Journal of Neuro-Oncology最新文献

Purpose: To review applications of cerebral spinal fluid (CSF) biomarkers for the diagnosis, monitoring and treatment of leptomeningeal metastatic disease (LMD) among patients with metastatic solid tumors.

Methods: A narrative review identified original research related to CSF biomarkers among patients with metastatic solid tumors and LMD. Pre-clinical research (e.g. studies conducted in animal models) was not included. A descriptive analysis of literature was undertaken, with a focus on clinical applications related to the diagnosis, monitoring and treatment of LMD.

Results: The low cellularity of CSF in comparison to plasma is an advantage for liquid biopsy, given that circulating tumor DNA (ctDNA) is not significantly diluted by genomic DNA from non-cancer cells. This results in higher variant allelic frequencies and increased sensitivity in detecting ctDNA compared to plasma. However, the clinical significance of positive ctDNA and/or circulating tumor cells (CTCs) in the CSF, particularly in the absence of other signs of LMD (either clinical and/or radiological), remains unclear. While the use of CSF liquid biopsy to monitor treatment response is promising, this approach requires prospective validation using larger sample sizes prior to adoption in routine clinical care. Discovery efforts involving proteomics and metabolomics have potential to identify proteins involved in the regulation of energy metabolism, vasculature, and inflammation in LMD, which in turn, may offer insights into novel treatment approaches.

Conclusion: CSF liquid biopsy should be incorporated in prospective studies for patients with LMD to validate promising diagnostic and/or predictive biomarkers of treatment response, as well as new therapeutic targets.

Diagnoses of CNS malignancies in the primary and metastatic setting have significantly advanced in the last decade with the advent of molecular pathology. Using a combination of immunohistochemistry, next-generation sequencing, and methylation profiling integrated with traditional histopathology, patient prognosis and disease characteristics can be understood to a much greater extent. This has recently manifested in predicting response to targeted drug therapies that are redefining management practices of CNS tumours. Radiotherapy, along with surgery, still remains an integral part of treating the majority of CNS tumours. However, the rapid advances in CNS molecular diagnostics have not yet been effectively translated into improving CNS radiotherapy. We explore several promising strategies under development to integrate molecular oncology into radiotherapy, and explore future directions that can serve to use molecular diagnostics to personalize radiotherapy. Evolving the management of CNS tumours with molecular profiling will be integral to supporting the future of precision radiotherapy.

Background: H3 histone 27 lysine (H3K27) trimethylation (H3K27me3), which is catalyzed by enhancer of zeste homolog 2 (EZH2), regulates gene expression through epigenetic mechanisms. H3K27me3 is used as a diagnostic marker for diffuse midline glioma and as a surrogate marker to distinguish posterior fossa ependymoma A and B. However, the clinical significance of the EZH2-H3K27me3 axis in astrocytoma, IDH-mutant has not been reported, prompting this investigation.

Methods: Thirty-three patients with astrocytoma, IDH-mutant treated at our institute were included in this study. Immunohistochemistry (IHC) targeting H3K27me3, H3K27M, EZH2, EZH inhibitory protein, IDH1-R132H, p53, ATRX, Ki-67, and MTAP was performed. Kaplan-Meier analysis and Cox regression analysis were performed to analyze the correlations of overall survival (OS) and progression-free survival (PFS) with various factors, including age, World Health Organization (WHO) grade, the extent of resection, and immunohistochemical results.

Results: The mean patient age was 40.6 ± 11.0 years. IHC for H3K27me3 was positive in 19 patients and negative in 14 patients. The WHO grade and Ki-67 index were significantly higher in the H3K27me3-positive group (p = 0.004 and p = 0.024, respectively). OS and PFS were significantly shorter in the H3K27me3-positive group (p = 0.002 and p = 0.026, respectively). Furthermore, the H3K27me3 and EZH2 double-positive group was associated with a higher WHO grade and higher Ki-67 index (p = 0.001 and p = 0.024, respectively). In the analysis of patients with WHO grade 2/3, double positivity for H3K27me3 and EZH2 was linked to significantly shorter OS and PFS (p = 0.0053 and p = 0.0048, respectively).

