Exploring the association of glioma tumor residuals from incongruent [18F]FET PET/MR imaging with tumor proliferation using a multiparametric MRI radiomics nomogram.

PURPOSE: The study aimed to using multiparametric MRI radiomics to predict glioma tumor residuals (TRFET over MR) derived from incongruent [18F]fluoroethyl-L-tyrosine ([18F]FET) PET/MR imaging. METHODS: One hundred ten patients with gliomas who underwent [18F]FET PET/MR scanning were retrospectively analyzed. The TRFET over MR was identified by the discrepancy-PET that the extent of resection (EOR) based on MRI subtracted the biological tumor volume on PET images. The MRI parameters and radiomics features were extracted based on EOR and selected by the least absolute shrinkage and selection operator to construct radiomics score (Rad-score). The correlation network analysis of all features was analyzed by Spearman's correlation tests. The methods for evaluating the clinical usefulness consisted of the receiver operating characteristic curve, the calibration curve, and decision curve analysis. RESULTS: The Rad-score of the patients with the TRFET over MR was significantly higher than those with the non TRFET over MR (p < 0.001). The Rad-score was significantly correlated with the discrepancy-PET (r = 0.72, p < 0.001), Ki-67 level (r = 0.76, p < 0.001), and epidermal growth factor receptor (EGFR) of gliomas (r = 0.75, p < 0.001), respectively. Moreover, there was a difference of the correlation network analysis between the TRPET over MR group and non TRFET over MR group. The nomogram combing Rad-score and clinical features had the greatest performance in predicting TRFET over MR (AUC = 0.90/0.87, training/testing). There was a significant difference in prognosis (median OS, 17 m vs. 43 m) between patients with TRFET over MR and non TRFET over MR based on nomogram prediction (p < 0.001). CONCLUSION: The nomogram based on MRI radiomics would predict gliomas tumor residuals caused by the absence of 18F-PET PET examination and adjust EOR to improve prognosis.

Simultaneous FET-PET and contrast-enhanced MRI based on hybrid PET/MR improves delineation of tumor spatial biodistribution in gliomas: a biopsy validation study.

PURPOSE: Glioma treatment planning requires precise tumor delineation, which is typically performed with contrast-enhanced (CE) MRI. However, CE MRI fails to reflect the entire extent of glioma. O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET may detect tumor volumes missed by CE MRI. We investigated the clinical value of simultaneous FET-PET and CE MRI in delineating tumor extent before treatment planning. Guided stereotactic biopsy was used to validate the findings. METHODS: Conventional MRI and 18F-FET PET were performed simultaneously on a hybrid PET/MR in 33 patients with histopathologically confirmed glioma. Tumor volumes were quantified using a tumor-to-brain ratio ≥ 1.6 (VPET) and a visual threshold (VCE). We visually assessed abnormal areas on FLAIR images and calculated Dice's coefficient (DSC), overlap volume (OV), discrepancy-PET, and discrepancy-CE. Additionally, several stereotactic biopsy samples were taken from "matched" or "mismatched" FET-PET and CE MRI regions. RESULTS: Among 31 patients (93.94%), FET-PET delineated significantly larger tumor volumes than CE MRI (77.84 ± 51.74 cm3 vs. 34.59 ± 27.07 cm3, P < 0.05). Of the 21 biopsy samples obtained from regions with increased FET uptake, all were histopathologically confirmed as glioma tissue or tumor infiltration, whereas only 13 showed enhancement on CE MRI. Among all patients, the spatial similarity between VPET and VCE was low (average DSC 0.56 ± 0.22), while the overlap was high (average OV 0.95 ± 0.08). The discrepancy-CE and discrepancy-PET were lower than 10% in 28 and 0 patients, respectively. Eleven patients showed VPET partially beyond abnormal signal areas on FLAIR images. CONCLUSION: The metabolically active biodistribution of gliomas delineated with FET-PET significantly exceeds tumor volume on CE MRI, and histopathology confirms these findings. Our preliminary results indicate that combining the anatomic and molecular information obtained from conventional MRI and FET-PET would reveal a more accurate glioma extent, which is critical for individualized treatment planning.

Glioneuronal tumours with features of rosette-forming glioneuronal tumours of the fourth ventricle and dysembryoplastic neuroepithelial tumours: a report of three cases.

