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.

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.

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.

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 PTENmutant 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.

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.

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.

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.

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.

Association between Cognitive Function, Behavioral and Psychological Symptoms of Dementia and White Matter Hyperintensities in Patients with Alzheimer's Disease and Mild Cognitive Impairment / 정신신체의학

OBJECTIVES: The aim of this study is to investigate correlation between degree of white matter hyperintensities (WMH) and neurocognitive function along with behavioral and psychological symptoms of dementia (BPSD) in Korean patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). METHODS: Participants were 115 elderly subjects diagnosed with Alzheimer's disease or mild cognitive impairment in this retrospective study. WMH in brain MRI were rated with standardized visual rating scales (Fazekas scales) and the subjects were divided into two groups according to Fazekas scale. Cognitive function was evaluated with Korean version of the consortium to establish a registry for Alzheimer's Disease (CERAD-K), and BPSD was evaluated with Korean neuropsychiatric inventory (K-NPI). Independent t-test was performed to analyze the relationship between the degree of WMH and neurocognitive functions & BPSD. RESULTS: Especially, the group with high severity of WMH showed significantly lower language fluency (p < 0.05). In addition, the group with high severity of WMH showed significantly higher score in K-NPI. CONCLUSIONS: There was a significant association between WMH and neurocognitive test related with executive function. Moreover, WMH seems to affect BPSD severity. Evaluation of WMH would provide useful information in clinical settings.

Pyogenic Vertebral Osteomyelitis: Clinical Features, Diagnosis, and Treatment

Pyogenic vertebral osteomyelitis (PVO) may result in neurological deficits and sequelae, so early diagnosis and appropriate treatment are critical. Many previous studies on PVO exist, but our paper has aimed to comprehensively summarize the clinical aspects of PVO. Through review of the vast literature on the clinical research of PVO an overview of the clinical characteristics, diagnostic methods, treatment and prognosis is provided.

Comparative Analysis Between Thoracic Spinal Cord and Sacral Neuromodulation in a Rat Spinal Cord Injury Model: A Preliminary Report of a Rat Spinal Cord Stimulation Model

OBJECTIVE: The purpose of this study is to compare a neuroprotective effect of thoracic cord neuromodulation to that of sacral nerve neuromodulation in rat thoracic spinal cord injury (SCI) model. METHODS: Twenty female Sprague Dawley rats were randomly divided into 4 groups: the normal control group (n=5), SCI with sham stimulation group (SCI, n=5), SCI with electrical stimulation at thoracic spinal cord (SCI + TES, n=5), and SCI with electrical stimulation at sacral nerve (SCI + SES, n=5). Spinal cord was injured by an impactor which dropped from 25mm height. Electrical stimulation was performed by the following protocol: pulse duration, 0.1ms; frequency, 20 Hz; stimulation time, 30 minutes; and stimulation duration at thoracic epidural space and S2 or 3 neural foramina for 4 weeks. Locomotor function, urodynamic study, muscle weights, and fiber cross sectional area (CSA) were investigated. RESULTS: All rats of the SCI + TES group expired within 3 days after the injury. The locomotor function of all survived rats improved over time but there was no significant difference between the SCI and the SCI + SES group. All rats experienced urinary retention after the injury and recovered self-voiding after 3-9 days. Voiding contraction interval was 25.5+/-7.5 minutes in the SCI group, 16.5+/-5.3 minutes in the SCI+SES group, and 12.5+/-4.2 minutes in the control group. The recovery of voiding contraction interval was significant in the SCI + SES group comparing to the SCI group (p<0.05). Muscle weight and CSA were slightly greater in the SCI + SES than in the SCI group, but the difference was not significant. CONCLUSION: We failed to establish a rat spinal cord stimulation model. However, sacral neuromodulation have a therapeutic potential to improve neurogenic bladder and muscle atrophy.

