Clinical Safety and Efficiency of the H-Port for Treatment of Leptomeningeal Metastasis.

Objective: To evaluate the usefulness of a cranial implantable chemoport, the H-port, as an alternative to the Ommaya reservoir for intraventricular chemotherapy/cerebrospinal fluid (CSF) access in patients with leptomeningeal metastasis (LM). Methods: One hundred fifty-two consecutive patients with a diagnosis of LM and who underwent H-port installation between 2015 and 2021 were evaluated. Adverse events associated with installation and intraventricular chemotherapy, and the rate of increased intracranial pressure (ICP) control via the port were evaluated for safety and efficacy. These indices were compared with published data of Ommaya (n=89), from our institution. Results: Time-to-install and installation-related complications of intracranial hemorrhage (n=2) and catheter malposition (n=5) were not significantly different between the two groups. Intraventricular chemotherapy-related complications of CSF leakage occurred more frequently in the Ommaya than in the H-port group (13/89 vs. 3/152, respectively, p<0.001). Intracranial hemorrhage during chemotherapy occurred only in the Ommaya group (n=4). The CSF infection rate was not statistically different between groups (14/152 vs. 12/89, respectively). The ICP control rate according to reservoir type revealed a significantly higher ICP control rate with the H-port (40/67), compared with the Ommaya result (12/58, p<0.001). Analyzing the ICP control rate based on the CSF drainage method, continuous extraventricular drainage (implemented only with the H-port), found a significantly higher ICP control rate than with intermittent CSF drainage (33/40 vs. 6/56, respectively, p<0.0001). Conclusion: The H-port for intraventricular chemotherapy in patients with LM was superior for ICP control; it had equal or lower complication rates than the Ommaya reservoir.

Leptomeningeal Metastasis in Gliomas : Clinical Characteristics and Risk Factors.

OBJECTIVE: Our objective is to analyze the occurrence, clinical course and risk factors for glioma patients with leptomeningeal metastasis (LM) according to different metastasis patterns and clinical variables. METHODS: We retrospectively reviewed data from 376 World Health Organization (WHO) grade II-IV adult glioma patients who were treated in the National Cancer Center from 2001 to 2020. Patients who underwent surgery at other institutions, those without initial images or those with pathologically unconfirmed cases were excluded. LM was diagnosed based on magnetic resonance imaging (MRI) findings or cerebrospinal fluid (CSF) cytology. The metastasis pattern was categorized as nodular or linear according to the enhancement pattern. Tumor proximity to the CSF space was classified as involved or separated, whereas location of the tumor was dichotomized as midline, for tumors residing in the thalamus, basal ganglia and brainstem, or lateral, for tumors residing in the cerebral and cerebellar hemispheres. RESULTS: A total of 138 patients were enrolled in the study. A total of 44 patients (38%) were diagnosed with LM during a median follow-up of 9 months (range, 0-60). Among the clinical variables, tumor proximity to CSF space, the location of the tumor and the WHO grade were significant factors for LM development in univariate analysis. In multivariate analysis, the midline location of the tumor and WHO grade IV gliomas were the most significant factor for LM development. The hazard ratio was 2.624 for midline located gliomas (95% confidence interval [CI], 1.384-4.974; p=0.003) and 3.008 for WHO grade IV gliomas (95% CI, 1.379-6.561; p=0.006). CONCLUSION: Midline location and histological grading are an important factor for LM in glioma patients. The proximity to the CSF circulation pathway is also an important factor for WHO grade IV glioma LM. Patients carrying high risks should be followed up more thoroughly.

Lumboperitoneal Shunt Combined With Ommaya Reservoir Enables Continued Intraventricular Chemotherapy for Leptomeningeal Metastasis With Increased Intracranial Pressure.

BACKGROUND: Intra-cerebrospinal fluid (CSF) chemotherapy for leptomeningeal metastasis (LM) can be delivered intraventricularly via an Ommaya reservoir. However, hydrocephalus associated with LM can interfere with chemotherapeutic drug distribution, and ventriculoperitoneal shunts can prevent drug distribution to the extra-ventricular CSF space. This study examined the feasibility of combining a lumboperitoneal (LP) shunt with an Ommaya reservoir to both control intracranial pressure and allow for intraventricular chemotherapy. METHODS: We identified 16 patients with LM who received both an Ommaya reservoir and an LP shunt, either concurrently or sequentially, and subsequently received intraventricular chemotherapy. The feasibility of this combination for intraventricular chemotherapy was evaluated by assessing 1) the distribution of intraventricularly injected drugs in CSF samples collected 0, 6, and 12 h post-injection and 2) adverse events associated with the procedure and drug administration. RESULTS: Patients received a median of seven rounds (range 1-37) of intraventricular chemotherapy during a median follow-up period of 5.2 months after LP shunt insertion. Pharmacokinetic data were obtained from six patients. Baseline methotrexate (MTX) levels from Ommaya reservoirs varied from 339.9 µM to 1,523.5 µM. CSF sampled from LP shunt reservoirs revealed an elimination half-life (t1/2) of 2.63 h, and the mean ratio of MTX concentration at 12 h to that at baseline was 0.05±0.05, ensuring drug distribution from the ventricle to the spinal canal. Nine patients (56%) underwent revision surgery due to catheter migration, malfunction, or infection. Among these patients, CSF infections attributable to intraventricular chemotherapy (n=3) occurred, but no infections occurred in later cases after we began to employ a complete aseptic technique. CONCLUSION: LP shunt combined with Ommaya reservoir insertion is a feasible option for achieving both intracranial pressure control and the continuation of intraventricular chemotherapy in patients with LM.