AIMS: To study three atypical glioneuronal tumours (GNTs), in order to shed light on the clinical and pathological features of this diverse tumour group. METHODS AND RESULTS: Clinical and neuropathological data for each case were retrospectively reviewed. Case 1 involved a 17-year-old boy with left leg movement difficulty. A mass lesion in the basal ganglia was detected radiologically; histopathological features included neurocytic/perivascular rosettes and a pilocytic astrocytoma component. Case 2 involved a 33-year-old man with intractable epilepsy. His left parietal lobe contained a cyst-like mass, resembling dysembryoplastic neuroepithelial tumour and rosette-forming glioneuronal tumour of the fourth ventricle microscopically. Case 3 involved a 21-year-old woman with a mass lesion in the mesencephalic tegmentum extending to the third and fourth ventricles and the suprasellar region. The lesion contained perivascular/neurocytic rosettes and an oligodendroglioma-like component. None of the tumours expressed an isocitrate dehydrogenase I mutation of the R132H type or contained a 1p/19q deletion, a BRAF(V600E) mutation, or KIAA1549-BRAF fusion. CONCLUSIONS: We describe three GNTs with atypical histopathology and locations. Additional cases and molecular studies are needed to better understand the biological nature of GNTs and to refine their classification system.

Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer.

INTRODUCTION: Brain metastasis, with the highest incidence in patients with lung cancer, significantly worsens prognosis and poses challenges to clinical management. To date, how brain metastasis evades immune elimination remains unknown. METHODS: Whole-exome sequencing and RNA sequencing were performed on 30 matched brain metastasis, primary lung adenocarcinoma, and normal tissues. Data from The Cancer Genome Atlas primary lung adenocarcinoma cohort, including multiplex immunofluorescence, were used to support the findings of bioinformatics analysis. RESULTS: Our study highlights the key role of intratumor heterogeneity of genomic alterations in the metastasis process, mainly caused by homologous recombination deficiency or other somatic copy number alteration-associated mutation mechanisms, leading to increased genomic instability and genomic complexity. We further proposed a selection model of brain metastatic evolution in which intratumor heterogeneity drives immune remodeling, leading to immune escape through different mechanisms under local immune pressure. CONCLUSIONS: Our findings provide novel insights into the metastatic process and immune escape mechanisms of brain metastasis and pave the way for precise immunotherapeutic strategies for patients with lung cancer with brain metastasis.

Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling.

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

Microsurgery for vestibular schwannoma: analysis of short-term clinical outcome.

BACKGROUND: Total removal of the vestibular schwannoma when preserving the function of the facial nerve is difficult. The objective of the current study was to investigate the short-term clinical outcome of vestibular schwannoma removal via retro-sigmoid approach. METHODS: One-hundred consecutive patients diagnosed with vestibular schwannoma were surgically treated between December 2018 and August 2019 in Xuanwu Hospital, Capital Medical University. The clinical classification, surgical position, gross total removal rate, the anatomical and functional preservation rates of facial nerve, and the postoperative complications were retrospectively analyzed. RESULTS: All 100 patients including 34 males and 66 females were operated on via retro-sigmoid approach. According to Koos vestibular schwannoma grading system, 18 cases were grade 2, 34 cases were grade 3, and 48 cases were grade 4. According to Hannover vestibular schwannoma grading system, 5 cases were T2, 6 cases were T3a, 8 cases were T3b, 30 cases were T4a, and 51 cases were T4b. Seventy-three surgeries were performed under lateral position, and 27 cases were operated under semi-sitting position. The gross total removal rate was 90.0%; the anatomic reservation rate of the facial nerve was 96.0%. According to the House-Brackman system, the facial nerve function was grades 1-2 in 78.0% cases, grade 3 in 7.0% cases, and grades 4-5 in 15% cases. For patients with effective hearing before operation, the hearing reservation rate was 19.0%. Two patients (2.0%) developed intracranial hematoma after operation. CONCLUSION: Most vestibular schwannoma could be completely removed with good postoperative facial nerve function. If total removal of tumor is difficult, we should give priority to the functional preservation of the nerve function.

The effects of different surgical positions (semi-sitting and lateral position) on the surgical outcomes of large vestibular schwannoma: study protocol for a randomized controlled trial.

