Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, ...especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5‐fluorouracil (5‐FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5‐FU resistance. Some are disease‐specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5‐FU. In this review, we construct a global outline of different mechanisms from disruption of 5‐FU‐metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial‐mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.
Colorectal cancer is the third most common cancer worldwide. 5‐Fluorouracil (5‐FU), a synthetic fluorinated pyrimidine analog requiring intracellular conversion into active metabolites, is the main chemotherapy used when colorectal cancer is at an advanced stage or at high risk of recurrence. However, resistance to this treatment exists, explaining a low 5‐year survival rate. We review the main mechanisms of 5‐FU resistance, especially those linked to tumor microenvironment and genetic alterations.
The treatment options available for colorectal cancer (CRC) have increased over the years and have significantly improved the overall survival of CRC patients. However, the response rate for CRC ...patients with metastatic disease remains low and decreases with subsequent lines of therapy. The clinical management of patients with metastatic CRC (mCRC) presents a unique challenge in balancing the benefits and harms while considering disease progression, treatment-related toxicities, drug resistance and the patient's overall quality of life. Despite the initial success of therapy, the development of drug resistance can lead to therapy failure and relapse in cancer patients, which can be attributed to the cancer stem cells (CSCs). Thus, colorectal CSCs (CCSCs) contribute to therapy resistance but also to tumor initiation and metastasis development, making them attractive potential targets for the treatment of CRC. This review presents the available CCSC isolation methods, the clinical relevance of these CCSCs, the mechanisms of drug resistance associated with CCSCs and the ongoing clinical trials targeting these CCSCs. Novel therapeutic strategies are needed to effectively eradicate both tumor growth and metastasis, while taking into account the tumor microenvironment (TME) which plays a key role in tumor cell plasticity.
MiRNAs have recently become a subject of great interest within cancers and especially colorectal cancers in diagnosis, prognosis, and therapy decisions; herein we review the current literature ...focusing on miRNAs in colorectal cancers, and we discuss future challenges to use this tool on a daily clinical basis. In liquid biopsies, miRNAs seem easily accessible and can give important information toward each step of the management of colorectal cancers. However, it is now necessary to highlight the most sensitive and specific miRNAs for each goal thanks to multicentric prospective studies. Conclusions: by their diversity and the feasibility of their use, miRNAs are getting part of the armamentarium of healthcare management of colorectal cancers.
Abstract
Evidence from previous studies suggests a protective effect of metformin in patients with colorectal cancer (CRC). The aim of this study was to examine the associations between metformin use ...and overall survival (OS) and disease-free survival (DFS) in CRC patients with type 2 diabetes mellitus (DM). We retrospectively included patients who underwent surgery for CRC at Limoges’ University Hospital between 2005 and 2019 and diagnosed with type 2 DM. Data on the characteristics of patients, CRC, comorbidities and drug exposure were collected from the electronic medical records. The exposure was the use of metformin and the outcomes were OS and DFS. We identified 290 CRC patients with type 2 DM. A total of 144 (49.7%) of them were treated with metformin. Metformin users were significantly younger, with higher body mass index and less diabetes-related complications compared to non-users. The 2-year OS was significantly higher in metformin users than in non-users (86.9 ± 2.9% vs. 71.0 ± 4.0%, p = 0.001). In multivariate analysis, metformin use was associated with better OS (adjusted hazard ratios aHR = 0.45 95% confidence interval 95% CI: 0.21–0.96) and better DFS (aHR = 0.31; 95% CI: 0.18–0.54). In conclusion, the use of metformin may improve OS and DFS in CRC patients with type 2 DM.
Despite therapeutic advances, colorectal cancer (CRC) is still one of the deadliest cancers, partly due to local recurrence and metastatic disease. Tumour cells that spread by gaining access to ...peripheral blood are called circulating tumour cells (CTCs). These may be present before there are any clinical signs, but can be detected within blood samples. CTCs from patients with CRC may be isolated in a laboratory for characterization and multiple analyses. In this review, we focus on the prognostic potential of CTCs detection, by evaluating the reported progress and applications of such analyses. Our search found 77 relevant studies that reported CTC detection in CRC. Both cell count and features were reported as promising prognosis biomarkers. Since CTCs are rare and can lose their differentiation, new tools are being developed to improve detection. CTCs may have potential as prognostic biomarkers for CRC in terms of survival prediction, anticipating chemotherapy resistance, and surgical planning. CTCs are not yet used in clinical practice, and further investigations are required in order to better frame their practical value.
Extravasation of Noncytotoxic Drugs David, Valentin; Christou, Niki; Etienne, Pauline ...
Annals of Pharmacotherapy,
08/2020, Letnik:
54, Številka:
8
Book Review, Journal Article
Recenzirano
Objective: Commonly used drugs may be dangerous in case of extravasation. The lack of information from health care teams can lead to delays in both diagnosis and treatments. This review aims at ...alerting health care professionals about drugs and risk factors for extravasation and outlines recommendations for the diagnosis and treatment of extravasation. Data Source: A literature search of MEDLINE/PubMed, Scopus, the Cochrane Library, and Google Scholar was performed from 2000 to December 2019 using the following terms: extravasation, central venous line, peripheral venous line, irritant, and vesicant. Study Selection and Data Extraction: Overall, 140 articles dealing with drug extravasation were considered potentially relevant. Each article was critically appraised independently by 2 authors, leading to the inclusion of 80 relevant studies, guidelines, and reviews. Articles discussing incidents of extravasation in the neonatal and pediatric population of patients were excluded. Data Synthesis: Training of health care teams and writing care protocols are important for an optimal management of extravasations. A prompt consultation should be achieved by a specialist surgeon. The surgical procedure, if necessary, will consist of wound debridement followed by an abundant lavage. Relevance to Patient Care and Clinical Practice: This review discusses the management of drug extravasations according to their mechanism(s) of toxicity on tissues. It highlights the importance of a close monitoring of patients and the training of health care teams likely to face this type of adverse event. Conclusions: Extravasations still contribute to significant morbidity and mortality. A good knowledge of risk factors and the implementation of easily and quickly accessible standardized care protocols are 2 key elements in both prevention and treatment of extravasations.
