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.

Clinical Experience of Bevacizumab for Radiation Necrosis in Patients with Brain Metastasis.

BACKGROUND: As the application of radiotherapy to brain metastasis (BM) increases, the incidence of radiation necrosis (RN) as a late toxicity of radiotherapy also increases. However, no specific treatment for RN is indicated except long-term steroids. Here, we summarize the clinical results of bevacizumab (BEV) for RN. METHODS: Ten patients with RN who were treated with BEV monotherapy (7 mg/kg) were retrospectively reviewed. RN diagnosis was made using MRI with or without perfusion MRI. Radiological response was based on Response Assessment in Neuro-Oncology criteria for BM. The initial response was observed after 2 cycles every 2 weeks, and maintenance observed after 3 cycles every 3-6 weeks of increasing length intervals. RESULTS: The initial response of gadolinium (Gd) enhancement diameter maintained stable disease (SD) in 9 patients, and 1 patient showed partial response (PR). The initial fluid-attenuated inversion recovery (FLAIR) response showed PR in 4 patients and SD in 6 patients. The best radiological response was observed in 9 patients. Gd enhancement response was 6 PR and 3 SD between 15-43 weeks. Reduction of FLAIR showed PR in 5 patients and SD in 4 patients. Clinical improvement was observed in all but 1 patient. Five patients were maintained on protocol with durable response up to 23 cycles. However, 2 patients stopped treatment due to primary cancer progression, 1 patient received surgical removal from tumor recurrence, and 1 patient changed to systemic chemotherapy for new BM. Grade 3 intractable hypertension occurred in 1 patient who had already received antihypertensive medication. CONCLUSION: BEV treatment for RN from BM radiotherapy resulted in favorable radiological (60%) and clinical responses (90%). Side effects were expectable and controllable. We anticipate prospective clinical trials to verify the effect of BEV monotherapy for RN.

Dexamethasone Interferes with Autophagy and Affects Cell Survival in Irradiated Malignant Glioma Cells.

OBJECTIVE: Radiation is known to induce autophagy in malignant glioma cells whether it is cytocidal or cytoprotective. Dexamethasone is frequently used to reduce tumor-associated brain edema, especially during radiation therapy. The purpose of the study was to determine whether and how dexamethasone affects autophagy in irradiated malignant glioma cells and to identify possible intervening molecular pathways. METHODS: We prepared p53 mutant U373 and LN229 glioma cell lines, which varied by phosphatase and tensin homolog (PTEN) mutational status and were used to make U373 stable transfected cells expressing GFP-LC3 protein. After performing cell survival assay after irradiation, the IC50 radiation dose was determined. Dexamethasone dose (10 µM) was determined from the literature and added to the glioma cells 24 hours before the irradiation. The effect of adding dexamethasone was evaluated by cell survival assay or clonogenic assay and cell cycle analysis. Measurement of autophagy was visualized by western blot of LC3-I/LC3-II and quantified by the GFP-LC3 punctuated pattern under fluorescence microscopy and acridine orange staining for acidic vesicle organelles by flow cytometry. RESULTS: Dexamethasone increased cell survival in both U373 and LN229 cells after irradiation. It interfered with autophagy after irradiation differently depending on the PTEN mutational status : the autophagy decreased in U373 (PTEN-mutated) cells but increased in LN229 (PTEN wild-type) cells. Inhibition of protein kinase B (AKT) phosphorylation after irradiation by LY294002 reversed the dexamethasone-induced decrease of autophagy and cell death in U373 cells but provoked no effect on both autophagy and cell survival in LN229 cells. After ATG5 knockdown, radiation-induced autophagy decreased and the effect of dexamethasone also diminished in both cell lines. The diminished autophagy resulted in a partial reversal of dexamethasone protection from cell death after irradiation in U373 cells; however, no significant change was observed in surviving fraction LN229 cells. CONCLUSION: Dexamethasone increased cell survival in p53 mutated malignant glioma cells and increased autophagy in PTEN-mutant malignant glioma cell but not in PTEN-wildtype cell. The difference of autophagy response could be mediated though the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway.

Efficacy of Slow Rate Ventriculolumbar Perfusion Chemotherapy for Leptomeningeal Carcinomatosis: Interim Result of a Phase II Study.