Conclusion: Positivity for H3K27me3, especially double positivity for H3K27me3 and EZH2, could be a poor prognostic factor for astrocytoma, IDH-mutant. These results suggest the utility of H3K27me3 and EZH2 as candidate markers for estimating the malignancy of astrocytoma, IDH-mutant.

Purpose: Methotrexate is one of the most essential single agents in patients with primary central nervous system lymphoma (PCNSL). However, 25-50% result in relapse with a poor prognosis. Therefore, studies on methotrexate resistance are warranted to explore salvage chemotherapy for recurrent PCNSL. Single-cell sequence analysis enables the characterization of novel cell types and provides a precise understanding of cancer biology.

Methods: Single-cell sequence analysis of parental and methotrexate-resistant PCNSL cells was performed. We used a Weighted Gene Co-expression Network Analysis to identify groups of significantly connected genes.

Results: We identified consensus modules in both the HKBML and TK datasets. HLA-DRβ1, HLA-DQβ1,and SNRPG were hub genes those detected in both datasets revealed by network analysis. Cyclosporine A was selected as the candidate drug for treating methotrexate-resistant cells.

Conclusion: The results of the present study characterized the methotrexate resistance-related signaling pathways in cultured PCNSL cells. Overall, these results may account for variations in treatment responses and lead potential novel therapeutic strategies for patients with PCNSL.

Purpose/objective(s): Small cell lung cancer (SCLC) is known to have high rates of development of brain metastases. Standard treatment has been whole brain radiation therapy (WBRT) but the role for more focused treatment and hippocampal avoidance has arisen in the past decade. In addition, with possible penetration of the central nervous system by more modern immunotherapies, the risk of distant failure may be lower. As such, we reviewed patients at our institution treated with stereotactic radiosurgery (SRS) to look at patterns, locations, and predictors of failure in the brain.

Materials/methods: A retrospective review and analysis of charts was done on 46 patients treated with SRS (no history of prior WBRT) for their brain metastases from SCLC. Multivariate analysis was used to determine significant prognostic factors influencing survival and local/distant failure. We tracked timing and type of immunotherapy, if any, as well as if patients failed in the hippocampus or required WBRT.

Results: There were 46 patients with 97 total brain metastases treated with SRS in this study. Median number of metastases was 2 (1-5). The median dose of radiation was 20 Gy (20-30) in 3 fractions (1-5) for all 97 tumors. 11 patients did not receive immunotherapy, whereas 35 patients had immunotherapy of some sort. Median overall survival (OS) for the entire cohort was 13 months, with a 12 month OS of 59% and 2 year OS of 30%. Cox regression did not reveal any significant predictors of OS, including age, sex, total volume, extracranial disease, KPS, immunotherapy, or number of metastases. 12 month and 24 month local control of disease was 95% and 80%, respectively. There were no significant predictors of local failure including volume, dose, or immunotherapy. 25 of the patients had distant brain failure, with a rate of distant failure of 38% and 64% for 6 and 12 months, respectively. Immunotherapy, number of metastases, total target volume, nor presence of extracranial disease was predictive of distant brain failure. WBRT free survival was also measured and found to be 73% at 1 year. There were no significant predictors for this measure. Lastly, five patients in this cohort showed failure in the hippocampus, where the rate of failure at 6 and 12 months was 16%.

Conclusion: Rates of distant brain failure in SCLC patients after SRS remain similar to those of NSCLC patients in the immunotherapy era. We did not show a decrease in distant failure rate based on immunotherapy use. The rate of hippocampal failure was quite low and should provide reassurance that SRS and techniques such as HA-IMRT can be reasonably used in these patients. Ongoing clinical trials will help provide more definitive answers in this arena.

Purpose: Pseudoprogression is an atypical imaging pattern of response to immunotherapy in patients with brain tumors. MR perfusion studies in this field are limited. The purpose of our study is to compare the perfusion features between pseudoprogression lesions in malignant gliomas and brain metastases treated with immunotherapy (iPsP) and the pseudoprogression after chemo-radiation therapy and radiation necrosis after radiation treatment (ChR-PsP & RN).

