A case of personalized and precision medicine: Pharmacometabolomic applications to rare cancer, microbiological investigation, and therapy.

RATIONALE: Advances in metabolomics, together with consolidated genetic approaches, have opened the way for investigating the health of patients using a large number of molecules simultaneously, thus providing firm scientific evidence for personalized medicine and consequent interventions. Metabolomics is an ideal approach for investigating specific biochemical alterations occurring in rare clinical situations, such as those caused by rare associations between comorbidities and immunosuppression. METHODS: Metabolomic database matching enables clear identification of molecular factors associated with a metabolic disorder and can provide a rationale for elaborating personalized therapeutic protocols. Mass spectrometry (MS) forms the basis of metabolomics and uses mass-to-charge ratios for metabolite identification. Here, we used an MS-based approach to diagnose and develop treatment options in the clinical case of a patient afflicted with a rare disease further complicated by immunosuppression. The patient's data were analyzed using proprietary databases, and a personalized and efficient therapeutic protocol was consequently elaborated. RESULTS: The patient exhibited significant alterations in homocysteine:methionine and homocysteine:thiodiglycol acid plasma concentration ratios, and these were associated with low immune system function. This led to cysteine concentration deficiency causing extreme oxidative stress. Plasmatic thioglycolic acid concentrations were initially altered and were used for therapeutic follow-up and to evaluate cysteine levels. CONCLUSIONS: An MS-based pharmacometabolomics approach was used to define a personalized protocol in a clinical case of rare peritoneal carcinosis with confounding immunosuppression. This personalized protocol reduced both oxidative stress and resistance to antibiotics and antiviral drugs.

Surface-activated chemical ionization-electrospray mass spectrometry in the analysis of urinary thiodiglycolic acid.

RATIONALE: Thiodiglycolic acid (TDGA) is a urinary metabolite of the oxazaphosphorine class of chemotherapeutics, in particular of ifosfamide. Ifosfamide metabolism generates chloroacetaldehyde (CAA), a toxic compound associated with neurotoxicity, nephrotoxicity, urotoxicity and cardiotoxicity. CAA, in turn, interacts with cellular thiol groups leading to GSH depletion, cell death and generation of thiodiglycolic acid (TDGA), as a final product. TDGA is mainly excreted in the urine. The ability to accurately measure TDGA in urine, therefore, will be a useful way of monitoring exposure to ifosfamide during chemotherapy. METHODS: TDGA in urine samples was measured with liquid chromatography coupled to mass spectrometry (LC/MS) by means of a novel Surface-Activated Chemical Ionization-Electrospray (SACI-ESI) or a classical ESI ion source alone. RESULTS: The SACI-ESI and ESI alone based methods for analysis of urinary TDGA were optimized and compared. A strong reduction in matrix effect together with enhanced quantification performances was obtained with the SACI-ESI when compared with ESI. In particular, an increase in quantification precision (from 85 to 95%) and accuracy (from 59 to 90%) were observed, which allowed for optimal detection of TDGA. CONCLUSIONS: The LC/SACI-ESI-MS approach provides a very sensitive and quantitative method for the analysis of TDGA. Thanks to the enhancement in sensitivity and matrix effect reduction, the SACI-ESI source enables the use of a relatively low-cost ion-trap mass spectrometer in the analysis of this toxicity biomarker in urine. Due to these characteristics, this approach would constitute an invaluable tool in the clinical laboratory, for measuring TDGA and other toxicity related biomarkers of chemotherapy with proper sensitivity and accuracy.