Different Metabolomic and Proteomic Profiles of Cerebrospinal Fluid in Ventricular and Lumbar Compartments in Relation to Leptomeningeal Metastases.

The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal LM, proved by MRI from 20 paired ventricular and lumbar CSF samples of LM patients, including 12 spinal LM (+) samples. In metabolome analysis, 9512 low-mass ions (LMIs) were identified-7 LMIs were abundant in all lumbar versus paired ventricular CSF samples, and 3 LMIs were significantly abundant in all ventricular CSF. In comparisons between spinal LM (+) CSF and LM (-) CSF, 105 LMIs were discriminative for spinal LM (+) CSF. In proteome analysis, a total of 1536 proteins were measured. A total of 18 proteins, including complement C3, were more highly expressed in all lumbar CSF, compared with paired ventricular CSF, while 82 proteins, including coagulation factor V, were higher in the ventricular CSF. Of 37 discriminative proteins, including uteroglobin and complement component C8 gamma chain, 4 were higher in all spinal LM (+) CSF versus spinal LM (-) CSF. We further evaluated metabolic pathways associated with these discriminative proteins using the Gene Ontology database. We found that 16/17 spinal LM (+) pathways, including complement activation, were associated with lumbar discriminative proteins, whereas only 2 pathways were associated with ventricular-discriminative proteins. In conclusion, we determined that metabolite and protein profiles differed between paired lumbar and ventricular CSF samples. The protein profiles of spinal LM (+) CSF showed more similarity with the lumbar CSF than the ventricular CSF. Thus, we suggest that CSF LMIs and proteins could reflect LM disease activity and that LM-associated differences in CSF are more likely to be present in the lumbar compartment.

Experimental Assessment of Leptomeningeal Metastasis Diagnosis in Medulloblastoma Using Cerebrospinal Fluid Metabolomic Profiles.

Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (-) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone.

Exploratory Profiling of Extracellular MicroRNAs in Cerebrospinal Fluid Comparing Leptomeningeal Metastasis with Other Central Nervous System Tumor Statuses.

The diagnosis of leptomeningeal metastasis (LM) is often difficult due to the paucity of cancer cells in cerebrospinal fluid (CSF) and nonspecific findings on neuroimaging. Investigations of extracellular microRNAs (miRNAs) in CSF could be used for both the diagnosis and study of LM pathogenesis because they reflect the activity of disseminating cancer cells. We isolated CSF extracellular miRNAs from patients (n = 65) of different central nervous system tumor statuses, including cancer control, healthy control, LM, brain metastasis (BM), and primary brain tumor (BT) groups, and performed miRNA microarrays. In unsupervised clustering analyses, all LM and two BM samples showed unique profiles. Among 30 miRNAs identified for LM-specific biomarkers via a Prediction Analysis of Microarrays, miR-335-5p and miR-34b-3p were confirmed in both the discovery and validation samples (n = 23). Next, we performed a significance analysis of the microarray (SAM) to extract discriminative miRNA profiles of two selected CSF groups, with LM samples revealing a greater number of discriminative miRNAs than BM and BT samples compared to controls. Using SAM comparisons between LM and BM samples, we identified 30 upregulated and 6 downregulated LM miRNAs. To reduce bias from different primary cancers, we performed a subset analysis with primary non-small cell lung cancer, and 12 of 13 upregulated miRNAs in LM vs. BM belonged to the upregulated miRNAs in LM. We identified possible target genes and their biological processes that could be affected by LM discriminative miRNAs in NSCLC using the gene ontology database. In conclusion, we identified a unique extracellular miRNA profile in LM CSF that was different from BM, suggesting the use of miRNAs as LM biomarkers in studies of LM pathogenesis.

Cerebrospinal Fluid Profiles and Their Changes after Intraventricular Chemotherapy as Prognostic or Predictive Markers for Patients with Leptomeningeal Carcinomatosis.

OBJECTIVE: Here, we evaluated whether cerebrospinal fluid (CSF) profiles and their changes after intraventricular chemotherapy for leptomeningeal carcinomatosis (LMC) could predict the treatment response or be prognostic for patient overall survival (OS) along with clinical factors. METHODS: Paired 1) pretreatment lumbar, 2) pretreatment ventricular, and 3) posttreatment ventricular samples and their CSF profiles were collected retrospectively from 148 LMC patients who received Ommaya reservoir installation and intraventricular chemotherapy. CSF profile changes were assessed by calculating the differences between posttreatment and pretreatment samples from the same ventricular compartment. CSF cell counts were further differentiated into total and other based on clinical laboratory reports. RESULTS: For the treatment response, a decreased CSF 'total' cell count tended to be associated with a 'controlled' increase in intracranial pressure (ICP) (p=0.059), but other profile changes were not associated with either the control of increased ICP or the cytology response. Among the pretreatment CSF profiles, lumbar protein level and ventricular cell count were significantly correlated with OS in univariable analysis, but they were not significant in multi-variable analysis. Among CSF profile changes, a decrease in 'other' cell count showed worse OS than 'no change' or increased groups (p=0.001). The cytological response was significant for OS, but the hazard ratio of partial remission was paradoxically higher than that of 'no response'. CONCLUSION: A decrease in other cell count of CSF after intraventricular chemotherapy was associated with poor OS in LMC patients. We suggest that more specific CSF biomarkers of cancer cell origin are needed.