BACKGROUND: To evaluate the efficacy of modified ventriculolumbar perfusion (VLP) chemotherapy with methotrexate on leptomeningeal carcinomatosis in terms of symptomatic response and side effects. METHODS: Previous infusion rate of 20 mL/h was reduced to 15 mL/h for the purpose of decreasing constitutional side effects of VLP such as nausea/vomiting, insomnia and confusion. The primary outcome was the response rate of increased intracranial pressure (ICP), and the secondary outcome was the occurrence of side effects compared to previous 20 mL/h trial. This interim analysis to validate the reduced infusion rate is not to affect the original effect of VLP chemotherapy. RESULTS: All forty-seven patients were enrolled including 22 patients with increased ICP. Thirteen patients out of these (59%) got normalized ICP after VLP chemotherapy. Moderate to severe (grade 2-3) confusion was observed in 3 patients (6%) and it was significantly reduced compared to those (23%) in the VLP 20 mL/h (p=0.017). Grade 2-3 nausea/vomiting was also reduced from 64% to 45% but failed to reach statistical significance (p=0.08). Median overall survival (OS) was 5.3 months (95% confidence interval, 3.55-7.05) and patients OS, who received maintenance VLP was significantly prolonged compared to patients who underwent induction VLP only (5.8 vs. 3.4 months, p=0.025). CONCLUSION: VLP of reduced perfusion rate (15 mL/h) showed compatible control rate of increased ICP at this interim analysis. Decreased moderate to severe side effects and prolonged OS in patients received maintenance VLP encourage us to evaluate the effectiveness of this trial further.

Discordance of Epidermal Growth Factor Receptor Mutation between Brain Metastasis and Primary Non-Small Cell Lung Cancer.

BACKGROUND: The aim of this study was to compare epidermal growth factor receptor (EGFR) mutations between non-small cell lung cancer (NSCLC) and corresponding brain metastases (BMs) in Korea society. METHODS: From 2011 to 2016, a total of 74 patients underwent surgical resection of a metastatic brain tumor from NSCLC. Among them, we performed retrospective analysis for 46 patients who underwent EGFR sequencing of primary NSCLC tissues. RESULTS: Among these 46 cases, 18 (39.1%) cases showed EGFR mutation in primary lung cancer. Detected mutation sites were exon 19 (8 cases), exon 21 (6 cases), exon 18 (1 cases), and multiple mutations (3 cases). In 18 cases of BM, EGFR mutation studies were done. Among them, 8 (25.6%) cases showed mutation on exon 19 (5 cases) or exon 21 (3 cases). To compare EGFR mutation status between primary lung cancer and BM, 18 paired tissues from both NSCLC and matched BM were collected. Four (22.5%) patients were discordant for the status of EGFR between primary and metastatic sites. CONCLUSION: EGFR mutations were significantly discordant between primary tumors and corresponding metastases in a significant portion of NSCLC. In treatment of BM of EGFR mutant metastatic NSCLC, due to possibility of discordance, pathologic confirming through brain biopsy is recommended.

Association of MRI findings with clinical characteristics and prognosis in patients with leptomeningeal carcinomatosis from non-small cell lung cancer.

PURPOSE: Magnetic resonance imagining (MRI) is helpful for diagnosis of leptomeningeal carcinomatosis (LMC) and localizing LMC symptoms. Goal of this study is how MRI findings of LMC are associated with clinical characteristics or prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: We retrospectively collected data on 283 patients with LMC from NSCLC, adenocarcinoma based on cerebrospinal fluid cytology. All patients had brain MRI with gadolinium enhancement at LMC diagnosis, and spinal MRI was performed at the physician's discretion. We evaluated the prognostic factors for overall survival (OS) of all patients and subgroup of patients with central nervous system cause of death. RESULTS: Two-hundred sixteen patients (76%) had definite or suggestive LMC findings and 67 had negative findings on brain MRI. Of the 37 patients who presented with cauda equina syndrome, 35 (95%) exhibited typical spinal MRI findings. Median OS of all patients was 3.65 months (95% confidence interval, 3.06-4.18). There was no significant difference in median OS between MRI-negative and MRI-positive groups (4.31 vs. 3.48 months, p = 0.711), whereas negative MRI finding showed longer median OS significantly in a subgroup of 77 patients with a central nervous system cause of death (p = 0.035). Considering clinical characteristics, progressive systemic disease, and altered mentality were significant prognostic factors associated with poor OS, whereas presenting symptom of headache with nausea/vomiting, intra-CSF chemotherapy, WBRT after LMC diagnosis, and concurrent RTKi treatment were significant for favorable OS in multivariable analysis. CONCLUSIONS: Positive MRI findings suggests heavier disease burden than negative MRI findings in patients with LMC who died of a central nervous system cause. Spinal MRI findings in patients with LMC correlate with cauda equina symptoms.