Methods: We retrospectively reviewed 25 iPsP lesions in 16 brain tumor patients and 48 ChR-PsP & RN lesions in 35 patients. The cerebral blood volume (CBV) of MR dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) was analyzed, and the mean and maximal values of the ratio of CBV (rCBV_mean and rCBV_max) of iPsPs and ChR-PsP & RNs were calculated and compared between these two groups using the Mann-Whitney U test. A receiver operating characteristic curve analysis was conducted, and the optimal cutoff of perfusion parameters were determined using the area under the curve, sensitivity, and specificity.

Results: The medians of rCBV_mean and rCBV_max in iPsP group were significantly higher (0.94 and 1.39 respectively) than ChR-PsP & RN group (0.67, p < 0.01 and 1.1, p = 0.01 respectively). The rCBV_mean value of 0.69 can differentiate the iPsP from ChR-PsP & RN with the area under the curve of 0.71, sensitivity of 0.72, and specificity of 0.56.

Conclusion: These findings may suggest immunotherapy-induced higher perfusion in the iPsP lesions compared to ChR-PsP & RN lesions in primary and metastatic brain tumors.

Background: Craniopharyngioma (CP), a benign tumor originating from remnants of Rathke's pouch in the sellar region, accounts for approximately 30% of all cases of craniopharyngioma. Radiation therapy has been used to treat CP patients for decades; however, there is still a lack of systematic reviews on the long-term tumor control outcomes in pediatric CP patients treated with external radiation therapy.

Methods: We conducted a comprehensive search of multiple databases for studies on the tumor progression rates of childhood-onset CP(COCP) patients who received external radiotherapy. We also recorded morbidities related to hypopituitarism and vasculopathy. A meta-analysis was performed to calculate the pooled incidence rates. Meta-regression was applied to explore potential sources of heterogeneity in the tumor progression rates.

Results: A total of 22 studies were included after screening and eligibility assessment in accordance with PRISMA guidelines. The median (mean) follow-up period ranged from 2 to 14.9 years. The pooled overall tumor progression rate was 0.10 (95% CI 0.07-0.15). The recurrence rates were 0.14 (95% CI 0.09-0.19) for photon therapy and 0.04 (95% CI 0.01-0.07) for proton therapy. Meta-regression indicated that none of the following underlying risk factors significantly affected the heterogeneity of the recurrence rate: radiation modality (photon vs. proton), median (mean) follow-up duration, or the proportion of patients who did not undergo surgical resection. The pooled incidence of growth hormone deficiency (GHD), thyroid hormone deficiency (THD), adrenocorticotropic hormone deficiency (ACTHD), gonadotropin-releasing hormone deficiency (GnRHD), and diabetes insipidus (DI) were 0.81 (95% CI 0.70-0.90), 0.88 (95% CI 0.79-0.95), 0.69 (95% CI 0.52-0.85), 0.43 (95% CI 0.38-0.49), and 0.56 (95% CI 0.33-0.78), respectively. The pooled morbidity rate for vasculopathy was 0.06 (95% CI 0.04-0.09), with similar rates observed for both photon and proton therapy.

Conclusion: Radiotherapy is a suitable adjuvant or alternative treatment method for childhood CP patients. However, patients inevitably face significant long-term treatment-related complications.

Purpose: Glioblastoma (GBM) that presents as leptomeningeal disease (LMD) is extremely rare and fatal. Limited data are available regarding incidence, clinical presentation, and management. Prognosis is poor and no treatment is known to improve survival.

Methods and results: We present a case report of a 72-year-old female who presented with depressed sensorium, ataxia, and myelopathy. Magnetic resonance imaging (MRI) showed diffuse supratentorial and spinal LMD. There was an absence of any detectable and distinct intraparenchymal lesion on neuroaxis imaging. Biopsy of the Sylvian fissure nodule revealed GBM. Steroid therapy was ineffective for symptom relief. She opted for palliative care and expired shortly after diagnosis.

Conclusion: To our knowledge, this is the first reported case of GBM presenting exclusively as LMD without a primary lesion. If systemic imaging techniques do not provide a biopsy target and cerebrospinal fluid (CSF) studies are non-diagnostic, tissue diagnosis from leptomeningeal biopsy is recommended. Palliative chemoradiation or best supportive care are reasonable treatment options.