Molecular Signature of Extracellular Vesicular Small Non-Coding RNAs Derived from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients: Functional Implication of miR-21 and Other Small RNAs in Cancer Malignancy.

Leptomeningeal metastasis (LM) is a fatal and rare complication of cancer in which the cancer spreads via the cerebrospinal fluid (CSF). At present, there is no definitive treatment or diagnosis for this deleterious disease. In this study, we systemically and quantitatively investigated biased expression of key small non-coding RNA (smRNA) subpopulations from LM CSF extracellular vesicles (EVs) via a unique smRNA sequencing method. The analyzed subpopulations included microRNA (miRNA), Piwi-interacting RNA (piRNA), Y RNA, small nuclear RNA (snRNA), small nucleolar RNAs (snoRNA), vault RNA (vtRNA), novel miRNA, etc. Here, among identified miRNAs, miR-21, which was already known to play an essential oncogenic role in tumorigenesis, was thoroughly investigated via systemic biochemical, miR-21 sensor, and physiological cell-based approaches, with the goal of confirming its functionality and potential as a biomarker for the pathogenesis and diagnosis of LM. We herein uncovered LM CSF extravesicular smRNAs that may be associated with LM-related complications and elucidated plausible pathways that may mechanistically contribute to LM progression. In sum, the analyzed smRNA subpopulations will be useful as targets for the development of therapeutic and diagnostic strategies for LM and LM-related complications.

Nanoparticles in 472 Human Cerebrospinal Fluid: Changes in Extracellular Vesicle Concentration and miR-21 Expression as a Biomarker for Leptomeningeal Metastasis.

Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes for LM. We measured nanoparticles in 472 human cerebrospinal fluid (CSF) from patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations. NTA revealed that the concentration of CSF nanoparticles was significantly increased in LM compared to other groups (2.80 × 108 /mL vs. 1.49 × 108 /mL, p < 0.01). Changes in NTA-measured nanoparticles concentration after intra-CSF chemotherapy were further examined in 33 non-small cell lung cancer patients with LM. Overall survival was longer for patients with increased EV than the others (442 vs. 165 days, p < 0.001). Markers of extracellular vesicles (CD9/CD63/CD81) significantly decreased in the EV-decreased group. MicroRNA-21 expression decreased in this favorable prognostic group, whereas it increased in the EV-decreased group. In conclusion, the elevated concentration of extracellular vesicles in cerebrospinal fluid in patients with LM may be a predictive marker for survival duration. Moreover, EV changes combined with microRNA-21 might be a biomarker for monitoring the efficacy of intracranial chemotherapy of LM in non-small cell lung cancer patients.

Comparative cerebrospinal fluid metabolites profiling in glioma patients to predict malignant transformation and leptomeningeal metastasis with a potential for preventive personalized medicine.

Glioma shows progression presenting as malignant transformation or leptomeningeal metastasis (LM). However, longitudinal biopsy of brain parenchyma is difficult due to its critical location, whereas cerebrospinal fluid (CSF) can be obtained serially with a little invasiveness of puncture. Thus, if we could find a biomarker for glioma progression, we could predict such event and determine therapeutic interventions as early as possible. In this study, we examined whether cerebrospinal fluid (CSF) metabolome profiles can reflect glioma grade, difference with non-glial tumor, and LM status. We selected 32 CSF samples from glioma patients, and compared them with 10 non-tumor control and seven non-glial brain tumor (medulloblastoma) samples. A total of 10,408 low-mass ions (LMIs) were detected as a candidate of metabolites using mass spectrometry, and representative LMIs were identified via the Human Metabolome Database. Grade IV gliomas showed eight LMIs, including acetic acid, of higher levels (summed sensitivity and specificity > 180%) than grade III gliomas. Grade IV gliomas demonstrated more abundant 30 LMIs, including glycerophosphate, compared with medulloblastoma, but none was mutually exclusive. Phospholipid derivatives were significantly more abundant in LM (-) than LM (+) gliomas regardless of glioma grade. LMIs representative of LM (+) gliomas were derivatives of glycolysis. We also verified discriminative LMIs based on mean expression level of each LMI (Student t test, p < 0.05) and evaluated the differences of the above analyses. Over 90% of metabolite pathways indicated from two analytical models were common to each other. Non-targeted mass spectrometry of CSF metabolites revealed significantly different profiles across gliomas that possibly permitted differentiation between glioma grades, LM, and non-glial brain tumors.