Clinical outcome of cerebrospinal fluid shunts in patients with leptomeningeal carcinomatosis.

BACKGROUND: Leptomeningeal carcinomatosis (LMC) is frequently associated with hydrocephalus, which quickly devastates the performance of the patient. Cerebrospinal fluid (CSF) shunt is a widely accepted treatment of choice, but the clinical outcomes in patients with LMC are not well studied. This study aimed to examine the efficacy of a CSF shunt in patients with LMC. METHODS: Seventy patients with LMC confirmed by cytology or magnetic resonance imaging (MRI) underwent ventriculoperitoneal (VP) or lumboperitoneal (LP) shunt surgery. We retrospectively analyzed the clinical characteristics of patients, symptom improvement after the shunt, rate of complications associated with the surgery, and overall survival. RESULTS: Fifty-five patients had systemic cancer as a preceding disease, including lung cancer (45), breast cancer (6), and others (4). Primary brain tumors were mainly glioma (7) and medulloblastoma (5). Fifty-one patients had VP shunt, and 19 had LP shunt. After surgery, preoperative symptoms "improved" in 35 patients (50%) and were "normalized" in 24 of those patients (34%). Shunt malfunction occurred in eight patients, and infection occurred in eight patients. Seventeen patients underwent revision due to infection, shunt malfunction, or over-drainage. There were no complications associated with peritoneal seeding during a median follow-up of 3.3 months after surgery. The median overall survival was 8.7 months (95% confidence interval, 6.0-11.4) from LMC diagnosis and 4.1 months from shunt surgery. CONCLUSION: VP or LP shunt is effective for patients with hydrocephalus from LMC in terms of symptom improvement and prolonging of overall survival with an acceptable rate of procedure-related complications. TRIAL REGISTRATION: This study was approved by the Institutional Review Board (IRB) of the National Cancer Center (retrospectively registered, NCC2018-0051 ).

In-Use Stability of the Rituximab Biosimilar CT-P10 (Truxima®) Following Preparation for Intravenous Infusion and Storage.

BACKGROUND: CT-P10 is the first biosimilar of the anti-CD20 monoclonal antibody, rituximab. CT-P10 is currently available in over 51 countries worldwide, where it is approved in the same indications as its reference product rituximab. In-use stability studies are conducted for biologics to determine how conditions (e.g., temperature, light, humidity, length of time stored) affect drug quality following dilution and storage in infusion bags. OBJECTIVE: We evaluated the in-use stability of CT-P10 for intravenous infusion stored diluted in infusion bags over longer periods than currently recommended by manufacturer guidelines. METHODS: CT-P10, within the final month of its 36-month shelf life, was diluted to 1.0 or 4.0 mg/mL and stored at 2-8 °C in polyethylene or polyvinylchloride infusion bags for 2, 4, and 6 weeks. CT-P10 infusion bags were incubated at room temperature for 24 h before analysis. Analyses included detection of sub-visible particles, formation of impurities and determination of charge variants, and heavy- and light-chain content. Cell-based CD20 binding affinity and complement-dependent cytotoxicity were also assessed. RESULTS: Diluted CT-P10 solutions remained clear, colorless, and free of visible particles irrespective of type of infusion bag, target concentration, or timepoint. Protein concentrations, sub-visible particles, pH, osmolality, and molecular weight and charge variants were stable across all timepoints and variables. The binding affinity and potency of CT-P10 remained unchanged, indicating that the efficacy of the antibody was maintained following in-use preparation. CONCLUSIONS: We demonstrated that CT-P10 was stable after refrigerated storage for up to 6 weeks followed by incubation at room temperature.

Local recurrence of brain metastasis reduced by intra-operative hyperthermia treatment.

