Central Nervous System Malignant Tumor Research Articles

Identifying brain tumor patients' subtypes based on pre-diagnostic history and clinical characteristics: a pilot hierarchical clustering and association analysis.

Central nervous system (CNS) tumors are severe health conditions with increasing incidence in the last years. Different biological, environmental and clinical factors are thought to have an important role in their epidemiology, which however remains unclear. The aim of this pilot study was to identify CNS tumor patients' subtypes based on this information and to test associations with tumor malignancy. 90 patients with suspected diagnosis of CNS tumor were recruited by the Neurosurgery Unit of IRCCS Neuromed. Patients underwent anamnestic and clinical assessment, to ascertain known or suspected risk factors including lifestyle, socioeconomic, clinical and psychometric characteristics. We applied a hierarchical clustering analysis to these exposures to identify potential groups of patients with a similar risk pattern and tested whether these clusters associated with brain tumor malignancy. Out of 67 patients with a confirmed CNS tumor diagnosis, we identified 28 non-malignant and 39 malignant tumor cases. These subtypes showed significant differences in terms of gender (with men more frequently presenting a diagnosis of cancer; p = 6.0 ×10-3) and yearly household income (with non-malignant tumor patients more frequently earning ≥25k Euros/year; p = 3.4×10-3). Cluster analysis revealed the presence of two clusters of patients: one (N=41) with more professionally active, educated, wealthier and healthier patients, and the other one with mostly retired and less healthy men, with a higher frequency of smokers, personal history of cardiovascular disease and cancer familiarity, a mostly sedentary lifestyle and generally lower income, education and cognitive performance. The former cluster showed a protective association with the malignancy of the disease, with a 74 (14-93) % reduction in the prevalent risk of CNS malignant tumors, compared to the other cluster (p=0.026). These preliminary data suggest that patients' profiling through unsupervised machine learning approaches may somehow help predicting the risk of being affected by a malignant form. If confirmed by further analyses in larger independent cohorts, these findings may be useful to create potential intelligent ranking systems for treatment priority, overcoming the lack of histopathological information and molecular diagnosis of the tumor, which are typically not available until the time of surgery.

Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors.

The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay. FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability. After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL. The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors.

Oncolytic viral therapy as promising immunotherapy against glioma

AbstractGlioma is a common primary central nervous system malignant tumor in clinical, traditional methods such as surgery and chemoradiotherapy are not effective in treatment. Therefore, more effective treatments need to be found. Oncolytic viruses (OVs) are a new type of immunotherapy that selectively infects and kills tumor cells instead of normal cells. OVs can mediate antitumor immune responses through a variety of mechanisms, and have the ability to activate antitumor immune responses, transform the tumor microenvironment from “cold” to “hot,” and enhance the efficacy of immune checkpoint inhibitors. Recently, a large number of preclinical and clinical studies have shown that OVs show great prospects in the treatment of gliomas. In this review, we summarize the current status of glioma therapies with a focus on OVs. First, this article introduces the current status of treatment of glioma and their respective shortcomings. Then, the important progress of OVs of in clinical trials of glioma is summarized. Finally, the urgent challenges of oncolytic virus treatment for glioma are sorted out, and related solutions are proposed. This review will help to further promote the use of OVs in the treatment of glioma.

Comparison of Acute Hematological Adverse Reactions Induced by Craniospinal Irradiation With Intensity-Modulated Radiotherapy and Conventional Radiotherapy.

