Leptomeningeal Seeding Research Articles

EXTH-60. OVERCOMING THE LEPTOMENINGEAL SEEDING OF MEDULLOBLASTOMA BY TARGETING HSP70

Abstract Purpose The development of leptomeningeal seeding (LMS) through the cerebrospinal fluid (CSF) is a common in medulloblastoma (MB) and a major cause of treatment failure. The mechanism of MB LMS remains unclear and effective treatment options are urgently required. This study aimed to discover molecules that can specifically target seeding cells by making a cellular model of MB LMS and analyzing their specific genetic and functional characteristics. METHODS: By repeated transplantation, separation, culture, seeding and non-seeding MB cells were isolated. The cellular characteristics of each group were compared and differentially expressed genes (DEGs) were determined through gene expression profiling. The therapeutic effect of the selected inhibitor on the selected protein was tested in vitro and in vivo. RESULTS: We separated seeding and non-seeding cells triply, with the DEGs analysis indicating that heat shock protein 70 (HSP70) was in the highest rank in the expression profile of the seeding cells, and pathway enrichment analysis revealed that the metabolism was the main pathway enriched in seeding cells. The proliferation of seeding cells (S3) was slower than that of non-seeding cells (N3), but there was no significant difference in viability. Notably, the wound-healing of S3 was delayed, but the adhesion ability on collagen was higher than N3. We tested the effect of HSP70 suppression. Among the six HSP70 inhibitors, VER155008 was efficiently sensitive to S3, and suppression of MRP proteins with HSP70 was observed. Importantly, the treatment of VER155008 reduced LMS along the spinal cord in vivo. In addition, a synergistic effect was observed in the combination treatment of VER155008 with 4-hydroperoxycyclophosphamide. CONCLUSION: Our study suggests that targeting HSP70 can be a promising treatment option to suppress the LMS of MB.

Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer with Brain Metastasis : The Role of Gamma Knife Radiosurgery.

ObjectiveImmune checkpoint inhibitors (ICIs) are approved for treating non-small-cell lung cancer (NSCLC); however, the safety and efficacy of combined ICI and Gamma Knife radiosurgery (GKS) treatment remain undefined. In this study, we retrospectively analyzed patients treated with ICIs with or without GKS at our institute to manage patients with brain metastases from NSCLC. MethodsWe retrospectively reviewed medical records of patients with brain metastases from NSCLC treated with ICIs between January 2015 and December 2017. Of 134 patients, 77 were assessable for brain responses and categorized into three groups as follows : group A, ICI alone (n=26); group B, ICI with concurrent GKS within 14 days (n=24); and group C, ICI with non-concurrent GKS (n=27). ResultsThe median follow-up duration after brain metastasis diagnosis was 19.1 months (range, 1–77). At the last follow-up, 53 patients (68.8%) died, 20 were alive, and four were lost to follow-up. The estimated median overall survival (OS) of all patients from the date of brain metastasis diagnosis was 20.0 months (95% confidence interval, 12.5–27.7) (10.0, 22.5, and 42.1 months in groups A, B, and C, respectively). The OS was shorter in group A than in group C (p=0.001). The intracranial disease progression-free survival (p=0.569), local progression-free survival (p=0.457), and complication rates did not significantly differ among the groups. Twelve patients showed leptomeningeal seeding (LMS) during follow-up. The 1-year LMS-free rate in treated with ICI alone group (69.1%) was significantly lower than that in treated with GKS before ICI treatment or within 14 days group (93.2%) (p=0.004). ConclusionGKS with ICI showed no favorable OS outcome in treating brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS. Further understanding of the mechanism, which remains unknown, may help improve the quality of life of patients with brain metastasis.

Clinical Characteristics of High-Grade Glioma with Primary Leptomeningeal Seeding at Initial Diagnosis in a Single Center Study.