BACKGROUND: There is an ongoing discussion about the advantages and disadvantages of different surgical positions (semi-sitting and lateral position) for vestibular schwannoma surgery. Each position has its advantages, disadvantages, challenges, and risk profiles. The objectives of this study are to compare the effects of different surgical positions (semi-sitting and lateral position) on the outcomes of large vestibular schwannoma, primarily including effectiveness and safety. METHODS: In this single-centre, open, randomized controlled trial, we will recruit a total of 116 participants according to the inclusion and exclusion criteria who will be randomized to an experimental group or control group. Patients will undergo operations in semi-sitting and lateral positions. The primary endpoint will be the percentage of gross total resection. The secondary endpoints will include the facial nerve function, hearing preservation, surgical position placement time, time of operation (skin-to-skin surgical time), hospital stay, total hospitalization fee, and complications. The follow-up period will be at least 12 months, during which time patients will be evaluated both clinically and radiologically. DISCUSSION: This issue is still debated after 30 years since the first large comparative study was published in 1989, so the study will be useful. Therefore, more high-quality studies are required to compare clinical outcomes, complications, and other factors associated with these two positions. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900027550 . Registered on 17 November 2019.

Formation of solid tumors by a single multinucleated cancer cell.

BACKGROUND: Large multinucleated cells (MNCs) commonly exist in tumorigenic cancer cell lines that are used widely in research. However, the contributions of MNCs to tumorigenesis are unknown. METHODS: In this study, MNCs were characterized in the murine fibrosarcoma cell line UV-2237 in vitro and in vivo at the single-cell level. RESULTS: The authors observed that MNCs originated from a rare subpopulation of mononuclear cells and were positive for a senescent marker, ß-galactosidase. In addition, MNCs were responsible for the majority of clonogenic activity when cultured in hard agar; they were more resistant to chemotherapeutic agents than mononuclear cells; they could undergo asymmetric division (producing mononuclear cells) and self-renewal in vitro and in vivo; and, most important; a single MNC produced orthotopic, subcutaneous tumors (composed mainly of mononuclear cells) that gave rise to spontaneous lung metastases in nude mice. CONCLUSIONS: The current results indicated that the growth of MNCs may be arrested under stress and that MNCs are highly resistant to chemotherapy and can generate clonal, orthotopic, metastatic tumors.

Partial response to Chinese patent medicine Kangliu pill for adult glioblastoma: A case report and review of the literature.

BACKGROUND: Glioblastoma is the most common type of brain tumor and is invariably fatal, with a mean survival time of 8-15 mo for recently diagnosed tumors, and a 5-year survival rate of only 7.2%. The standard treatment for newly diagnosed glioblastoma includes surgery followed by concurrent chemoradiotherapy and further adjuvant temozolomide. However, the prognosis remains poor and long-term survival is rare. This report aimed to demonstrate a new therapeutic strategy for the treatment of glioblastoma. CASE SUMMARY: A patient was referred to the Department of Neurosurgery with an intracranial space-occupying lesion with a maximum diameter of approximately 5 cm. The tumor was compressing functional areas, and the patient accordingly underwent partial resection and concurrent chemoradiotherapy. The imaging and pathological findings were consistent with a diagnosis of glioblastoma with oligodendroglioma differentiation (World Health Organization IV). The patient was finally diagnosed with glioblastoma. However, the patient discontinued treatment due to intolerable side effects, and was prescribed Kangliu pill (KLP) 7.5 g three times/d, which he has continued to date. Significant shrinkage of the tumor (maximum diameter reduced from about 3.5 to about 2 cm) was found after 3 mo of KLP therapy, and the tumor was further reduced to about 1 cm after 3 years. The patient's symptoms of headache, limb weakness, and left hemiplegia were relieved, with no side effects. CONCLUSION: KLP has been a successful intervention for glioblastoma, and the current case indicates that traditional Chinese medicine may offer effective alternative therapies for glioblastoma.

First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose.

Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted. TRIAL REGISTRATION NUMBERS: NCT03423992.

Outcomes after semisitting and lateral positioning in large vestibular schwannoma surgery: A single-center comparison.