With the update of equipment, the hospital base of this study began to adopt craniospinal irradiation (CSI) intensity-modulated radiotherapy (IMRT) in May 2018 to replace the traditional CSI conventional radiotherapy (CRT) technology. The purpose of this study was designed to compare the differences in acute hematological adverse reactions induced by CSI-IMRT and CSI-CRT. The clinical data and hematological data of 102 patients with central nervous system malignant tumors who underwent CSI treatment at the 900th Hospital of Joint Logistics Support Force of PLA from January 2008 to August 2022 were analyzed retrospectively. The patients included 63 men and 39 women, aged 3 to 56 years old. On the basis of the radiotherapy technique used, the patients were divided into the CSI-IMRT group (38 cases) and CSI-CRT group (64 cases). Acute hematological adverse reactions during radiotherapy were compared between the two groups according to the Common Terminology Criteria for Adverse Events version 4.0. The Mann-Whitney U test was used to compare the measurement data, and the χ2 test was used to compare the count data. No significant difference was found between the CSI-IMRT group and the CSI-CRT group in terms of sex, histopathological type, tumor location, spinal cord invasion, surgery, and the Eastern Cooperative Oncology Group score (χ2 = 0.004 to 6.213; all P > .05). No significant difference was found in onset time of myelosuppression (11 days (interquartile range [IQR]: 7 to 14; minimum [min] to maximum [max]: 0 to 26) vs 8 days (IQR: 7 to 15; min to max: 3 to 29)) and nadir time of myelosuppression (21 days (IQR: 18 to 25; min to max: 12 to 35) vs 22 days (IQR: 15 to 25; min to max: 12 to 36)) between the CSI-IMRT group and the CSI-CRT group (Z = -0.856, -0.248; all P > .05). There were no significant differences in the incidence of decreased white blood cell counts (WBC), platelet counts, and hemoglobin concentration between the CSI-IMRT group and the CSI-CRT group, 86.8% (33/38) vs 78.1% (50/64), 57.9% (22/38) vs 42.2% (27/64), 57.9% (22/38) vs 53.1% (34/64); χ2 = 1.195, 2.357, 0.219; all P > .05. There were no significant differences in the incidence of decreased WBC, platelet counts, and hemoglobin concentration (severe myelosuppression) in grades III and IV, 23.7% (9/38) vs 21.9% (14/64), 7.9% (3/38) vs 3.1% (2/64), 5.3% (2/38) vs 9.4% (6/64); χ2 = 0.045, 1.164, 0.558; all P > .05. There was no significant difference in the incidence of myelosuppression and severe myelosuppression (grade III or above) induced by CSI-IMRT and CSI-CRT. CSI-IMRT is worthy of further clinical application.

Prognostic Value of Choline and Other Metabolites Measured Using 1H-Magnetic Resonance Spectroscopy in Gliomas: A Meta-Analysis and Systemic Review.

Glioma is the most prevalent primary central nervous system malignant tumor, with high heterogeneity observed among different grades; therefore, non-invasive prediction of prognosis could improve the clinical management of patients with glioma. 1H-magnetic resonance spectroscopy (MRS) can estimate metabolite levels non-invasively. Multiple studies have investigated its prognostic value in gliomas; however, no consensus has been reached. PubMed and Embase databases were searched up to 20 October 2022 to identify studies investigating the prognostic value of metabolites using 1H-MRS in patients with glioma. Heterogeneity across studies was evaluated using the Q and I2 tests, and a fixed- or random-effects model was used to estimate the combined overall hazard ratio (HR). Funnel plots and Begg tests were used to assess publication bias. Higher choline levels were associated with shorter overall survival (HR = 2.69, 95% CI, 1.92-2.99; p < 0.001) and progression-free survival (HR = 2.20, 95% CI, 1.16-4.17; p = 0.02) in all patients; however, in pediatric gliomas, it showed no significant correlation with overall survival (HR = 1.60, 95% CI, 0.97-2.64; p = 0.06). The estimated choline level by 1H-MRS could be used to non-invasively predict the prognosis of patients with adult gliomas, and more studies are needed to evaluate the prognostic value of other metabolites.

Single-Cell Sequencing Analysis Identified ASTN2 as a Migration Biomarker in Adult Glioblastoma.

Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 updated World Health Organization classification of central nervous system tumors first mentioned the classification of adult glioma and pediatric glioma based on the molecular diagnosis. Thus, we used single-cell RNA sequencing analysis to explore the diversity and similarities in the occurrence and development of adult and pediatric types. ASTN2, which primarily encodes astrotactin, has been reported to be dysregulated in various neurodevelopmental disorders. Although some studies have demonstrated that ASTN2 plays an important role in glial-guided neuronal migration, there are no studies about its impact on glioblastoma cell migration. Subsequent single-cell RNA sequencing revealed ASTN2 to be a hub gene of a cell cluster which had a poor effect on clinical prognosis. Eventually, a western blot assay and a wound-healing assay first confirmed that ASTN2 expression in glioblastoma cell lines is higher than that in normal human astrocytes and affects the migration ability of glioblastoma cells, making it a potential therapeutic target.