BackgroundHigh-grade glioma (HGG) with primary leptomeningeal seeding (PLS) at initial diagnosis is rare. The purpose of this study was to identify its clinical features and to describe the clinical treatment outcomes.MethodsWe retrospectively reviewed the medical records of patients with HGG (World Health Organization grade III or IV) at our institution between 2004 and 2019, and patients with PLS at the initial diagnosis were enrolled in the study. Clinical features, such as the location of leptomeningeal seeding, surgical methods, and degree of resection, were sorted based on electronic medical records also containing performance scale, and hematological and serological evaluations. Radiological findings and immunohistochemical categories were confirmed. Furthermore, we sought to determine whether controlling intracranial pressure (ICP) via early cerebrospinal fluid (CSF) diversion increases overall survival (OS) after the initial diagnosis.ResultsOf the 469 patients with HGG in our institution, less than 2% had PLS at the initial diagnosis. Most patients suffered from headache, diplopia, and dizziness. Pathological findings included 7 glioblastomas and 2 anaplastic astrocytomas. Seven of the 9 patients underwent CSF diversion. All patients were administered concurrent chemoradiotherapy (CCRT) with temozolomide, 89% of which started adjuvant temozolomide and 33% of which completed the six cycles of adjuvant temozolomide. The OS of patients with HGG and PLS was 8.7 months (range, 4-37), an extremely poor result compared to that of other studies. Also, the 1-year and 2-year OS rates were 44.4% and 16.7%, respectively.ConclusionDiagnosis and treatment of HGG with PLS are challenging. Aggressive control of ICP followed by early initiation of standard CCRT seems to be helpful in improving symptoms. However, despite aggressive treatment, the prognosis is poor. A multicenter trial and research may be necessary to create a standardized protocol for this disease.

High Cell-Free DNA Levels in Cerebrospinal Fluid Predict Leptomeningeal Seeding of Hematologic Malignancy.

Background and PurposeThe main difficulty when diagnosing leptomeningeal metastases (LMSs) is the low sensitivity of cytology. Cancer cells release cell-free DNA (cfDNA) during proliferation and apoptosis, and so we analyzed the cfDNA level as a biomarker for LMSs in hematologic malignancy.MethodsThis study prospectively enrolled 20 patients with hematologic malignancy who underwent cerebrospinal fluid (CSF) analysis. LMS was diagnosed based on both CSF cytology and clinical findings.ResultsThe CSF level of cfDNA was higher in patients with LMSs (108.17±84.84 ng/mL, mean±standard deviation) than in non-LMS patients (14.23±2.78 ng/mL). The sensitivity of cfDNA was higher than that of cytology (100% vs. 87%).ConclusionsThe cfDNA level in the CSF can be used as a supplemental marker for diagnosing LMS in hematologic malignancy patients.

RARE-17. PRIMARY DIFFUSE LEPTOMENINGEAL GLIOMATOSIS OF HIGH GRADE TUMORS

Abstract Primary diffuse leptomeningeal gliomatosis(PDLG) of high grade glioma(HGG) is a rarely documented phenomenon observed in less than 5% of glioblastoma(GBM). Purposes of this study are to investigate the clinical outcomes of PDLG of HGG and to analyze the results according to the procedures of operations. We retrospectively reviewed the medical records of 469 patients of HGG at our institute between 2004 and 2019 and 9 of who with PDLG were enrolled in our study. These 9 patients satisfying the condition of Karnofsky performance status ≥70 and Eastern Cooperative Oncology Group performance status ≤2 were conducted the primary surgical biopsy with or without intracranial pressure control. All patients finished the surgery within about 11 days after the detection of leptomeningeal seeding(LMS) on preoperative MRI images and completed the concurrent chemoradiotherapy(CCRT) with temozolomide(TMZ). Among 9 patients, 7 patients started adjuvant temozolomide and 3 patients completed the six cycles of it. 7 patients had done ICP control operation such as ommaya reservoir insertion, extraventricular drainage, and ventriculoperitoneal shunt within 23.3 days after defined as PLDG and survived nearly 10 months. Their pathologic findings were turned out to be seven glioblastomas and two anaplastic astrocytomas. Their median overall survival was 14 months and the 1- and 2-year overall survival rates were 50.8±17.7% and 16.9±15%, respectively. Compared to the 10-year study of GBM in the same institute between 2004 and 2011, in which 67 patients finished with CCRT with TMZ, the median overall survival was 19 months and the 1- and 2-year overall survival rates were 78.3% and 41.7%. The results indicate that PLDG has a worse outcome and overall survival rate is lower than GBM without LMS, so the earlier start of standard CCRT right after aggressive control of increased ICP like conducting CSF diversion might be helpful for the elongation of life expectancy.

