Leptomeningeal Spread in Glioblastoma: Diagnostic and Therapeutic Challenges

Chen

et al. 2021

Preprint

Purpose Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor with a bad outcome. Leptomeningeal disease (LMD) is a severe complication of GBM, with a worse outcome and have no effective treatment. A combination chemotherapy was conducted to evaluated the effective of GBM patients with LMD. Methods A retrospective analysis was conducted of GBM patients diagnosed with LMD between January 2012 and December 2019 in our institution. All these patients accepted at least one cycle of combination therapy combination intrathecal methotrexate(MTX) with systemic chemotherapy. Clinical and pathological data were analyzed to explore the effective treatment and the outcome of GBM patients with LMD. Results Twenty-six patients were enrolled in this study. The median time from GBM diagnosis to LMD development was 9.3 months (range 2–59 months). The median overall survival of LMD patients from diagnosis after accepted systemic chemotherapy combination with intrathecal methotrexate was 10.5 months (range 2–59 months). In the Cox univariate analysis, gross resection of tumor (p = 0.022), KPS༞60 (p = 0.002) and Ommaya reservoir implantation (p༜0.001) were correlated with survival. Multivariate analysis showed that KPS༞60 (p = 0.037) and Ommaya reservoir implantation (p = 0.014) were positive factors correlated with survival. The common toxicities of combination therapy were myelotoxicity and gastrointestinal reactions. According to Common Terminology Criteria of Adverse Events 4.03, most of the toxicities were less than grade 3. Conclusion Intrathecal methotrexate combined with systemic chemotherapy is an effective treatment for GBM patients with LMD and has mild treatment-related side effects.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Intrathecal methotrexate combination with systemic chemotherapy in glioblastoma patients with leptomeningeal metastases

Chen

et al. 2021

Preprint

“…GBM is the leading type of glial tumor and most aggressive primary brain tumor in adults [ 36 ]. Despite considerable advances in treatment modalities including surgery, radiation, and chemotherapy, GBM patients eventually develop resistance to therapy, and the overall survival (OS) rate remains under 2 years, due to the heterogeneous character of GBM [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

An Integrated Bioinformatics Study of a Novel Niclosamide Derivative, NSC765689, a Potential GSK3β/β-Catenin/STAT3/CD44 Suppressor with Anti-Glioblastoma Properties

Mokgautsi

Wen

Lawal

et al. 2021

IJMS

Despite management efforts with standard surgery, radiation, and chemotherapy, glioblastoma multiform (GBM) remains resistant to treatment, which leads to tumor recurrence due to glioma stem cells (GSCs) and therapy resistance. In this study, we used random computer-based prediction and target identification to assess activities of our newly synthesized niclosamide-derived compound, NSC765689, to target GBM oncogenic signaling. Using target prediction analyses, we identified glycogen synthase kinase 3β (GSK3β), β-Catenin, signal transducer and activator of transcription 3 (STAT3), and cluster of differentiation 44 (CD44) as potential druggable candidates of NSC765689. The above-mentioned signaling pathways were also predicted to be overexpressed in GBM tumor samples compared to adjacent normal samples. In addition, using bioinformatics tools, we also identified microRNA (miR)-135b as one of the most suppressed microRNAs in GBM samples, which was reported to be upregulated through inhibition of GSK3β, and subsequently suppresses GBM tumorigenic properties and stemness. We further performed in silico molecular docking of NSC765689 with GBM oncogenes; GSK3β, β-Catenin, and STAT3, and the stem cell marker, CD44, to predict protein-ligand interactions. The results indicated that NSC765689 exhibited stronger binding affinities compared to its predecessor, LCC09, which was recently published by our laboratory, and was proven to inhibit GBM stemness and resistance. Moreover, we used available US National Cancer Institute (NCI) 60 human tumor cell lines to screen in vitro anticancer effects, including the anti-proliferative and cytotoxic activities of NSC765689 against GBM cells, and 50% cell growth inhibition (GI50) values ranged 0.23~5.13 μM. In summary, using computer-based predictions and target identification revealed that NSC765689 may be a potential pharmacological lead compound which can regulate GBM oncogene (GSK3β /β-Catenin /STAT3 / CD44) signaling and upregulate the miR-135b tumor suppressor. Therefore, further in vitro and in vivo investigations will be performed to validate the efficacy of NSC765689 as a novel potential GBM therapeutic.

“…Previous reports demonstrated the increased risk of leptomeningeal metastasis after surgical ventricular entry in high grade gliomas ( 14 – 16 ). Furthermore, patients with leptomeningeal and intraventricular tumor seeding in high grade gliomas are known to exhibit a dismal prognosis with a median survival of 2 to 6 months after being diagnosed with seeding metastases ( 14 , 15 , 17 – 19 ).…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Whole-Ventricular Radiotherapy in Patients Undergoing Maximal Tumor Resection for Glioblastomas Involving the Ventricle

et al. 2021

Background and PurposePatients with glioblastoma (GBM) involving the ventricles are at high risk of ventricle opening during surgery and potential ventricular tumor spread. We evaluated the effectiveness of whole-ventricular radiotherapy (WVRT) in reducing intraventricular seeding in patients with GBM and identified patients who could benefit from this approach.Methods and MaterialsWe retrospectively reviewed the data of 382 patients with GBM who underwent surgical resection and temozolomide-based chemoradiotherapy. Propensity score matching was performed to compensate for imbalances in characteristics between patients who did [WVRT (+); n=59] and did not [WVRT (–); n=323] receive WVRT. Local, outfield, intraventricular, and leptomeningeal failure rates were compared.ResultsAll patients in the WVRT (+) group had tumor ventricular involvement and ventricle opening during surgery. In the matched cohort, the WVRT (+) group exhibited a significantly lower 2-year intraventricular failure rate than the WVRT (–) group (2.1% vs. 11.8%; P=0.045), with no difference in other outcomes. Recursive partitioning analysis stratified the patients in the WVRT (–) group at higher intraventricular failure risk (2-year survival, 14.2%) due to tumor ventricular involvement, MGMT unmethylation, and ventricle opening. WVRT reduced the intraventricular failure rate only in high-risk patients (0% vs. 14.2%; P=0.054) or those with MGMT-unmethylated GBM in the matched cohort (0% vs. 17.3%; P=0.036).ConclusionsWVRT reduced the intraventricular failure rate in patients with tumor ventricular involvement and ventricle opening during surgery. The MGMT-methylation status may further stratify patients who could benefit from WVRT. Further prospective evaluation of WVRT in GBM is warranted.