Abstract 5746: Analysis of molecular characteristics of gliomas harboring gene fusions

Abstract Background: Genotyping plays an important role in tumor diagnosis and prognosis. The 2016 central nervous system (CNS) WHO added molecular parameters to classify CNS tumors on the basis of routine histological features, but the characteristics of gene fusion variations have not been clarified in CNS tumors. Methods: In order to identify the characteristics of gene fusions in Chinese patients with CNS malignant tumors, we retrospectively analyzed the next-generation sequencing data of 234 patients (pts) with gene fusions. Results: According to WHO classification of CNS tumor, 121 pts (51.7%) were low-grade gliomas (LGG, grade I, II), and 113 pts (48.3%) were high-grade gliomas (HGG, grade III, IV). The age of pts with LGG (14.1 ± 16.1) was significantly lower than HGG pts (50.2 ± 17.4) (P<0.0001). There was no significant gender difference between them (P = 0.161). In the fusion map of pts with LGG, gene fusions of KIAA1549-BRAF (n=82, 67.7%) and FGFR3-TACC3 (n=7, 5.8%) occurred frequently. Meanwhile, there were 5.7% pts carrying BRAF fusions with other partners, and some other sporadic fusions. Among HGG cases, the most frequent gene fusion was FGFR3-TACC3 (n=36, 31.9%), followed by fusions in EGFR (n=22, 19.5%), MET (n=16, 14.2%), BRAF (n=8, 7.1%), ROS1 (n=5, 4.4%), and other sporadic genes. It can be seen that gene fusion characteristics varied from gliomas with different malignant degrees. KIAA1549-BRAF fusion tended to occur in LGG (67.7% vs. 2.7%, P < 0.0001) than HGG, and FGFR3-TACC3 tended to occur in HGG ( 31.9% vs. 5.8%, P< 0.0001) than LGG. In addition, FGFR3-TACC3 fusion pts were exclusive with IDH1/2 mutations, but tended to be co-mutate with TERT promoter variants (P<0.0001). IDH-mutation-positive glioma usually exhibit a better clinical result, while TERT promoter-mutated glioma predicts a poor outcome. We also found that 75% (12/16) of MET fusion-positive gliomas pts had TP53 co-coexisting and 56.3% (9/16) of MET fusion-positive gliomas pts co-occurred with MET amplification, while only 0.9% (1/105) of pts harboring other fusions were MET amplification positive. Meanwhile, 95.0% (21/22) of EGFR fusion-positive pts co-occurred with EGFR amplification. Conclusion: By comprehensively analyzing the gene fusion map of Chinese patients with gliomas, we found the gene fusion characteristics of LGG differed from that of HGG. These fusion features may be important molecular information for judging the grade of malignancy and prognosis of patients. Citation Format: Jidong Wang, Yushuai Han, Weiran Wang, Tonghui Ma. Analysis of molecular characteristics of gliomas harboring gene fusions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5746.

Bioinformatics analysis of LMAN1 expression, clinical characteristics, and its effects on cell proliferation and invasion in glioma

Glioma is the most common primary central nervous system malignant tumor with high heterogeneity and poor prognosis. So far, the complex pathological process of glioma has not been fully elucidated, and there is a lack of effective biomarkers for the diagnosis and molecular targeted therapy of glioma. Using bioinformatics methods, 77 upregulated and 89 downregulated differentially expressed genes (DEGs) were detected by intersection analysis in different gene expression datasets of glioma cases from public databases. Then, GO and KEGG pathway analysis revealed that the biological functions of these upregulated DEGs were mainly focused on immune response, and the signaling pathways were mainly enriched in integrin family cell surface interactions. The overexpression of the LMAN1 gene of interest was then confirmed using the TCGA dataset and further verified by qRT-PCR in 29 clinical samples and 5 glioma cell lines. Furthermore, high expression of LMAN1 was found to be associated with higher WHO grade, IDH status, and 1p/19q co-deletion. Survival analysis showed that high expression of LMAN1 was associated with poor prognosis in glioma. Gene set enrichment analysis (GSEA) indicated that many cancer-related pathways were associated with LMAN1-high phenotype. Protein-protein interaction (PPI) analysis revealed significant interaction between LMAN1 and MCFD2, F8, and TMED10. Finally, cell experiments showed that LMAN1 knockdown significantly inhibited the proliferation, migration and invasion and promoted apoptosis in glioma cells. This study highlighted the malignant role of LMAN1 in gliomas and provided a potentially valuable biomarker for prognosis evaluation and molecular targeted therapy of glioma.