Endoscope-Assisted Pedicle Screw Fixation using the Pedicle Guidance System

OBJECTIVE: The aims of this study were to present the newly developed pedicle guidance system for minimally invasive pedicle screw fixation under endoscopic visualization and to evaluate the feasibility, safety, and efficacy of this device. METHODS: The authors designed a special guidance device that allows a pedicle screw to be inserted with ease and accuracy under endoscopic visualization. The system consists of a bone biopsy needle (Jamshidi type needle), fiducial pins, a pushing trocar, retriever, specialized awls, and probes. After making an inch-long paramedian skin incision, the bone biopsy needle was percutaneously inserted into the pedicle, as in vertebroplasty, and the fiducial pin was inserted through the needle after removing the inner cannula. The fiducial pin was advanced into the vertebral body until the threaded distal end was positioned 1-2 cm away from the posterior bony structure. The biopsy needle was removed, leaving the fiducial pin in position. The operative wound was then dilated with a step dilator, a tubular retractor was introduced, and an endoscope was placed. Decompressive laminectomy and interbody fusion were then performed. A tubular retractor was repositioned in order to visualize the fiducial pins. A cannulated awl was used to create a hole over the fiducial pin. The pedicle trajectory was prepared using a cannulated probe, and a pedicle screw was inserted under fluoroscopic and endoscopic guidance. RESULT: Fifteen patients underwent surgery using this method. In all cases, the screws were safely inserted without misplacement. The overall operative time ranged from 180 min to 260 min (mean 219.3 min). There were no procedure related complications. CONCLUSION: This newly designed device proved to be practical, time saving, and useful for endoscope-assisted pedicle screw fixation.

Granulocytic Sarcoma Presenting as Epidural Mass in Lumbosacral Spine: A Case Report

Granulocytic sarcoma, as known as chloroma, is a localized solid tumor consisting of immature myeloid cells. It is a infrequent extramedullary manifestation of acute or chronic leukemias and can often precede their bone marrow involvement. Spinal involvement of granulocytic sarcoma is very rare. A 17-year-old man presented with low back pain, gluteal pain and perianal numbness for 1 month. Lumbar spine magnetic resonance imaging (MRI) was taken under impression of herniated lumbar intervertebral disc and showed an epidural mass at the lumbosacral spinal canal. Leukocytosis, thrombocytopenia and anemia were found on blood cell count. Excisional biopsy of mass was done and the histopathologic examination confirmed the diagnosis of granulocytic sarcoma. Subsequent bone marrow biopsy revealed myelodysplastic syndrome. He had received anti-leukemic chemotherapy and the size of lumbosacral mass was markedly decreased. As a granulocytic sarcoma of spinal column is uncommon, high index of suspicion is inevitable to diagnose it. Therefore it must be included as a differential diagnosis of spinal epidural mass.

Time- dependent Changes of the Infarct Volume in a Rat Stroke Model: A Comparison of the Use of MRI and TTC- staining as Monitoring Tools / 대한뇌혈관외과학회지

OBJECTIVES: Serial changes of focal ischemic lesions as seen on magnetic resonance (MR) images and triphenyltetrazolium chloride (TTC)-stained samples of transient middle cerebral artery occlusion in a rat model were evaluated to investigate the natural course of the lesions and the feasibility of the use of each method as a monitoring tool. METHODS: Transient middle cerebral artery occlusion (MCAO) was induced in fifteen adult female Sprague Dawley rats using the method of intraluminal vascular occlusion. Two hours after MCAO was induced, reperfusion was performed. Serial MR images were obtained and the volume of the brain infarct was estimated. For macroscopic and microscopic evaluation of the ischemic lesions, the ten animals were sacrificed at different times after MCAO. The rat brains were then removed and six coronal sections were made. Each section was incubated at 37 degrees C in 2% TTC solution for 15 minutes. RESULTS: Postischemic injury evaluations that were made periodically for eight weeks revealed that the lesion volume as determined from T2 maps had reached a peak on the second day after ischemic injury and the volume decreased afterwards for one week; by the fourth week, the lesion volume again increased to stabilize initial lesion development. There were considerable discrepancies between the infarct area of the samples determined by TTC staining and the in vivo infarct area estimated from the MR images, especially for late stages. CONCLUSION: T2 map MR images, with a careful consideration of the natural course of infarction development, can provide an adequate and noninvasive means to evaluate the degree of ischemic injury under diverse experimental circumstances.