Project description:Most solid tumors, including colorectal cancers, shed cell-free DNA (ctDNA) in the blood. ctDNA can be analyzed to generate molecular profiles which capture the heterogeneity of the disease more comprehensively then tumor tissue biopsies. This approach commonly called 'liquid biopsy' can be applied to monitor response to therapy, to assess minimal residual disease and to uncover the emergence of drug resistance. This review will discuss current and future developments of ctDNA analysis in the clinical management of colorectal cancer patients.
Project description:BackgroundPrevious studies supported a link between the ABO blood type and survival for several types of malignancies. Nonetheless, the relationship between ABO blood type and survival in colon cancer patients has not been rigorously evaluated. The goal of this retrospective analysis was to discern the correlations between ABO blood group and colon cancer survival.MethodsA total of 1555 colon cancer patients that underwent curative-intent surgery between October 1995 and June 2002 were eligible for this study. The primary outcomes measured were the association between ABO blood group and patient survival.ResultsCompared with patients with non-AB blood types (blood types A, B, and O), patients with blood type AB were more likely to have better survival. The mean overall survival (OS) of the blood type AB patients was 113.9 months, whereas the mean OS of the non-AB blood type patients was significantly lower, 106.1 months (P<0.001, log-rank test). Compared with patients with blood type AB, the hazard ratios for patients with A, B, and O were 4.37 (95% confidence interval (95% CI), 2.65-7.20), 2.99 (95% CI, 1.81-4.96), and 2.78 (95% CI, 1.69-4.56), respectively.ConclusionsBlood type AB is a favourable prognostic factor for patients with colon cancer.
Project description:We performed whole blood gene expression profiling in 26 patients undergoing laparoscopic surgery for colon cancer stage I-III UICC. Saples were taken the day before surgery (-1), day one postoperatively (+1) and day 10 postoperatively (+10). The aim of the study was to investigate whether gene expression was altered after laparoscopic colon cancer surgery.
Project description:Epithelial?to?mesenchymal transition (EMT) confers stem cell?like phenotype and more motile properties to carcinoma cells. During EMT, the expression of E?cadherin decreases, resulting in loss of cell?cell adhesion and increased migration. Expression of Twist1 and other pleiotropic transcription factors, such as Snail, is known to activate EMT. We established primary colon cancer cell cultures from samples of operated patients and validated cultures by cytogenetic and molecular biology approaches. Western blot assay, quantitative real?time PCR and immunofluorescence were performed to investigate the expression of E?cadherin, vimentin, ??catenin, cytokeratin?20 and ?18, Twist1, Snail, CD44, cyclooxygenase?2 (COX2), Sox2, Oct4 and Nanog. Moreover, cell differentiation was induced by incubation with LiCl?containing medium for 10 days. We observed that these primary colorectal cancer (CRC) cells lost expression of the E?cadherin epithelial marker, which was instead expressed in cancer and normal colon mucosa of the same patient, while overexpressed vimentin (mesenchymal marker), Twist1, Snail (EMT markers) and COX2. Cytokeratin?18 was expressed both in tissues and cell cultures. Expression of stem cell markers, such as CD44, Oct4 and Nanog, were also observed. Following differentiation with the glycogen synthase kinase 3? (GSK3?) inhibitor LiCl, the cells began to express E?cadherin and, at once, Twist1 and Snail expression was strongly downregulated, suggesting a MET?reverting process. In conclusion, we established primary colon mesenchymal cancer cell cultures expressing mesenchymal and epithelial biomarkers together with high level of EMT transcription factors. We propose that they could represent a good model for studying EMT and its reverting mechanism, the mesenchymal?to?epithelial transition (MET). Our observation indicates that LiCl, a GSK3? inhibitor, induces MET in vitro, suggesting that LiCl and GSK3? could represent, respectively, interesting drug, and target for CRC therapy.
Project description:Immunotherapies are treatments that use a patient's immune system to combat disease. One important type of immunotherapy employed in cancer treatments is the delivery of monoclonal antibodies to block growth receptors. In this manuscript, we develop a methodology that enables accurate and simple evaluation of antibody-type drug delivery using MALDI-MSI. To overcome the mass-range limitation that prevents the detection of large therapeutic antibodies, we used in situ reduction and alkylation to break disulfide bonds to generate smaller fragments. These smaller fragments are more readily ionized and detected by MALDI-MSI without loss of spatial information on the parent drug. As a proof of concept study, we evaluated the distribution of cetuximab in 3D colon cell cultures. Cetuximab is a monoclonal antibody that binds to the extracellular domain of epidermal-growth-factor receptor (EGFR), which is often overexpressed in colorectal cancer (CRC) and mediates cell differentiation, proliferation, migration, and angiogenesis. Cetuximab directly inhibits tumor growth and metastasis and induces apoptosis. By performing on-tissue reduction followed by MALDI-MSI analysis, we successfully mapped the time-dependent penetration and distribution of cetuximab in spheroids derived from two different colon-cancer cell lines (HT-29 and DLD-1). The localization patterns were further confirmed with IF staining of the drug. Changes in other biomolecules following drug treatment were also observed, including the elevation of ATP in spheroids. The developed method has also been applied to map cetuximab distribution in patient-derived colorectal-tumor organoids (CTOs). Overall, we believe this powerful label-free approach will be useful for visualizing the heterogeneous distribution of antibody drugs in tissues and tumors and will help to monitor and optimize their use in the clinic.
