Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.

Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2+ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression.

HER2+ breast leptomeningeal carcinomatosis (HER2+ LC) occurs when tumor cells spread to cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2+ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2+ LC tumors might efficiently target HER2+ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2+ LC (Lepto) cell lines from nodular HER2+ LC tissues. These lines are phenotypically CD326+CD49f-, confirming that they are derived from HER2+ LC tumors, and express surface CD44+CD24-, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2+ breast cancer lines in vitro and in vivo. Interestingly, the three Lepto lines overexpressed Jumonji domain-containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion in vitro. JIB04 treatment of patient-derived xenograft mouse models in vivo reduced HER2+ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2+ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. SIGNIFICANCE: HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models.

Four lines of anaplastic lymphoma kinase inhibitors and brain radiotherapy in a long-surviving non-small-cell lung cancer anaplastic lymphoma kinase-positive patient with leptomeningeal carcinomatosis.

Lung cancer is the most common tumor and the leading cause of cancer-related death worldwide. Approximately 6.7% of non-small-cell lung cancers (NSCLCs) show anaplastic lymphoma kinase (ALK) rearrangement and could benefit from ALK-targeted treatment. Various anti-ALK drugs have been developed during the past years, but it is actually controversial which sequence and which ALK inhibitor is recommended for a single patient. Leptomeningeal carcinomatosis (LC) is associated with a poor prognosis, with an overall survival of 2-4 months for treated patients. The data about LC management derive mainly from retrospective studies, being an exclusion criterion for most trials. Intrathecal chemotherapy and whole-brain radiotherapy (WBRT), associated with a systemic treatment, are the most commonly used approach. Here we present a case of NSCLC harboring an ALK translocation treated with four lines of ALK inhibitors and receiving WBRT for LC, showing an overall survival of ∼5 years from the diagnosis of metastatic disease. This case report focuses mainly on several controversial clinical aspects, that is, the sequence of treatment in ALK-positive NSCLC, the ALK inhibitors' efficacy on brain disease and beyond progression, the management of LC, and the role of WBRT despite the risk of cognitive impairment.

Phase I feasibility study for intrathecal administration of trastuzumab in patients with HER2 positive breast carcinomatous meningitis.

PURPOSE: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT). METHODS: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics. RESULTS: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease. CONCLUSIONS: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing. REGISTRATION IDENTIFICATION: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1).

Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread.

Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status.

miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring through the regulation of DHFR, integrins, and CD47.

BACKGROUND: The main cause of death in medulloblastoma is recurrence associated with leptomeningeal dissemination. During this process, the role of microRNAs (miRs) in the acquisition of metastatic phenotype remains poorly understood. This study aimed to identify the miR involved in leptomeningeal dissemination and to elucidate its biological functional mechanisms. MATERIALS AND METHODS: We analyzed the miR expression profiles of 29 medulloblastomas according to the presence of cerebrospinal fluid (CSF) seeding. Differentially expressed miRs (DEmiRs) were validated in 29 medulloblastoma tissues and three medulloblastoma cell lines. The biological functions of the selected miRs were evaluated using in vitro and in vivo studies. RESULTS: A total of 12 DEmiRs were identified in medulloblastoma with seeding, including miR-192. The reduced expression of miR-192 was confirmed in the tumor seeding group and in the medulloblastoma cells. Overexpression of miR-192 inhibited cellular proliferation by binding DHFR. miR-192 decreased cellular anchoring via the repression of ITGAV, ITGB1, ITGB3, and CD47. Animals in the miR-192-treated group demonstrated a reduction of spinal seeding (P < 0.05) and a significant survival benefit (P < 0.05). CONCLUSIONS: Medulloblastoma with seeding showed specific DEmiRs compared with those without. miR-192 suppresses leptomeningeal dissemination of medulloblastoma by modulating cell proliferation and anchoring ability.

High-dose erlotinib for refractory leptomeningeal metastases after failure of standard-dose EGFR-TKIs.