Patient-Derived Xenotransplant of CNS Neoplasms in Zebrafish: A Systematic Review.

Glioblastoma and neuroblastoma are the most common central nervous system malignant tumors in adult and pediatric populations. Both are associated with poor survival. These tumors are highly heterogeneous, having complex interactions among different cells within the tumor and with the tumor microenvironment. One of the main challenges in the neuro-oncology field is achieving optimal conditions to evaluate a tumor’s molecular genotype and phenotype. In this respect, the zebrafish biological model is becoming an excellent alternative for studying carcinogenic processes and discovering new treatments. This review aimed to describe the results of xenotransplantation of patient-derived CNS tumors in zebrafish models. The reviewed studies show that it is possible to maintain glioblastoma and neuroblastoma primary cell cultures and transplant the cells into zebrafish embryos. The zebrafish is a suitable biological model for understanding tumor progression and the effects of different treatments. This model offers new perspectives in providing personalized care and improving outcomes for patients living with central nervous system tumors.

Use of Chicken Embryos as an Angiogenesis Model for Central Nervous System Malignant Tumor Research.

To demonstrate the usability of chicken chorioallantoic membrane (CAM) as an angiogenesis model for the development and treatment of malignant tumors of the central nervous system. A fresh tumor tissue piece taken from Glioblastoma patients, a malignant tumor of the central nervous system, was transferred to the CAM of chicken embryos and left to incubate in the incubator and their development was monitored. After examining the results of the study macroscopically, CAM tissue samples were evaluated both histochemically and immunohistochemically in terms of angiogenic factors VEGF (Vascular Endothelial Growth Factor), bFGF (basic Fibroblast Growth Factor) and PDGF (Platelet Derived Growth Factor). According to histochemical findings obtained from our study when compared with control embryos, blood vessels, fibroblast count and inflammatory infiltration were observed more in the tumor transplanted groups, especially in the tumordeveloping CAM region. There was also intense pleomorphism and marked hypercellularity in the cells. In our immunohistochemical findings, it was determined that bFGF, PDGF, VEGF staining intensities were higher in tumor transplanted groups compared to control groups, and this elevation was more pronounced in the tumor-developing region. As a result, it has been shown that the chicken embryo CAM model may be a suitable in vivo model for cancer angiogenesis studies. The protocol we created in this study will be a source for projects related to the use of therapeutic agents in cancer angiogenesis.

RETRACTED ARTICLE: Exosomal SNHG16 secreted by CSCs promotes glioma development via TLR7

BackgroundGlioma is one of the most common central nervous system malignant tumors, accounting for 45~60% of adult intracranial tumors. However, the clinical treatment of glioma is limited. It is of great significance to seek new therapeutic methods for glioma via gene therapy.MethodsLong non-coding RNA (lncRNA) SNHG16 expression level was measured by microarray and qRT-PCR assay; ISH was used to identify the location of SNHG16. Cancer stem cells (CSCs) were separated from glioma tissues and identified using immunofluorescence. Exosomes were isolated from CSCs and cancer cells and identified by TEM and western blot. MTT, wound healing, transwell, and colony formation assay were performed to explore the role of SNHG16 or si-SNHG16 from CSCs on progression of glioma cells. RIP was used to verify the interaction between SNHG16 and TLR7. The experiment of Xenograft used for exploring the function of SNHG16/ TLR7/MyD88/NFκB/c-Myc on growth on glioma in vivo.ResultsMicroarray assay showed long non-coding RNA (lncRNA) SNHG16 was upregulated in glioma. Followed qRT-PCR also showed an increase of SNHG16 in glioma tissues; high expression of SNHG16 indicated a poor prognosis in glioma patients. Interestingly, SNHG16 was packaged into exosomes and derived from CSCs. Functional analysis showed exo-SNHG16 secreted by CSCs promoted the progression of glioma cell lines SHG44 and U251. Furthermore, SNHG16 interacted with TLR7 and activated NFκB/c-Myc signaling in glioma cells. And the silencing of TLR7 inhibited the progression of SHG44 and U251 cells by exo-SNHG16 from CSCs. In vivo tumorigenesis experiments showed that exo-SNHG16 induced glioma progression by activating TLR7/MyD88/NFκB/c-Myc signaling.ConclusionOur study suggested CSC-derived exo-SNHG16 promoted cancer progression by activating TLR7/MyD88/NFκB/c-Myc signaling pathway.