OBJECTIVE: The semisitting position (SSP) and lateral position (LP) in vestibular schwannoma (VS) surgery each have advantages and disadvantages, and which position is superior overall is debatable. Our objective was to determine the optimal position for surgical treatment of VSs with a diameter ≥3 cm. METHODS: We retrospectively evaluated consecutive patients with a large VS treated between January 2010 and July 2020. Patients were grouped by surgical position and analyzed. RESULTS: We enrolled 259 patients (LP group, n = 156; SSP group, n = 103). The resection extent was not significantly different between the SSP (gross-total resection [GTR], n = 89 [88.1%], near-total resection [NTR], n = 10 [9.9%], subtotal resection [STR], n = 2 [2.0%]) and LP (GTR, n = 125 [80.1%]; NTR, n = 24 [15.4%]; STR, n = 7 [4.5%]) groups. The rate of GTR with facial nerve (FN) functional preservation was higher in the SSP group than in the LP group (P = 0.014) at eight days after the operation. However, during follow-up (SSP group median, 31.5 months; LP group median, 19.5 months), there was no significant between-group difference in FN functional preservation. Two patients in the SSP group required conversion to the LP due to severe intraoperative venous air embolism (VAE). CONCLUSION: Compared with the LP, the SSP did not produce significantly better FN outcomes in patients with a large VS. The duration of surgery was significantly longer in SSP cases than in LP cases. Given the risk of VAE associated with the SSP, the selection of the optimal surgical position should be made with caution on an individual basis.

Glioma Imaging by O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Diffusion-Weighted MRI and Correlation With Molecular Phenotypes, Validated by PET/MR-Guided Biopsies.

Gliomas exhibit high intra-tumoral histological and molecular heterogeneity. Introducing stereotactic biopsy, we achieved a superior molecular analysis of glioma using O-(2-18F-fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI). Patients underwent simultaneous DWI and FET-PET scans. Correlations between biopsy-derived tumor tissue values, such as the tumor-to-background ratio (TBR) and apparent diffusion coefficient (ADC)/exponential ADC (eADC) and histopathological diagnoses and those between relevant genes and TBR and ADC values were determined. Tumor regions with human telomerase reverse transcriptase (hTERT) mutation had higher TBR and lower ADC values. Tumor protein P53 mutation correlated with lower TBR and higher ADC values. α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX) correlated with higher ADC values. 1p/19q codeletion and epidermal growth factor receptor (EGFR) mutations correlated with lower ADC values. Isocitrate dehydrogenase 1 (IDH1) mutations correlated with higher TBRmean values. No correlation existed between TBRmax/TBRmean/ADC/eADC values and phosphatase and tensin homolog mutations (PTEN) or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Furthermore, TBR/ADC combination had a higher diagnostic accuracy than each single imaging method for high-grade and IDH1-, hTERT-, and EGFR-mutated gliomas. This is the first study establishing the accurate diagnostic criteria for glioma based on FET-PET and DWI.

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal®) in glioma patients in China.

BACKGROUND: Temozolomide is an alkylating agent approved by the U.S. Food and Drug Administration in 1999 for the treatment of patients with primary brain tumors. The aim of this study was to confirm the bioequivalence and safety of two strengths (20-100 mg) of generic temozolomide in the form of TOZ039 and Temodal® capsules administered to brain tumor patients. STUDY DESIGN: An open-label, randomized, two-phase, two-period, crossover pharmacokinetic study was performed in a single institution. The reference and test drugs were prescribed at a dose of 150 mg/m2 daily from days 1 to 5 of a 28-day cycle in the first phase; in the second phase, either a 150- or 200-mg/m2 dose was prescribed, depending on patient tolerance. On days 1 and 2 of each phase, a fixed 200-mg dose was administered either as ten 20-mg capsules in the first cycle or two 100-mg capsules in the second cycle. Drug administration in the first two days was randomized, i.e., if TOZ309 was administered on day 1, Temodal® was administered on day 2, and vice versa. The rest of the prescribed dose was administered in the form of Temodal® and spread equally over days 3-5. Blood samples were obtained for pharmacokinetic evaluation on days 1 and 2. Bioequivalence was demonstrated if the geometric means ratio of the three main pharmacokinetic parameters (mean maximum plasma concentration (Cmax), area under the concentration-time curve (AUC) 0-t, AUC 0-∞) fell within the equivalence boundary of 80-125%. RESULTS: Twenty-nine glioblastoma multiforme or anaplastic astrocytoma patients were enrolled and dosed with the test and reference formulations under fasting conditions. The 90% confidence interval of the geometric means ratio for Cmax (91.08%, 106.18%), AUC0-t (98.62%,102.18%), and AUC0-∞ (98.65%, 102.21%) was well within the 80%-125% range for the 20-mg capsule, as was the Cmax (90.49%, 113.32%), AUC0-t (99.89%, 104.63%) and AUC0-∞ (99.99%, 104.67%) for the 100-mg capsule drug product. Additionally, all the secondary pharmacokinetic parameters were not significantly different. After two cycles of treatment, there was no mortality among the 29 patients, treatment-related severe adverse events, or events that would require study discontinuation; however, one significant adverse effect (life-threatening seizures) occurred and was related to disease progression. Adverse events were reported in 82.8% (24/29) patients, and treatment emergent adverse events were reported in 72.4% (21/29) patients. CONCLUSION: It can be concluded that 20-mg and 100-mg capsules of TOZ309 are bioequivalent to Temodal® capsules of the same strength under fasting conditions. TRIAL REGISTRATION: https://www.chinadrugtrials.org.cn/index.html , CTR2017 0122.

