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.
Assessment of KRAS status is mandatory in patients with metastatic colorectal cancer (mCRC) before applying targeted therapy. We describe here a blinded prospective study to compare KRAS and BRAF ...mutation status data obtained from the analysis of tumor tissue by routine gold-standard methods and of plasma DNA using a quantitative PCR-based method specifically designed to analyze circulating cell-free DNA (cfDNA). The mutation status was determined by both methods from 106 patient samples. cfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. For the seven tested KRAS point mutations, the method exhibited 98% specificity and 92% sensitivity with a concordance value of 96%. Mutation load, expressed as the proportion of mutant alleles in cfDNA, was highly variable (0.5-64.1%, median 10.5%) among mutated samples. CfDNA was detected in 100% of patients with mCRC. This study shows that liquid biopsy through cfDNA analysis could advantageously replace tumor-section analysis and expand the scope of personalized medicine for patients with cancer.
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.
Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells.Two major ...hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential.These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer(CRC),one of the most commonly diagnosed and lethal cancers worldwide.The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells.Furthermore,the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells.These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence,though they represent less than 2.5%of the tumor mass.The stromal environment surrounding the tumor cells,referred to as the tumor niche,also supports angiogenesis,which supplies the oxygen and nutrients needed for tumor development.Anti-angiogenic therapy,such as with bevacizumab,a monoclonal antibody against vascular-endothelial growth factor,significantly prolongs the survival of metastatic CRC patients.However,such treatments are not completely curative,and a large proportion of patient tumors retain chemoresistance or show recurrence.This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells,as well as discusses the mechanisms contributing to their maintenance.Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks,namely angiogenic and proliferative attributes,could improve survival and decrease adverse effects induced by unnecessary chemotherapy.
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.
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.
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.
Hartmann's reversal procedures are often fraught with complications or failure to recover. This being a fact, it is often difficult to select patients with the optimal indications for a reversal. The ...post-recovery morbidity and mortality rates in the literature are heterogeneous between 0.8 and 44%. The identification of predictive risk factors of failure of such interventions would therefore be very useful to help the practitioner in his approach. Given these elements, it was important to us to analyze the practice of two French university hospitals in order to highlight such risk factors and to allow surgeons to select the best therapeutic strategy. We performed a bicentric observational retrospective study between 2010 and 2015 that studied the characteristics of patients who had undergone Hartmann surgery and were subsequently reestablished. The aim of the study was to identify factors influencing morbidity and postoperative mortality of Hartmann's reversal. Primary outcome was complications within the first 90 postoperative days. 240 patients were studied of which 60.4% were men. The mean age was 69.48 years. The median time to reversal was 8 months. 79.17% of patients were operated as emergency cases where the indication was a diverticular complication (39.17%). Seventy patients (29.2%) underwent a reversal and approximately 43% of these had complications within the first 90 postoperative days. The mean age of these seventy patients was 61.3 years old and 65.7% were males. None of them benefited from a reversal in the first three months. We identified some risk factors for morbidity such as pre-operative low albuminemia (p = 0.005) and moderate renal impairment (p = 0.019). However, chronic corticosteroid use (p = 0.004), moderate renal insufficiency (p = 0.014) and coronary artery disease (p = 0.014) seem to favour the development of anastomotic fistula, which is itself, a risk factor for mortality (p = 0.007). Our study highlights an important rate of complications including significant anastomotic fistula after Hartmann's reversal. Precarious nutritional status and cardiovascular comorbidities should clearly lead us to reconsider the surgical indication for continuity restoration.
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