Exosomal lncRNA ROR1-AS1 Derived from Tumor Cells Promotes Glioma Progression via Regulating miR-4686.

ObjectiveGlioma is one of the most common central nervous system malignant tumors, accounting for 45%–60% of adult intracranial tumors. However, the clinical treatment of glioma is limited. It is of great significance to seek new therapeutic methods for glioma via gene therapy.Materials and MethodsMicroarray is used to identify the lncRNAs that are differentially expressed in glioma. The expression of long non-coding RNA (lncRNA) ROR1-AS1 and miR-4686 was detected by qRT-PCR. Exosomes were isolated from the supernatant of normal and cancerous cells, and TEM was used for exosomes identification. MTT assay, wound healing assay, transwell assay, and colony formation assay were used to detect the exo-ROR1-AS1 function on proliferation, migration, and invasion in glioma cells. Luciferase assay and RIP assay were used to identify the relationship between lncRNA ROR1-AS1 and miR-4686. The effect of exo-ROR1-AS1 on tumorigenesis of glioma was confirmed by the xenograft nude mice model.ResultsROR1-AS1 was up-regulated in glioma tissues, and the high expression of ROR1-AS1 indicated a poor prognosis in glioma patients. Interestingly, ROR1-AS1 was packaged into exosomes and derived from tumor cells. Functional analysis showed exo-ROR1-AS1 promoted the progression of glioma cell lines SHG44 and U251. Furthermore, ROR1-AS1 acted as a sponge of miR-4686 and inhibited its expression. Functionally, forced expression of miR-4686 removed the promoted effects of lncRNA ROR1-AS1 on glioma development. In vivo tumorigenesis experiments showed that exo-ROR1-AS1 promoted glioma development via miR-4686 axis.ConclusionOur study suggested tumor cells derived exo-ROR1-AS1 promoted glioma progression by inhibiting miR-4686, which might be a potential therapeutic target for glioma clinical treatment.

Glioblastoma con componente neuronal primitivo

Los glioblastomas representan la neoplasia maligna del sistema nervioso central más común en adultos. Estos pueden presentar diversos patrones histológicos, siendo el Glioblastoma con Componente Neuronal Primitivo (GCNP), uno de los más raros. La siguiente presentación de caso, corresponde a una Mujer de 49 años, con antecedente de adenocarcinoma mucinoso en cérvix, tratado con quimioterapia hacía 2 años, y referida por una masa en cerebro. Al estudio microscópico el diagnóstico fue de un Glioblastoma con Componente Neuronal Primitivo.

SUN-279 A Rare Case of Atypical Rhaboid Teratoid Tumour with Germinoma Differentiation in a 59 Year Old Woman

Atypical teratoid/rhabdoid tumours (ATRT) are a rare class of central nervous system malignant tumours which are comprised of elements of ectoderm and mesoderm germ-cell layers, but exhibit microscopic similarity to skeletal muscle. These tumours are more commonly seen in pediatric patients, with few case reports recently describing adult patients with this condition, in particular middle-aged women.1–3 We present the case of a previously healthy 59-year-old woman who was found incidentally to have a pituitary mass on CT head, with retrospective symptoms of headaches, polyuria, polydipsia, diplopia, and low blood pressure. At presentation, she was found biochemically to have pan-hypopituitarism with a left cranial nerve six deficit, with an MRI depicting a 19.5 x 22 x 11 mm suprasellar mass extending into the infundibulum and hypothalamus, with displacement of the optic chiasm; repeat imaging ruled out apoplexy. She was started on supplemental levothyroxine and hydrocortisone replacement therapy, and sent for urgent transsphenoidal resection, which was complicated afterwards by hypernatremia from diabetes insipidus. Preliminary reports were suggestive of germinoma given the diffuse presence of Oct 3/4 and C-kit, with a proliferation index of 99%; further cytology of lumbar puncture revealed no malignant cells. However, upon further pathological analysis, her tumour demonstrated loss of INI-1 expression, which is diagnostic of ATRT. Given the mixed features on immunohistochemistry, the final diagnosis was concluded as an atypical teratoid/rhabdoid tumour of the sella turcica with germinoma differentiation. A multi-disciplinary approach consisted of initial radiotherapy, with chemotherapy targeted towards a germinoma-type tumour, and pituitary hormone replacement including treatment for central diabetes insipidus. This represents a unique case of a rare tumour with germinoma differentiation in an older patient that has not been previously reported.