CMET-01. IMMUNE CHECKPOINT INHIBITORS FOR NON-SMALL CELL LUNG CANCER WITH BRAIN METASTASIS: THE ROLE OF GAMMA KNIFE RADIOSURGERY

Abstract PURPOSE Immune checkpoint inhibitors (ICIs) are approved for the treatment of non-small cell lung cancer (NSCLC), but the safety and efficacy of the combined treatment with ICIs and gamma knife radiosurgery (GKS) remain undefined. METHODS We retrospectively reviewed the medical records of patients with brain metastases from NSCLC who were treated with ICIs between January 2015 and December 2017 at our institute. Of the 134 patients identified, 77 who were assessable for brain responses were categorized into three groups based on the medication administered and GKS: Group A, ICI alone; Group B, ICI with concurrent GKS within 14 days; and Group C, ICI with non-concurrent GKS. RESULTS The median follow-up duration after the diagnosis of brain metastases was 19.1 (range, 1–68.7) months. At the last follow-up, 48 patients (62.3%) died. The overall survival was shorter in Group A than in Groups B and C (P=0.001). There were no statistically significant differences in the intracranial disease progression-free survival (P=0.514), local progression-free survival (P=0.358), and complication rates among the three groups. Twelve patients presented with leptomeningeal seeding (LMS) during follow-up. There was a significant difference in the LMS-free duration from the time of administering ICIs (P=0.011) and the diagnosis of metastasis (P< 0.001). CONCLUSION GKS in combination with ICI showed no favorable overall survival outcome in the treatment of brain metastasis from NSCLC. However, GKS with ICI did not increase the risk of complications. Furthermore, compared with ICI alone, GKS with ICI may be associated with a reduced incidence of LMS.

Leptomeningeal enhancement on preoperative brain MRI in patients with glioblastoma and its clinical impact.

Leptomeningeal enhancement (LME) on preoperative brain magnetic resonance imaging (MRI) does not always indicate leptomeningeal seeding (LMS). With Stupp's regimen, authors have treated glioblastoma patients with LME on preoperative brain MRI but here we tried to find the clinical impact of LME. From 2005 to 2015, 290 patients with glioblastoma have been treated with Stupp's regimen at Samsung Medical Center. Among these, 33 patients showed LME on preoperative brain MRI. We compared the clinical outcomes between the patients with or without LME on preoperative brain MRI and analyzed the clinical results according to changes of LME at following MRI. The median survival was 23 months, and 2-year overall survival (OS) and disease-free survival (DFS) rate was 46.3% and 19.6%, respectively. Prognostic factors for OS and DFS were Karnofsky performance status, extent of resection and adjuvant chemotherapy. MGMT promoter methylation status was a significant prognostic factor for DFS. However, LME was not a significant prognostic factor for OS (P=0.156) or DFS (P=0.193). Among the 33 patients with LME on preoperative MRI, 21 (63.6%) showed persistent LME at the next MRI. A statistically significant difference in 2-year survival was evident between patients with and without persistent LME (OS, 17.3% and 70.1%, respectively, P=0.044; DFS, 5.3% and 54.0%, respectively, P=0.006). The most common pattern of failure was local recurrence. However, patients with persistent LME displayed a higher incidence of LMS than patients without LME. LME on preoperative brain MRI did not affect the clinical results in glioblastoma patients treated with the Stupp's regimen. However, persistence of LME was associated with poor survival and high possibility of LMS. For these patients, the postoperative adjuvant treatment should focus on palliative aim or more aggressive treatment scheme should be followed to overcome the disastrous results.

Outcome of gamma knife radiosurgery for metastatic brain tumors derived from non-small cell lung cancer.

The purpose of this study was to analyze outcomes in patients treated with gamma knife radiosurgery (GKS) for brain metastases from non-small cell lung cancer (NSCLC). We retrospectively reviewed the medical records of 817 patients who underwent GKS for brain metastases from NSCLC between January 2002 and December 2012. A total of 1363 GKS procedures were performed for 2970 lesions. The median overall survival time from the initial GKS was 13 months and the salvage treatment-free survival from the first GKS was 6.5 months. Younger age (≤65 years), female sex, better RPA class, higher DS-GPA score, adenocarcinoma, synchronous onset, and lower integrated value of the "numbers and cumulative volume of tumors" were associated with better outcomes. Among the 601 patients with an available follow up image, the pattern of the first progression after initial GKS was the development of new lesions in 356 patients (59.2 %), regrowth of treated lesions in 106 patients (17.6 %), and leptomeningeal seeding (LMS) in 51 patients (8.5 %). Among the deceased, the last MRI performed prior to death was evaluated in 409 patients and showed progression in 263 patients (64.3 %), despite multiple salvage treatments. LMS was identified in 63 patients (15.4 %); a rate much higher than the incidence at first progression. Intracranial tumor burden, defined as the integrated value of the "number of the lesions and cumulative tumor volume", is a new prognostic factor of greater significance than tumor volume or number alone when analyzed as separate factors. Although the cause of death was not progression of brain lesions in the majority of patients, the brain lesions tended to have been persistently progressive in most patients, despite repeated salvage treatment. LMS is an important pattern of treatment failure, in addition to local progression or development of new lesions, particularly in the terminal phase of the disease.