BACKGROUND: After initial response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), approximately one-third of patients develop central nervous system (CNS) metastases, including leptomeningeal metastases (LM). To achieve longer survival, control of CNS metastases is important, but therapeutic options are limited for LM after failure of standard-dose EGFR-TKIs. METHODS: We retrospectively evaluated the efficacy and safety of high-dose erlotinib in EGFR-mutant non-small cell lung cancer (NSCLC) patients with refractory LM after failure of standard-dose EGFR-TKIs. Survivals from diagnosis of LM to death were compared in patients with or without high-dose erlotinib. RESULTS: Between January 2007 and April 2013, we identified 35 patients with EGFR-mutant NSCLC, complicated with LM, and 12 underwent high-dose erlotinib, while the other 23 received only standard-dose EGFR-TKIs. In patients receiving high-dose erlotinib, magnetic resonance imaging response was confirmed in 3 (30 %) of 10 evaluable patients. Median time to CNS progression was 2.3 months (95 % confidence interval [CI] 1.8-5.5 months). Performance status and neurological symptoms improved in 4 (33 %) of 12 and 6 (50 %) of 12 patients, respectively. No severe adverse events (≥grade 3) associated with high-dose erlotinib were observed. Median survival time from diagnosis of LM in patients with high-dose erlotinib was 6.2 months (95 % CI 2.5-8.5 months), and in those without 5.9 months (95 % CI 1.3-7.8 months) (p = 0.94). CONCLUSION: High-dose erlotinib suggested its efficacy and safety in some patients with refractory LM. It represents a potential therapeutic option against LM after failure of standard-dose EGFR-TKIs, especially to palliate LM-related neurological symptoms.

Breast cancer and leptomeningeal disease (LMD): hormone receptor status influences time to development of LMD and survival from LMD diagnosis.

Leptomeningeal disease (LMD) occurs in 5 % of breast cancer patients. The aim of this study was to identify risk factors related to survival and time to development of LMD in breast cancer patients. A retrospective analysis of breast cancer patients with LMD, evaluated in MDACC between 1995 and 2011. 103 patients with diagnosis of breast cancer and LMD were identified (one male). The median age at LMD diagnosis was 49.2 years. 78.2 % had invasive ductal carcinoma. Hormone receptors (HRs) were positive in 55.3 % of patients, 47.4 % were human epidermal growth factor receptor 2-positive and 22.8 % were triple negative. 52 % of the patients were treated with WBRT, 19 % with spinal radiation, 36 % with systemic chemotherapy and 55 % with intrathecal chemotherapy. Estimated median overall survival from time of breast cancer diagnosis was 3.66 years. Median survival from time of LMD diagnosis was 4.2 months. Time from breast cancer diagnosis to LMD was 2.48 years. In multivariate analysis, HR status and stage at diagnosis were significantly associated with time to LMD diagnosis (p < 0.05). In triple negative patients, time to LMD was shorter. In patients who were HR positive, time to LMD was longer. Survival from LMD diagnosis was significantly associated with both treatment, as well as positive HR status (multivariate analysis p < 0.05). In conclusion LMD has dismal prognosis in breast cancer patients. HR status contributes to time to LMD diagnosis and survival from LMD diagnosis. The impact of treatment aimed at LMD cannot be ascertained in our retrospective study due to the inherent bias associated with the decision to treat.

Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry.

Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.

Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival.

The aim of the study was to define biological subtypes of breast cancer that have the propensity to metastasize to the leptomeninges and to assess factors influencing survival from detection of leptomeningeal metastatis (LM). One hundred and eighteen consecutive breast cancer patients with LM were treated in one institution, between the years 1999 and 2009; 40.5 % of patients had triple-negative subtype, 37.5 % had luminal A subtype and 22 % had HER2-positive subtypes (luminal B and HER2). Of patients with LM, 35 % had lobular cancer. Median survival from the detection of LM was 18 weeks, and 1-year survival was 16 %. Cox multivariate analysis revealed that performance status and systemic treatment statistically significantly influenced survival of patients with LM. Triple-negative biological subtype and lobular histological type of breast cancer had the propensity to metastasize to the leptomeninges. Performance status and systemic treatment ordered after detection of LM statistically significantly influenced survival.