Expression Profile Analysis Identifies a Novel Five-Gene Signature to Improve Prognosis Prediction of Glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive primary central nervous system malignant tumor. The median survival of GBM patients is 12–15 months, and the 5 years survival rate is less than 5%. More novel molecular biomarkers are still urgently required to elucidate the mechanisms or improve the prognosis of GBM. This study aimed to explore novel biomarkers for GBM prognosis prediction. The gene expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets of GBM were downloaded. A total of 2241 overlapping differentially expressed genes (DEGs) were identified from TCGA and GSE7696 datasets. By univariate COX regression survival analysis, 292 survival-related genes were found among these DEGs (p < 0.05). Functional enrichment analysis was performed based on these survival-related genes. A five-gene signature (PTPRN, RGS14, G6PC3, IGFBP2, and TIMP4) was further selected by multivariable Cox regression analysis and a prognostic model of this five-gene signature was constructed. Based on this risk score system, patients in the high-risk group had significantly poorer survival results than those in the low-risk group. Moreover, with the assistance of GEPIA http://gepia.cancer-pku.cn/, all five genes were found to be differentially expressed in GBM tissues compared with normal brain tissues. Furthermore, the co-expression network of the five genes was constructed based on weighted gene co-expression network analysis (WGCNA). Finally, this five-gene signature was further validated in other datasets. In conclusion, our study identified five novel biomarkers that have potential in the prognosis prediction of GBM.

The Risk of Radiogenic Second Cancer Based on Differential DVH: Central Nervous System Malignant Tumor in Children.

Objectives:To quantify the risk of radiogenic second cancer in pediatric patients receiving hippocampal-sparing craniospinal irradiation either with intensity-modulated radiation therapy or tomotherapy due to the development of a solid second cancer after radiotherapy using the concept of excess absolute risk.Methods:Computed tomography images of 15 pediatric patients who received craniospinal irradiation treatment were selected for this study. For each case, intensity-modulated radiation therapy and tomotherapy plans were computed. Then, the dosimetry parameters were analyzed. Differential dose–volume histograms were generated, and the excess absolute risks were calculated for each plan of each patient.Results:The tomotherapy group was superior to the intensity-modulated radiation therapy group in target area homogeneity index (P < .001). Tomotherapy offered greater hippocampal sparing than intensity-modulated radiation therapy in terms of D 2% (15.66 vs 23.05 Gy, P < .001) and Dmean (9.79 vs 20.29 Gy, P < .001). Tomotherapy craniospinal irradiation induced a much higher risk than intensity-modulated radiation therapy craniospinal irradiation to the thyroid and lungs (excess absolute risk: thyroid 28.7 vs 26.9 per 10 000 PY, P = .010; lung 20.5 vs 18.9 per 10 000 PY, P = .003). Both techniques conferred a higher risk to the stomach, but there was little difference. In addition, the 2 plans induced less carcinogenic risk to the liver (excess absolute risk 4.2 vs 4.0 per 10 000 PY, P = .020).Conclusions:The tomotherapy plan has obvious advantages in the protection of the hippocampus for children undergoing craniospinal irradiation treatment. Tomotherapy increased the risk of radiogenic second cancer in organ at risk, and therefore, it is imperative to take the risk factor into consideration in the formulation of treatment protocols.

The synergistic effects of valproic acid and fluvastatin on apoptosis induction in glioblastoma multiforme cell lines.