Intracranial Germinoma with Leptomeningeal Seeding Along Both Trigeminal Nerves

Intracranial Germinoma with Leptomeningeal Seeding Along Both Trigeminal Nerves

Leptomeningeal seeding in patients with brain metastases treated by gamma knife radiosurgery

To characterize the development of leptomeningeal seeding (LMS) in patients with brain metastases after gamma knife radiosurgery (GKRS). Eight hundred and twenty-seven patients that underwent GKRS as a part of an initial treatment plan for brain metastases between January 2002 and December 2010 were included in the study. Six hundred and fifty patients were treated with GKRS alone and 177 patients received GKRS combined with upfront whole brain radiation therapy (WBRT). Actuarial curves for overall survival (OS) and the development of LMS were plotted using the Kaplan-Meier method. Median overall survival for all patients was 55 weeks (95 % CI, 47.8-62.2), and the overall incidence of LMS was 5.3 %. The actuarial rates for LMS at 6 and 12 months were 3.1 and 5.8, respectively. Uni- and multivariate analysis suggested that breast cancer and a large number of metastases (n ≥ 4) are significant risk factors of LMS (P < 0.05). Regarding treatment modalities, the addition of WBRT was found to have a significant impact on lowering the risk of LMS by multivariate analysis (P = 0.045). LMS is an important pattern of CNS failure. The risk of LMS following GKRS may be associated with multiple lesions, breast cancer, and the omission of WBRT. Additional data from large-scale, randomized controlled trials are required to identify risk factors associated with the LMS more accurately.

Risk for leptomeningeal seeding after resection for brain metastases: implication of tumor location with mode of resection

Surgical spillage has been one of the causative factors for the development of leptomeningeal seeding (LMS) after resection of brain metastases. In this paper, the authors' goal was to define the factors related to the development of LMS and to evaluate the difference according to tumor location. The authors retrospectively analyzed 242 patients who had undergone resection for brain metastases. The factors investigated included tumor location with proximity to the CSF pathway (that is, contacting, involved with, or separated from the CSF pathway), the method of resection, and the use of the Cavitron Ultrasonic Surgical Aspirator (CUSA). A total of 39 patients (16%) developed LMS at a median of 6.0 months (range 1-42 months) after resection. The risk of developing LMS was significantly higher in patients whose tumors were resected piecemeal than in those whose tumors were removed en bloc, with a hazard ratio (HR) of 4.08 (p < 0.01). The incidence of LMS was significantly higher in patients in whom the CUSA was used, and the HR was 2.64 (p < 0.01). The proximity of tumor to the CSF pathway in the involved group conferred an increased risk of LMS compared with the separated group (HR 11.36, p < 0.01). The risk of piecemeal resection for LMS was significant only in involved lesions (p < 0.01), and the use of the CUSA in both contact and involved lesions increased the incidence of LMS (p < 0.01 and p < 0.03, respectively). The authors suggest that piecemeal resection using the CUSA should be limited because of the risk of postsurgical LMS, especially when the tumor is in contact with the CSF pathway.

Ventriculoperitoneal shunt for hydrocephalus caused by central nervous system metastasis

The development of better diagnostic tools and therapeutic modalities has increased the incidence of central nervous system (CNS) metastasis in malignant tumor patients. Hydrocephalus can result from CNS metastasis and frustrate cancer treatment. The authors sought to investigate the outcomes and the roles of ventriculoperitoneal shunts (VPS) in patients with CNS metastasis. The medical records of 50 consecutive patients who underwent VPS for hydrocephalus related to CNS metastasis were analyzed retrospectively. Data included features of primary malignancies, CNS involvement, clinical course and surgical outcome. Median patient age was 55.0years (range 25-77), and 30 female and 20 male patients were included in the study. At the time of VPS, 10 patients had parenchymal metastases only and 40 patients had leptomeningeal seeding (LMS). Symptom improvement was observed postoperatively in 40 patients (80%), mean Karnofsky performance status (KPS) scale change was from 37.8 to 46.0, and median survival from VPS was 3.0months (2days to 54months). A ventricular opening pressure of >30cmH(2)O (HR 6.44, 95% CI 1.26-32.9, P=0.02) and further cancer treatment after VPS (HR 0.17, 95% CI 0.07-0.42, P<0.0001) were found to be independent risk factors of poorer and better survival, respectively. Hydrocephalus in CNS metastasis requiring VPS is commonly associated with LMS. VPS is an effective palliative measure and an adequate cancer treatment after VPS may provide the best means of improving survival.