Plasma metabolomics, lipidomics and cytokinomics profiling predict disease recurrence in metastatic colorectal cancer patients undergoing liver resection
Susan CostantiniElena Di GennaroFrancesca CaponeAlfonso De StefanoGuglielmo NastiCarlo VitaglianoSergio Venanzio SetolaFabiana TatangeloPaolo DelrioFrancesco IzzoAntonio AvalloneAlfredo Budillon
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In metastatic colorectal cancer (mCRC) patients (pts), treatment strategies integrating liver resection with induction chemotherapy offer better 5-year survival rates than chemotherapy alone. However, liver resection is a complex and costly procedure, and recurrence occurs in almost 2/3rds of pts, suggesting the need to identify those at higher risk. The aim of this work was to evaluate whether the integration of plasma metabolomics and lipidomics combined with the multiplex analysis of a large panel of plasma cytokines can be used to predict the risk of relapse and other patient outcomes after liver surgery, beyond or in combination with clinical morphovolumetric criteria.Peripheral blood metabolomics and lipidomics were performed by 600 MHz NMR spectroscopy on plasma from 30 unresectable mCRC pts treated with bevacizumab plus oxaliplatin-based regimens within the Obelics trial (NCT01718873) and subdivided into responder (R) and non-R (NR) according to 1-year disease-free survival (DFS): ≥ 1-year (R, n = 12) and < 1-year (NR, n = 18). A large panel of cytokines, chemokines, and growth factors was evaluated on the same plasma using Luminex xMAP-based multiplex bead-based immunoassay technology. A multiple biomarkers model was built using a support vector machine (SVM) classifier.Sparse partial least squares discriminant analysis (sPLS-DA) and loading plots obtained by analyzing metabolomics profiles of samples collected at the time of response evaluation when resectability was established showed significantly different levels of metabolites between the two groups. Two metabolites, 3-hydroxybutyrate and histidine, significantly predicted DFS and overall survival. Lipidomics analysis confirmed clear differences between the R and NR pts, indicating a statistically significant increase in lipids (cholesterol, triglycerides and phospholipids) in NR pts, reflecting a nonspecific inflammatory response. Indeed, a significant increase in proinflammatory cytokines was demonstrated in NR pts plasma. Finally, a multiple biomarkers model based on the combination of presurgery plasma levels of 3-hydroxybutyrate, cholesterol, phospholipids, triglycerides and IL-6 was able to correctly classify patients by their DFS with good accuracy.Overall, this exploratory study suggests the potential of these combined biomarker approaches to predict outcomes in mCRC patients who are candidates for liver metastasis resection after induction treatment for defining personalized management and treatment strategies.Keywords:
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The intestinal microflora plays important roles in the health of the host, such as nutrient processing and the modulation of intestinal immune responses. The constituents of the diet greatly affect the composition of the microbiota and its metabolites. The human intestinal microbiota is made up of around 100 trillion microbial cells encompassing at least 300 species. Consuming probiotics may lead to changes in the intestinal microflora that influence host health. Metabolomics is a powerful tool for revealing metabolic changes in biofluids, tissues, and organs of hosts induced by the consumption of probiotics, and lipidomics in particular is a technical approach that focuses on the analysis of lipids in various cells and biofluids. Metabolomics and lipidomics have been used to investigate intracellular and extracellular metabolites as well as for the nontargeted profiling and fingerprinting of metabolites. Based on metabolomics and lipidomics investigations, we reviewed the effects of consuming probiotics on metabolic profiles in controlled intestinal environments. We also discuss the associations between metabolic changes and human diseases after consuming probiotics in uncontrolled intestinal environments. In addition, we review the metabolic changes that take place within the food matrix during probiotic fermentation.
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背景・目的: oxaliplatin base の化学療法が大腸癌腹膜播種症例に与える影響について検討した。対象・方法: 2006 年1月～2012 年11 月の間に，腹膜播種陽性Stage IV 大腸癌と診断され，oxaliplatin base の化学療法を導入した49 例（oxaliplatin施行群）と，それ以前に5─FU 系の全身化学療法を施行した26 例（control 群）を対象。oxaliplatin 導入前後のoverall survival（OS）を比較。また，oxaliplatin 施行群のOS に関して臨床病理学的因子を共変量とし，単変量，多変量解析を行い，予後因子を検討した。結果: oxalplatin 施行群はcontrol 群より有意に生存期間が延長していた（中央値 20.5 か月 vs 11.7 か月，p＝0.04）。oxaliplatin 施行群におけるOS に対するfavorable factor として，70 歳以下（p＝0.03），原発巣切除（p＝0.02）が同定された。結語: oxaliplatin base の化学療法は大腸癌腹膜播種症例においても生存期間を改善させた。腹膜播種の程度に関係なく原発巣切除を70 歳以下の症例に行い，速やかにoxaliplatin base の化学療法を導入することが予後向上につながることが示唆された。
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Colorectal cancer is one of the leading causes of cancer death. The mainstay of chemotherapy in colorectal cancer patients for the past 40 years has been fluorouracil (5-FU). Oxaliplatin (Eloxatin) is a novel platinum compound with promising activity in colorectal cancer. As a single agent, oxaliplatin has produced response rates of 12% to 24% in patients with previously untreated advanced colorectal cancer, and 10% to 11% in patients with relapsed or refractory advanced colorectal cancer. In phase II trials, oxaliplatin combined with 5-FU, with or without leucovorin, was associated with response rates of 60% and higher when used as front-line therapy, and when used in patients with relapsed or refractory advanced colorectal cancer, response rates ranged from 25% to 50%. In the front-line setting, two randomized trials of 5-FU and leucovorin, with or without oxaliplatin, demonstrated that the addition of oxaliplatin significantly increases response rate and time to tumor progression, but not survival, over 5-FU plus leucovorin alone. The reasons for this discrepancy are unclear, and several possibilities are being considered. Additional phase III trials are underway to clarify the contribution of oxaliplatin in the treatment of patients with locally advanced and metastatic colorectal cancer.
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Dynamic changes in circulating and tissue metabolites and lipids occur in response to exercise-induced cellular and whole-body energy demands to maintain metabolic homeostasis. The metabolome and lipidome in a given biological system provides a molecular snapshot of these rapid and complex metabolic perturbations. The application of metabolomics and lipidomics to map the metabolic responses to an acute bout of aerobic/endurance or resistance exercise has dramatically expanded over the past decade thanks to major analytical advancements, with most exercise-related studies to date focused on analyzing human biofluids and tissues. Experimental and analytical considerations, as well as complementary studies using animal model systems, are warranted to help overcome challenges associated with large human interindividual variability and decipher the breadth of molecular mechanisms underlying the metabolic health-promoting effects of exercise. In this review, we provide a guide for exercise researchers regarding analytical techniques and experimental workflows commonly used in metabolomics and lipidomics. Furthermore, we discuss advancements in human and mammalian exercise research utilizing metabolomic and lipidomic approaches in the last decade, as well as highlight key technical considerations and remaining knowledge gaps to continue expanding the molecular landscape of exercise biology.
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