ALK inhibitor crizotinib combined with intrathecal methotrexate treatment for non-small cell lung cancer with leptomeningeal carcinomatosis.

Anaplastic lymphoma kinase (ALK) inhibitor has shown dramatic efficacy in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangements in phase I trial. Herein we report two cases of NSCLC patients with leptomeningeal carcinomatosis (LM), treated with ALK inhibitor under emergent use of investigational new drug combined with intrathecal methotrexate treatment. Progression free survival was 10 months and 6 months, respectively, and little additional toxicities were observed. These results suggest that ALK inhibitor might be safely administered even in patients or those with metastases in central nervous system.

[Leptomeningeal meningitis related to breast cancer overexpressing HER2: is there a place for a more specific treatment?]. / Méningites carcinomateuses des cancers du sein surexprimant HER2 : pour un traitement spécifique ?

Leptomeningeal metastases are very commonly associated with breast cancer. The prognosis is very poor in the short term with an overall median survival less than 6 months. Based on pragmatic and historical considerations intrathecal chemotherapy (IT) are considered to be the adequate treatment. However overall results are disappointing. Despite specific and symptomatic treatment, improvement in survival and quality of life remains very modest, highlighting the importance for ongoing research for developing new molecules or on improving the use a better use of those available today. The incidence of leptomeningeal metastases is particularly marked in cases of overexpression of HER2. The main hypothesis is there may be a better control of extra-cerebral localisations with trastuzumab therefore intra-cerebral recurrences may be encountered preferentially as they are not reached by this high molecular weight monoclonal antibody (148  kD). Analyses performed in the cerebrospinal fluid following intravenous trastuzumab showed extremely low levels of the antibody and support the hypothesis that leptomeningeal metastasis of HER2-overexpressing breast carcinoma remain potentially sensitive to HER2-type receptor inhibition by a target agent under the condition of by-passing the meningeal blood brain barrier. Intra-ventricular or IT administered with trastuzumab would reach high loco-regional therapeutic concentrations in the cerebro-meningeal without risk for normal non-expressing HER2 leptomeningeal tissue. This strategy has been successfully tested on several animal models. A limited number of administrations in humans have been described in the literature, with weekly doses up to 100  mg. No specific toxicity has been described and some data suggest a potential benefit in survival despite the real difficulties for adequate interpretations. Furthermore, a multicentric phase I-II clinical trial, of which the Curie institute is the sponsor and investigating the intra-thecal administration and the efficacy of the trastuzumab will begin very soon. More studies are needed to measure the exact impact of small molecule inhibitors of tyrosine kinase on the leptomeningeal localizations.

Vascular endothelial growth factor antisense oligonucleotides inhibit leptomeningeal metastasis in vivo.

To determine the level of vascular endothelial growth factor (VEGF) protein produced in tumor tissues and to evaluate the effect of antisense oligonucleotides directed against VEGF on tumor growth and animal survival in a rabbit model of leptomeningeal carcinomatosis. New Zealand White (NZW) rabbits were injected with VX2 tumor cells transfected with or without VEGF antisense constructs. The time course of VEGF protein expression in tumor tissues was then examined by immunohistochemistry and western blot analysis. VEGF concentrations in serum and cerebrospinal fluid (CSF) were determined by enzyme-linked immunosorbent assay (ELISA). The efficacy of VEGF antisense therapy was evaluated by calculation of the survival rate and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Immunohistochemical analysis and immunoblotting showed that VEGF protein expression was significantly decreased in tissues from rabbits given VEGF antisense treatment. Serum and CSF VEGF concentrations were also markedly reduced during the first 15 days after tumor inoculation in antisense-treated animals. VEGF antisense therapy resulted in prolonged animal survival. Furthermore, while some meningeal nodular enhancement was evident in almost all of the VX2-inoculated rabbits, meningeal enhancement and thickening was clearly suppressed after VEGF antisense treatment. These results indicate that VEGF antisense oligonucleotides have a potent anti-tumor activity in a rabbit model of VX2 leptomeningeal carcinomatosis. In addition, DCE-MRI provides highly accurate measurements for the detection of experimentally induced leptomeningeal carcinomatosis and could be used as a suitable method for assessing in vivo tumor growth and angiogenesis.