CXCR4 expression varies significantly among different subtypes of glioblastoma multiforme (GBM) and its low expression or hypermethylation might predict favorable overall survival.

BACKGROUND: CXCR4 is an oncogene in glioblastoma multiforme (GBM) but the mechanism of its dysregulation and its prognostic value in GBM have not been fully understood. RESEARCH DESIGN AND METHODS: Bioinformatic analysis was performed by using R2 and the UCSC Xena browser based on data from GSE16011 in GEO datasets and in GBM cohort in TCGA database (TCGA-GBM). Kaplan Meier curves of overall survival (OS) were generated to assess the association between CXCR4 expression/methylation and OS in patients with GBM. RESULTS: GBM patients with high CXCR4 expression had significantly worse 5 and 10 yrs OS (p < 0.05). Across different GBM subtypes, there was an inverse relationship between overall DNA methylation and CXCR4 expression. CXCR4 expression was significantly lower in CpG island methylation phenotype (CIMP) group than in non CIMP group. Log rank test results showed that patients with high CXCR4 methylation (first tertile) had significantly better 5 yrs OS (p = 0.038). CONCLUSION: CXCR4 expression is regulated by DNA methylation in GBM and its low expression or hypermethylation might indicate favorable OS in GBM patients.

MicroRNA-322 attenuates aluminum maltolate-induced apoptosis in the human SH-SY5Y neuroblastoma cell line.

Aluminum-maltolate (Al­Malt) is a potent apoptosis inductor, which has been widely reported as an etiologic factor in Alzheimer's disease (AD). MicroRNA-322 (miR­322) is a vital regulator in various biological processes. The aim of the current study was to identify the role and possible underlying mechanism of miR­322 in Al­Malt­induced apoptosis. Eight concentrations of Al­Malt were prepared and used for treating the human neuroblastoma cell line, SH­SY5Y. Subsequent to treatment with Al­Malt for 3 days, cell viability, apoptosis and the expression levels of apoptosis­associated factors were measured. In addition, the mRNA expression level of miR­322 was monitored. Furthermore, cells were transfected with an miR­322 mimic and/or treated with Al­Malt, and cell viability, apoptosis and the expression levels of apoptosis­associated factors were measured again. Al­Malt significantly inhibited cell viability, but promoted apoptosis. The apoptosis­associated factors, V­Myc avian myelocytomatosis viral oncogene homolog (c­Myc), Bcl-2-associated X protein, caspase­3 and cleaved caspase­3 were markedly upregulated by Al­Malt. The mRNA expression level of miR­322 was negatively regulated by Al­Malt. Furthermore, miR­322 attenuated the apoptosis induced by Al­Malt and recovered the expression changes of these four factors. Thus, miR­322 may attenuate Al­Malt­induced apoptosis by recovering the expression change of c­Myc. Furthermore, miR­322 may be involved in the pathogenesis of Al­Malt­associated AD.

Invasive benign meningioma: Clinical characteristics, surgical strategies and outcomes from a single neurosurgical institute.

The aim of the present study was to improve the prognosis for patients with invasive benign meningioma by increasing the precision of pre-operative evaluation and refining the surgical resection strategy. A retrospective review of all the cases of invasive benign meningioma admitted to a single institute from 2005 to 2010 was conducted. The clinical characteristics, magnetic resonance imaging (MRI) findings, refined surgical strategies and outcomes were summarized and analyzed. There were 19 cases of invasive benign meningioma among 254 cases of meningioma. Of the earliest 4 cases, a traditional extra-capsular surgical removal approach was applied, which resulted in permanent neurological deficits for all cases. A modified surgical strategy combining intra- and extra-capsular resection techniques was employed for the subsequent 15 cases, which lead to mild neurological impairment in only 1 case. Pre-operative recognition of this unique sub-type of meningioma maybe facilitated by its typical MRI study findings, and the combination of intra- and extra-capsular resection techniques may be of critical importance in achieving complete tumor removal while maintaining intact neurological functions.

Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication.

Gliomas are the most common type of primary brain tumor. Using current standard treatment regimens, the prognosis of patients with gliomas remains poor, which is predominantly due to the resistance of glioma cells to chemotherapy. The organ microenvironment has been implicated in the pathogenesis and survival of tumor cells. Thus, the aim of the present study was to test the hypothesis that astrocytes (the housekeeping cells of the brain microenvironment) may protect glioma cells from chemotherapy and to investigate the underlying mechanism. Immunofluorescent and scanning electron microscopy demonstrated that glioma cells were surrounded and infiltrated by activated astrocytes. In vitro co-culture of glioma cells with astrocytes significantly reduced the cytotoxic effects on glioma cells caused by various chemotherapeutic agents, as demonstrated by fluorescein isothiocyanate-propidium iodide flow cytometry. Transwell experiments indicated that this protective effect was dependent on physical contact and the gap junctional communication (GJC) between astrocytes and glioma cells. Microarray expression profiling further revealed that astrocytes upregulated the expression levels of various critical survival genes in the glioma cells via GJC. The results of the present study indicated that the organ microenvironment may affect the biological behavior of tumor cells and suggest a novel mechanism of resistance in glioma cells, which may be of therapeutic relevance clinically.

Concurrence of Fahr's disease and brain tumor: A case report and review of the literature.

Fahr's disease is a rare entity characterized by abnormal calcification in the bilateral basal ganglion regions and cerebellum. Concurrence of Fahr's disease with brain tumor is associated with an even lower incidence; the present study describes the fifth such case, in which a 32-year-old female presented with a 1-month history of headache and unsteady walking. Pathology and imaging studies resulted in a diagnosis of low-grade astrocytoma with calcified deposition. The patient recovered uneventfully. Following a review of the literature, several similarities among the reported cases were revealed. Patients were relatively young at the onset of the disease. The pathological diagnosis for all brain tumors was astrocytoma. The cerebellum was the predominant location of the brain tumor. The imaging studies of these cerebral astrocytomas were almost identical, with a cystic glioma occurring adjacent to a neighboring calcified dentate nucleus. Furthermore, the development of astrocytoma in the bilateral cerebellar hemisphere was not uncommon, which warrants close follow-up for these patients.

Astrocytes upregulate survival genes in tumor cells and induce protection from chemotherapy.

In the United States, more than 40% of cancer patients develop brain metastasis. The median survival for untreated patients is 1 to 2 months, which may be extended to 6 months with conventional radiotherapy and chemotherapy. The growth and survival of metastasis depend on the interaction of tumor cells with host factors in the organ microenvironment. Brain metastases are surrounded and infiltrated by activated astrocytes and are highly resistant to chemotherapy. We report here that coculture of human breast cancer cells or lung cancer cells with murine astrocytes (but not murine fibroblasts) led to the up-regulation of survival genes, including GSTA5, BCL2L1, and TWIST1, in the tumor cells. The degree of up-regulation directly correlated with increased resistance to all tested chemotherapeutic agents. We further show that the up-regulation of the survival genes and consequent resistance are dependent on the direct contact between the astrocytes and tumor cells through gap junctions and are therefore transient. Knocking down these genes with specific small interfering RNA rendered the tumor cells sensitive to chemotherapeutic agents. These data clearly demonstrate that host cells in the microenvironment influence the biologic behavior of tumor cells and reinforce the contention that the organ microenvironment must be taken into consideration during the design of therapy.

The brain microenvironment and cancer metastasis.

The process of metastasis consists of a series of sequential, selective steps that few cells can complete. The outcome of cancer metastasis depends on multiple interactions between metastatic cells and homeostatic mechanisms that are unique to one or another organ microenvironment. The specific organ microenvironment determines the extent of cancer cell proliferation, angiogenesis, invasion and survival. Many lung cancer, breast cancer, and melanoma patients develop fatal brain metastases that do not respond to therapy. The blood-brain barrier is intact in and around brain metastases that are smaller than 0.25 mm in diameter. Although the blood-brain barrier is leaky in larger metastases, the lesions are resistant to many chemotherapeutic drugs. Activated astrocytes surround and infiltrate brain metastases. The physiological role of astrocytes is to protect against neurotoxicity. Our current data demonstrate that activated astrocytes also protect tumor cells against chemotherapeutic drugs.