Glioblastoma multiforme (GBM) is the most common primary central nervous system malignant tumor. It responds poorly to standard therapies, such as surgical resection, radiation therapy and chemotherapy. Many chemotherapeutic drugs are focused on apoptosis induction and radiation sensitivity. Inhibition of histone acetylation via histone deacetylase inhibitor (HDACI) is one such strategy. Statins (or 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) are classical drugs used to lower cholesterol but also inhibitors of histone deacetylation activity. This study analyzes the combinatory effects of valproic acid (VPA) and fluvastatin on apoptosis induction in GBM8401 cells. The results show that they act synergistically in inducing γ-H2AX and apoptosis accompanied by higher acetylated histones H3 and H4. Downregulation of p53 occurred by VPA alone and fluvastatin alone, but not at their combined application; upregulation of p21 at the protein level was induced by each of the drugs alone and no further increase occurred at combined application. The drug BEZ235 inhibited phosphorylation of Akt and attenuated the level of γ-H2AX as well as cleaved PARP (cPARP) induced at combined application of VPA and fluvastatin. Induction of apoptosis within a 48h incubation period was massive when measured as the subG1 peak (97%) and was detected after a 24h incubation at low level when assayed with PE Annexin V. Synergistic apoptosis induction was demonstrated also after 24h incubation by the appearance of cPARP. Partial silencing of p21 reduced cPARP as well as the percentage of apoptotic cells in the subG1 peak. However, partial silencing of p53 had no effect on apoptosis. Such findings offer a better understanding of the mechanism of action of HDACIs in combination with statins that may guide the development of a new combinatory reposition for the treatment of GBM.

Treatment of primary central nervous system lymphoma

As a kind of rare central nervous system malignant tumor, primary central nervous system lymphoma (PCNSL) has poor prognosis, and the main treatment include surgery, radiotherapy and chemothe-rapy. Stereotactic biopsy has become a routine diagnostic method of PCNSL, because of which has the advantage of minimally invasive and convenient. Whole brain radiotherapy is a standardized treatment method for the multifocal PCNSL, which can delay the progress of tumor in a short term. The therapeutic regimen based on high dose methotrexate leads to significant changes in the PCNSL treatment and it has become an effective treatment measure. Effective comprehensive treatment is the key to extending survival time and improving the quality of life for the patients with PCNSL. Key words: Lymphoma; Central nervous system neoplasms; Radiotherapy; Drug therapy; Methotrexate

Successful Treatment of a Recurrent Choroid Plexus Carcinoma with Surgery Followed by High-Dose Chemotherapy and Stem Cell Rescue

Choroid plexus carcinoma (CPC) is a rare central nervous system malignant tumor with a dismal prognosis, especially in the case of incomplete resection or recurrence. The authors report long-term survival of a 1-year-old patient with recurrent CPC and Li-Fraumeni syndrome with surgical resection and high-dose chemotherapy (HDC) consisting of single cycle of Busulfan and Thiotepa followed by autologous stem cell rescue without the use of radiation therapy. Remarkably the patient remains without evidence of recurrence 5 years after completion of therapy. Additional studies are necessary to determine the role of HDC and stem cell rescue in patients with recurrent CPC.

Primary spinal cord melanoma in thoracic spine with leptomeningeal dissemination and presenting hydrocephalus.

Primary spinal cord melanoma is a rare central nervous system malignant tumor. Usually it resembles an intradural extramedullary (IDEM) nerve sheath tumor or melanoma. We experienced a patient with upper thoracic primary IDEM spinal cord melanoma who was diagnosed to be with hydrocephalus and without intracranial lesions. Initial symptoms of the patient were related to the hydrocephalus and the primary spinal cord melanoma was diagnosed eight months later. At the first operation, complete resection was impossible and the patient refused additional radiotherapy or chemotherapy. At 22 months after surgery, the patient revisited our institution with recurrent both leg weakness. Leptomeningeal dissemination was present in the whole spinal cord and only partial resection of tumor was performed. The symptoms slightly improved after surgery. Primary spinal cord melanoma is extremely rare but complete resection and additional radiotherapy or chemotherapy can prolong the disease free interval. Hydrocephalus or signs of increased intracranial pressure may be the diagnostic clue of spinal cord malignancy and progression.