(1) Background: Metformin, an anti-diabetic drug, seems to protect against aggressive acquisition in colorectal cancers (CRCs). However, its mechanisms are still really unknown, raising questions ...about the possibility of its positive impact on non-diabetic patients with CRC. (2) Methods: An
study based on human colon cancer cell lines and an
study with different colon cancer stages with proteomic and transcriptomic analyses were initiated. (3) Results: Metformin seems to protect from colon cancer invasive acquisition, irrespective of glucose concentration. (4) Conclusions: Metformin could be used as an adjuvant treatment to surgery for both diabetic and non-diabetic patients in order to prevent the acquisition of aggressiveness and, ultimately, recurrences.
Cancers of the digestive system, including esophageal, gastric, pancreatic, hepatic, and colorectal cancers, have a high incidence and mortality worldwide. Efficient therapies have improved patient ...care; however, many challenges remain including late diagnosis, disease recurrence, and resistance to therapies. Mechanisms responsible for these aforementioned challenges are numerous. This review focuses on neurotrophins, including NGF, BDNF, and NT3, and their specific tyrosine kinase receptors called tropomyosin receptor kinase (Trk A, B, C, respectively), associated with sortilin and the p75 neurotrophin receptor (p75NTR), and their implication in digestive cancers. Globally, p75NTR is a frequently downregulated tumor suppressor. On the contrary, Trk and their ligands are considered oncogenic factors. New therapies which target NT and/or their receptors, or use them as diagnosis biomarkers could help us to combat digestive cancers.
Background Nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are often discovered at a small size. No clear consensus exists on the management of NF-PNETs ≤ 2 cm. The aim of our study was to ...determine the prognostic value of indicators of malignancy in sporadic NF-PNETs ≤ 2 cm. Methods Eighty patients were evaluated retrospectively in 7 French University Hospital Centers. Patients were managed by operative resection (operative group OG) or observational follow-up (non-OG NOG). Pathologic characteristics and outcomes were analyzed. Results Sixty-six patients (58% women) were in the OG (mean age, 59 years; 95% CI, 56.0–62.3; mean tumor size, 1.6 cm; 95% CI, 1.5–1.7); 14 (72% women, n = 10) were in the NOG (mean age, 63 years; 95% CI, 56–70; mean tumor size, 1.4 cm; 95% CI, 1.0–1.7). All PNETs were ranked using the European Neuroendocrine Tumor Society grading system. Fifteen patients (19%) had malignant tumors defined by node or liver metastasis (synchronous or metachronous). The median disease-free survival was different between malignant and nonmalignant PNETs, respectively: 16 (range, 4–72) versus 30 months (range, 1–156; P = .03). On a receiver operating characteristic (ROC) curve, tumor size had a significant impact on malignancy (area under the curve AUC, 0.75; P = .03), but not Ki-67 (AUC, 0.59; P = .31). A tumor size cutoff was found on the ROC curve at 1.7 cm (odd ratio, 10.8; 95% CI; 2.2–53.2; P = .003) with a sensitivity of 92% and a specificity of 75% to predict malignancy. Conclusion Based on our retrospective study, the cutoff of 2 cm of malignancy used for small NF-PNETs could be decreased to 1.7 cm to select patients more accurately.
Initially, NEUROTENSIN (NTS) has been shown to play physiological and biological functions as a neuro-transmitter/modulator in the central nervous system and as an endocrine factor in the periphery, ...through its binding to two kinds of receptors: NTSR1 and 2 (G protein-coupled receptors) and NTSR3/sortilin (a vacuolar protein-sorting 10-domain receptor). NTS also plays oncogenic roles in many types of cancer, including digestive cancers. In tumor tissues, NTS and NTSR1 expression is higher than in healthy ones and is associated with poor prognosis. NTS and NTRS1 promote cancer progression and play key functions in metastatic processes; they modulate several signaling pathways and they contribute to changes in the tumor microenvironment. Conversely, NTRS2 involvement in digestive cancers is poorly understood. Discovered for mediating NTS biological effects, sortilin recently emerged as a promising target as its expression was found to be increased in various types of cancers. Because it can be secreted, a soluble form of sortilin (sSortilin) appears as a new serum biomarker which, on the basis of recent studies, promises to be useful in both the diagnosis and tumor progression monitoring. More precisely, it appears that soluble sortilin can be associated with other receptors like TRKB. These associations occur in exosomes and trigger the aggressiveness of cancers like glioblastoma, leading to the concept of a possible composite theranostic biomarker. This review summarizes the oncogenic roles of the NTS signaling pathways in digestive cancers and discusses their emergence as promising early diagnostic and/or prognostic biomarkers and therapeutic targets.
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