Project description:Anaerobes are an important but uncommon cause of bloodstream infections (BSIs). For pediatric patients, routine inclusion of an anaerobic blood culture alongside the aerobic remains controversial. We implemented automatic anaerobic blood culture alongside aerobic blood cultures in a pediatric emergency department (ED) and sought to determine changes in recovery of obligate and facultative anaerobes. This was a cohort study in a pediatric ED (August 2015 to July 2018) that began in February 2017. Blood culture positivity results for true pathogens and contaminants were assessed, along with a secondary outcome of time to positivity (TTP) of blood culture. A total of 14,180 blood cultures (5,202 preimplementation and 8,978 postimplementation) were collected, with 8.8% (456) and 7.1% (635) positive cultures in the pre- and postimplementation phases, respectively. Of 635 positive cultures in the postimplementation phase, aerobic blood cultures recovered 7.6% (349/4,615), whereas anaerobic blood cultures recovered 6.6% (286/4,363). In 211/421 (50.0%) paired blood cultures, an organism was recovered in both cultures. The number of cases where organisms were only recovered from an aerobic or an anaerobic bottle in the paired cultures were 126 (30.0%) and 84 (20.0%), respectively. The TTP was comparable regardless of bottle type. Recovery of true pathogens from blood cultures was approximately 7?h faster than recovery of contaminants. Although inclusion of anaerobic blood cultures only recovered 2 (0.69%) obligate anaerobes, it did allow for recovery of clinically significant pathogens that were negative in aerobic blood cultures and supports the routine collection of both bottles in pediatric patients with a concern of bloodstream infections.
Project description:Co-cultures of colon cancer cells and cancer-associated fibroblasts recapitulate the aggressive features of mesenchymal-like colon cancer
Project description:Background:Both pre-operative anemia and perioperative (intra- and/or post-operative) blood transfusion have been reported to increase post-operative complications in patients with colon cancer undergoing colectomy. However, their joint effect has not been investigated. The purpose of this study was to evaluate the joint effect of pre-operative anemia and perioperative blood transfusion on the post-operative outcome of colon-cancer patients after colectomy. Methods:We identified patients from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database 2006-2016 who underwent colectomy for colon cancer. Multivariate logistic regression analysis was employed to assess the independent and joint effects of anemia and blood transfusion on patient outcomes. Results:A total of 35,863 patients-18,936 (52.8%) with left-side colon cancer (LCC) and 16,927 (47.2%) with right-side colon cancer (RCC)-were identified. RCC patients were more likely to have mild anemia (62.7%) and severe anemia (2.9%) than LCC patients (40.2% mild anemia and 1.4% severe anemia). A total of 2,661 (7.4%) of all patients (1,079 [5.7%] with LCC and 1,582 [9.3%] with RCC) received a perioperative blood transfusion. Overall, the occurrence rates of complications were comparable between LCC and RCC patients (odds ratio [OR]?=?1.01; 95% confidence interval [CI]?=?0.95-1.07; P?=?0.750). There were significant joint effects of anemia and transfusion on complications and the 30-day death rate (P for interaction: 0.010). Patients without anemia who received a transfusion had a higher risk of any complications (LCC, OR?=?3.51; 95% CI?=?2.55-4.85; P?<?0.001; RCC, OR?=?3.74; 95% CI?=?2.50-5.59; P?<?0.001), minor complications (LCC, OR?=?2.54; 95% CI?=?1.63-3.97; P?<?0.001; RCC, OR?=?2.27; 95% CI?=?1.24-4.15; P?=?0.008), and major complications (LCC, OR?=?5.31; 95% CI?=?3.68-7.64; P?<?0.001; RCC, OR?=?5.64; 95% CI?=?3.61-8.79; P?<?0.001), and had an increased 30-day death rate (LCC, OR?=?6.97; 95% CI?=?3.07-15.80; P?<?0.001; RCC, OR?=?4.91; 95% CI?=?1.88-12.85; P?=?0.001) than patients without anemia who did not receive a transfusion. Conclusions:Pre-operative anemia and perioperative transfusion are associated with an increased risk of post-operative complications and increased death rate in colon-cancer patients undergoing colectomy.
Project description:Colon cancer is one of the most common malignancies causing the majority of cancer-related deaths. Gelsolin (GSN) has been found to be dysregulated in various cancers. However, the secreted GSN in colon cancer remains largely unknown. In the present study, we explored the expression profile of GSN in colon cancer tissues and the diagnostic value of serum GSN in colon cancer. In addition, the effects of secreted GSN in colon cancer cells were studied. We thus found that immunoreactive GSN levels were significantly lower in colon cancer tissues than those in non-tumor colon tissues. Functional studies demonstrated that secreted GSN could restrain cell invasion and migration in vitro. Mechanistically, dose dependent recombinant GSN down-regulated the expression of MMP2 and MMP9, which might restrain the process of cell invasion and migration. Furthermore, serum levels of GSN were significantly lower in colon cancer patients than those in healthy volunteers, and ROC curves showed serum level of GSN had a better diagnostic value for colon cancer (AUC=0.932) than the traditional tumor biomarker Carcinoembryonic Antigen (CEA) or Carbohydrate Antigen 19-9 (CA199). In conclusion, our results suggest that the secreted GSN restrains the invasion and migration of colon cancer cells. Meanwhile, the serum GSN may be a new biomarker for the diagnosis of colon cancer.