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 5 26) and normal groups (n 5 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 crossvalidation 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 3 10 214 ), creatine (p < 7 3 10 28 ), lactate (p < 9 3 10 24 ), alanine (p < 7.9 3 10 23 ) and citrate (p < 3 3 10 24 ) 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 5 0.3881 and p 5 6.66 3 10 24), 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.Leptomeningeal carcinomatosis (LC) is a devastating complication of systemic cancer that occurs in 5-10% of patients with solid tumors, more frequently adenocarcinoma, and is observed most commonly in patients with breast cancer, lung cancer or melanoma.1 Especially, lung cancer is one of the most common primary cancers that cause central nervous system (CNS) metastases, and the incidence of LC is increasing as lung cancer patients survive longer with more advanced treatment modalities. [2][3][4][5] In addition, with the expansion of therapeutic options for systemic treatment of lung cancer, including targeted therapies, the landscape for treating LC is changing. Although some drugs have demonstrated activity within the CNS, they have limitation to pass the blood-brain barrier. 6,7 Early and accurate diagnosis of LC and treatment initiation could offer the best chance of controlling symptoms and prevent the establishment of irreversible neurologic deficits that impair the patient's quality of life. 1,8,9 However, LC diagnosis currently remains a challenge. CSF cytology shows higher specificity (theoretical 100%) than MRI analysis (about 77%) and a sensitivity of 75% upon repeated spinal tapping.10,11 One

Retrospective Analysis of Cerebrospinal Fluid Profiles in 228 Patients with Leptomeningeal Carcinomatosis : Differences According to the Sampling Site, Symptoms, and Systemic Factors

“…Efforts are underway to find a CSF biomarker from cancer-specific microRNA or metabolites that is an active initiator or specific byproduct of LMC123). We agree with those research trends, as we found that gross CSF profiles of cell counts and protein levels are poor indicators of LMC activity, especially when sampled from the ventricle.…”

Complement Component 3 Adapts the Cerebrospinal Fluid for Leptomeningeal Metastasis

“…Moreover, given the dynamic nature of CSF production and C3a generation, we anticipate that CSF composition will be similarly in flux, and would be unlikely to achieve a steady state. Previous attempts to establish CSF biomarkers of metastasis including myo-inositol (An et al, 2015), β-microglobolin (Svatonova et al, 2014), and others (Walbert and Groves, 2010) have failed to prove useful across a diverse tumor types. Remarkably, we find that C3 is present in the CSF of patients with leptomeningeal metastasis from different types of cancer, and at levels above those of CSF from patients with brain parenchymal metastases or with no CNS metastasis.…”

Application of 3D Fast Spin-Echo T1 Black-Blood Imaging in the Diagnosis and Prognostic Prediction of Patients with Leptomeningeal Carcinomatosis

“…The diagnosis was made in 1 of 2 ways: (1) a CSF cytology positive for malignant cells, which was repeated up to three times or (2) MRI scans showing LC on both initial and 2-3 month follow-up studies in patients with suspicious cytology (atypical cells) or biochemical test (elevated protein level and/or decreased glucose level in CSF). 1,7,8,10,[16][17][18][19] The various MR imaging findings used for the diagnosis included superficial sulcal/cisternal enhancement, sulcal/cisternal obliteration, multiple tiny superficial nodules along the sulci/cistern, enhancement of cranial nerves, and hydrocephalus. 7,10 LC may grow in a linear pattern, creating a thin layer of cells spread diffusely over the brain surfaces, or in a nodular growth pattern, involving the leptomeninges in a multifocal skip pattern with intervening tumor-free areas.…”

“…For the infratentorial area, it was scored as 0 (absent) or 1 (present). 19 In addition, other imaging parameters were also collected, including the presence and number of brain metastases, the presence of hydrocephalus, the pattern of LC (linear or nodular), and the location of LC in the brain.…”