PURPOSE: Brain metastasis is a common complication in cancer patients. Local recurrence after total resection of metastatic brain tumor has been frequently reported. In this study, we developed a new hyperthermia device and applied it to metastatic brain tumor patients intra-operatively to study if hyperthermia treatment could reduce local tumor recurrence. MATERIALS AND METHODS: A total of 63 metastatic brain patients were enrolled in the study with an informed consent obtained from every patient. After total resection of the tumor, the hyperthermia device was applied intra-operatively to the resection cavity. The surrounding brain tissue at 5 mm in depth from the tumor resection margin was raised to 42.5 °C for a total of 60 minutes (Clinical Research Information Service Registration Number: KCT0001308). RESULTS: A total of 10 local recurrences were observed in 63 patients who received hyperthermia treatment showing a local recurrence rate of 15.8%. It was significantly lower than the local recurrence rate of those who received conventional treatment (34%) when analyzed with one tailed z-test (p value: .001). Kaplan-Meier analysis also showed a significantly lower recurrence rate in the hyperthermia treatment group (p value: .0003). Complications included two cases of seizures and two cases of wound infection. CONCLUSIONS: Results of this study suggest that intra-operative hyperthermia treatment after total resection of metastatic brain tumor could reduce local recurrence of tumor. We believe that intra-operative hyperthermia treatment could be used as an adjuvant therapy to surgery and post-operative radiotherapy, or as a salvage treatment in patients who cannot receive further radiotherapy.

Treatment Results and Prognostic Factors of Brain Metastases From Ovarian Cancer: A Single Institutional Experience of 56 Patients.

OBJECTIVES: The most appropriate treatments for brain metastases from ovarian cancer have not been established mainly because of its rarity. The objective of this study was to describe clinical results of treatment and prognostic factors of patients with brain metastases from ovarian cancer treated at a single institution. MATERIALS AND METHODS: We retrieved information from the electronic medical records of 56 consecutive patients (2.8%) with brain metastases, from a total of 2008 patients with ovarian cancer. Endpoints were the pattern of treatment failure, progression-free survival, and overall survival (OS). RESULTS: Radiation was the most common initial treatment for brain metastases (59%), followed by surgery (23%). The median progression-free survival was 9.8 months. Radiological progression was confirmed in 20 patients: 7 had leptomeningeal carcinomatosis (37%), 8 had local recurrence, and 5 had distant recurrence. Median OS was 11.25 months, and the 1-year OS rate was 48.2%. Patients received surgery for single metastasis as initial treatment showed median OS of 24.1 months, which was significantly prolonged compared with the other patients (P = 0.0002). Of the 48 patients who died, 29 (60%) died of systemic disease and 7 (15%) died of central nervous system progression. Karnofsky Performance Status greater than or equal to 70, control of systemic cancer, serous histology, and surgery for brain metastases were associated with improved OS in multivariable analysis (P < 0.05). CONCLUSIONS: Surgical resection for single or symptomatic brain metastases from ovarian cancer prolonged OS significantly. Multimodality treatment, including control of systemic cancer, appeared to be an important factor in prolonging OS.

A Novel Implantable Cerebrospinal Fluid Reservoir : A Pilot Study.

OBJECTIVE: The purpose of this pilot study was to examine the safety and function of the newly developed cerebrospinal fluid (CSF) reservoir called the V-Port. METHODS: The newly developed V-Port consists of a non-collapsible reservoir outlined with a titanium cage and a connector for the ventricular catheter to be assembled. It is designed to be better palpated and more durable to multiple punctures than the Ommaya reservoir. A total of nine patients diagnosed with leptomeningeal carcinomatosis were selected for V-Port insertion. Each patient was followed up for evaluation for a month after the operation. RESULTS: The average operation time for V-Port insertion was 42 minutes and the average incision size was 6.6 cm. The surgical technique of V-Port insertion was found to be intuitive by all neurosurgeons who participated in the pilot study. There was no obstruction or leakage of the V-Port during intrathecal chemotherapy or CSF drainage. Also, there were no complications including post-operative intracerebral hemorrhage, infection and skin problems related to the V-Port. CONCLUSION: V-Port is a safe and an easy to use implantable CSF reservoir that addresses problems of other implantable CSF reservoirs. Further multicenter clinical trial is needed to prove the safety and the function of the V-Port.