Combined chemotherapy with carboplatin plus irinotecan showed favorable efficacy in a patient with relapsed small cell carcinoma of the prostate complicated with meningeal carcinomatosis.

We report the case of a 65-year-old man with recurrent prostate cancer who presented with meningeal carcinomatosis. In September 2007, he had been diagnosed with mixed type small cell carcinoma and adenocarcinoma at clinical stage T4N1M1 (primary prostate tumor with multiple bone, liver, and lymph node metastases) and hormonal therapy had been administered. Following an increase in the level of pro-gastrin-releasing peptide (ProGRP), combined chemotherapy with cisplatin plus etoposide was implemented and showed efficacy in targeting the small cell carcinoma. In March 2008, he presented with signs of meningeal irritation; his condition deteriorated quickly and multiple brain metastases were confirmed by magnetic resonance imaging (MRI). A sample of cerebrospinal fluid collected by lumbar puncture showed cancer cells and an elevated level of ProGRP. Small cell carcinoma of the prostate complicated with meningeal carcinomatosis was diagnosed. A different chemotherapy regimen was then administered, consisting of a combination of carboplatin plus irinotecan, which is one of the most common first-line treatments for extensive-stage small cell lung carcinoma. From day 20 after the initiation of this therapy, he gradually recovered from the signs of meningeal irritation, and brain MRI showed nearly normal findings; also, the serum level of ProGRP was reduced. In conclusion, we report the efficacy of combined treatment with carboplatin plus irinotecan for small cell carcinoma of the prostate complicated with meningeal carcinomatosis. Because this clinical condition is extremely rare, a gold standard treatment has yet to be established.

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab.

INTRODUCTION: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of alpha-particle emitting (211)At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. METHODS: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 muCi (211)At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 muCi (211)At-labeled trastuzumab or saline. In Experiment 3, animals received 28 muCi (211)At-labeled trastuzumab, 30 muCi (211)At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. RESULTS: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 muCi (211)At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 muCi (211)At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with (211)At-labeled TPS3.2 and (211)At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the (211)At-trastuzumab-treated groups. CONCLUSION: Intrathecal (211)At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

Intrathecal synthesis of tumor markers is a highly sensitive test in the diagnosis of leptomeningeal metastasis from solid cancers.

BACKGROUND: Identification of neoplastic cells in cerebrospinal fluid (CSF) by cytological analysis is the key diagnostic feature of leptomeningeal metastasis (LM). Because of the lack of sensitivity of this test, considerable efforts have been made to identify alternative diagnostic markers. Data from the literature suggest that measurement of tumor markers (TM) in CSF may be helpful for improving the diagnosis. METHODS: We analyzed the concentrations of the TM carcinoembryonic antigen (CEA), CA15.3, CA125 and CA19.9 in both CSF and serum from 18 patients with neoplastic meningitis diagnosed by CSF cytology. We also performed these same measurements in 50 patients affected by other neurological diseases (OND) in order to evaluate putative intrathecal synthesis. In addition, CSF and serum concentrations of the proangiogenic factor VEGF (vascular endothelial growth factor) were evaluated. RESULTS: All LM patients showed intrathecal synthesis for at least one TM. In one patient, a negative CSF cytology after treatment paralleled normalization of tumor marker synthesis. None of the OND patients displayed intrathecal TM synthesis. The VEGF Index (CSF/serum VEGF relative to CSF/serum albumin ratios) was significantly higher in LM patients compared with the control group. However, significant overlap between LM patients and values seen in those with OND was observed. CONCLUSIONS: Evaluation of intrathecal TM synthesis is a specific, sensitive, reliable, and reproducible diagnostic tool, and is useful to support diagnosis of carcinomatous meningitis.