title: An NMR metabolomics approach for the diagnosis of leptomeningeal carcinomatosis in lung adenocarcinoma cancer patients.
abstract: Leptomeningeal carcinomatosis (LC) is a metastatic cancer invading the central nervous system (CNS). We previously reported a metabolomic diagnostic approach as tested on an animal model and compared with current modalities. Here, we provide a proof of concept by applying it to human LC originating from lung cancer, the most common cause of CNS metastasis. Cerebrospinal fluid from LC (n = 26) and normal groups (n = 41) were obtained, and the diagnosis was established with clinical signs, cytology, MRI and biochemical tests. The cytology on the CSF, the current gold standard, exhibited 69% sensitivity (~100% specificity) from the first round of CSF tapping. In comparison, the nuclear magnetic resonance spectra on the CSF showed a clear difference in the metabolic profile between the LC and normal groups. Multivariate analysis and cross-validation yielded the diagnostic sensitivity of 92%, the specificity of 96% and the area under the curve (AUC) of 0.991. Further spectral and statistical analysis identified myo-inositol (p < 5 × 10(-14)), creatine (p < 7 × 10(-8)), lactate (p < 9 × 10(-4)), alanine (p < 7.9 × 10(-3)) and citrate (p < 3 × 10(-4)) as the most contributory metabolites, whose combination exhibited an receiver-operating characteristic diagnostic AUC of 0.996. In addition, the metabolic profile could be correlated with the grading of radiological leptomeningeal enhancement (R(2) = 0.3881 and p = 6.66 × 10(-4)), suggesting its potential utility in grading LC. Overall, we propose that the metabolomic approach might augment current diagnostic modalities for LC, the accurate diagnosis of which remains a challenge.
authors.affiliation: College of Pharmacy, Natural Product Research Institute, Seoul National University, San 56-1 Sillim-dong, Gwanak-gu, 151-742, Seoul, Republic of Korea.
authors.forename: Yong Jin
authors.initials: YJ
authors.lastname: An
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Cho
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.forename: Jin Wook
authors.initials: JW
authors.lastname: Kim
authors.forename: He
authors.initials: H
authors.lastname: Wen
authors.forename: Chul-Kee
authors.initials: CK
authors.lastname: Park
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Seung Hong
authors.initials: SH
authors.lastname: Choi
authors.forename: Sunghyouk
authors.initials: S
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000556:secondary; D000409:Alanine / Q000134:cerebrospinal fluid; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D019343:Citric Acid / Q000134:cerebrospinal fluid; D003401:Creatine / Q000134:cerebrospinal fluid; D006801:Humans; D007294:Inositol / Q000134:cerebrospinal fluid; D019344:Lactic Acid / Q000134:cerebrospinal fluid; D008175:Lung Neoplasms / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D055756:Meningeal Carcinomatosis / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000556:secondary; D055442:Metabolome; D015999:Multivariate Analysis; D012372:ROC Curve
chemical_list: D014408:Biomarkers, Tumor; D019343:Citric Acid; D019344:Lactic Acid; D007294:Inositol; D003401:Creatine; D000409:Alanine
keywords: CSF; diagnosis; leptomeningeal carcinomatosis; metabolomics; metastasis