating hospitals. Neither the eligible group nor the curative group showed significant differences between the two trial transfusions in survival, disease-free survival, cancer recurrence rates, or overall infection rates after an average follow-up of 36 months. Patients who had a curative resection and who received blood of any sort had a lower 3-year survival than non-transfused patients (69% vs 81%, p=0·001) and a higher infection rate (39% vs 24%, p<0·001). Colorectal cancer recurrence rates, however, were not influenced by blood transfusion (30% vs 26%, p=0·22).These combined observations confirm the association between blood transfusion and poor patient survival but indicate that the relation is not due to promotion of cancer.

ADJUVANT THERAPY OF COLORECTAL CANCER: AN OVERVIEW

The substantial recurrence rate of colorectal cancer following potentially curative resection has fuelled the search for effective adjuvant therapy. Previous trials using 5-fluorouracil (5-FU) as a single agent or in combination chemotherapy regimens have not demonstrated meaningful benefits, an impression reflected in the results of a meta-analysis encompassing large patient numbers. Newer developments utilizing intraportal chemotherapy and the combination of 5-FU and levamisole have resulted in lower recurrence rates and improved survival in patients with colon cancer. In advanced disease, the biochemical modulation of 5-FU by Leucovorin has been shown to prolong survival in some studies. Combined chemotherapy and radiotherapy or chemotherapy alone have showed promising results in rectal cancer. These developments have now been incorporated into ongoing trials.