Applied Sciences  
Article  
Exploring Serum NMR-Based Metabolomic Fingerprint of Colorectal Cancer Patients: Effects of Surgery and Possible Associations with Cancer Relapse  
[PERSON] 1,2,1(r), [PERSON] 3,1, [PERSON] 3, [PERSON] 3,4(r), [PERSON] 5(r), [PERSON] 5, [PERSON] 3, [PERSON] 6, [PERSON] 3,7, [PERSON] 6, [PERSON] 6, [PERSON] 3, [PERSON] 5(r), [PERSON] 4, [PERSON] 1,2,2, [PERSON] 1,2,2,1,3,4,5 and [PERSON] 3,4(r)  
Magnetic Resonance Center (CERM) and Department of Chemistry \"[PERSON]\", University of Florence, 50019 Sesto Fiorentino, Italy; [EMAIL_ADDRESS] (A.V. ); [EMAIL_ADDRESS] (C.L.) Consorzio Interuniversitario Risanzeg Magnetiche Metallo Proteine (CIRMMP), 50019 Sesto Fiorentino, Italy  
[PERSON]; [PERSON], [PERSON]; [PERSON], [PERSON]; [PERSON], [PERSON]; [PERSON], [PERSON]; [PERSON] [PERSON]. diagnosed at early stage (stage 1 to 3), and surgery is the primary treatment option with curative intent for this type of disease [4]. Unfortunately, about 35% of these patients develop cancer relapse, which, in the majority of cases, occurs within the first 2-3 years after surgery [5; 6]. TNM staging at diagnosis, based on depth of tumor wall invasion (T), lymph node involvement (N), and presence of distant metastasis (M), is currently the principal instrument available to predict risk of relapse, and thus to identify patients who may have potential benefits from adjuvant treatment [7; 8]. Colorectal cancer is a heterogeneous disease, even within the same pathological stage, with different characteristics of clinical onset and different individual response to treatment. Moreover, patients with stage II and III CRC are shown to have different prognoses, particularly those who receive adjuvant chemotherapy, with 5-year overall survival (OS) ranging between 50% and 90% [9]. Adjuvant chemotherapy is strongly indicated in stage III disease, which is associated with a reduction of the relative risk of death of 33%, and an absolute survival benefit of 5-10% [10]. In stage III, the use of oxaliplatin in addition to fluoropyrimidines yields a further significant advantage of about 5% in terms of disease-free survival (DFS) and OS. Conversely, the therapeutic indication in patients with stage II CRC is controversial, as treatment with 5-Fluorouracil has an absolute benefit of 3-4% [11; 12]. In patients with clinicopathologicalally high-risk stage II disease [13], decision-making around adjuvant chemotherapy treatment needs to be carefully evaluated and discussed, considering also recurrence risk factors such as baseline carcinoembryonic antigen and vascular invasion [7]. There is no evidence to support the use of adjuvant chemotherapy in stage I disease. Considering all the above mentioned data, identifying patients who are most likely to benefit from adjuvant chemotherapy and preventing the other patients from futile treatments and unnecessary exposure to toxicity is crucial in stage II disease. Early detection of disease relapse is extremely relevant in CRC, as radical surgical intervention in patients with oligometastatic CRC can achieve a proven survival benefit. Therefore, early detection of relapse could potentially increase cure rates. Postoperative surveillance with clinical, radiological, and markers examination is often unable to identify early metastatic disease and/or postoperative minimal residual disease. Based on these considerations, improved risk stratification tools are required to reduce the number of patients treated unnecessarily. Metabolomics is defined as the comprehensive measurement of the ensemble of metabolites present in a biological specimen, the so-called metabolome [14]. Metabolites represent, at the same time, the downstream output of the genome, transcriptome, and proteome, as well as the upstream input from various exogenous factors such as environment, lifestyle, diet, and drug administration [15].