Giant cell tumor of bone of temporal bone and skull base: report of 6 cases.

OBJECTIVE: Five cases of giant cell tumor of bone (GCTB) in the head and neck region were reported, with a main focus on the radiological findings to identify common characteristics for the diagnosis of GCTB in these sites. MATERIALS AND METHODS: Five consecutive patients diagnosed with GCTB were retrospectively selected. Radiological features on conventional and advanced MR sequences and CT were analyzed. HE staining and immunohistochemical examination were performed using antibodies against p63 and CD68. RESULTS: The common clinical features were local mass (3/5), tinnitus (3/5) and headache (2/5). Radiologically, all the cases were well-circumscribed osteolytic lesion, majority of cases demonstrated an expansile growth pattern and "soap bubble" appearance on CT (4/5). On MRI, the tumors showed predominantly hypointensity both on T1WI and T2WI, and no evidence of restricted diffusion on DWI. Intratumoral hemorrhage (2/5), cystic alternation (2/5) and very low signal on T2WI in the periphery region of the tumor (4/5) was found. Fluid-fluid level was noted in one case, which was eventually verified to be GCTB with secondary aneurysmal bone cyst (ABC). With contrast agent, all the cases showed striking (3/5) or mild to intermediate (2/5) enhancement. CONCLUSIONS: Although the above described radiological findings are not specific for GCTB in head and neck region, a well-defined osteolytic lesion in the bones of head and neck region with "soap bubble" appearance on CT and hypointensity on T2WI with very low signal in the peripheral region of the tumor on MRI highly suggest GCTB for patient ages 20 to 40.

Effects of gonadotropin-releasing hormone analog (GnRHa) immunization on the gonadal transcriptome and proteome of tilapia (Oreochromis niloticus).

Gonadotropin releasing hormone (GnRH) plays an important role in the regulation of vertebrate reproduction. Studies have shown that immunization against GnRHa can induce sexually sterile tilapia. To explore the mechanism behind this, in this study, RNA-seq and data-independent acquisition (DIA) techniques were used to study the transcriptome and proteome of the gonad of tilapia immunized with GnRHa. 644 differentially expressed genes (80 upregulated and 564 downregulated) and 1150 differentially expressed proteins (351 upregulated and 799 downregulated) were identified. There were 209 genes with consistent differential expression patterns in the transcriptomic and proteomic analyses, of which 9 were upregulated and 200 downregulated, indicating that the gonad gene expression was inhibited by GnRHa immunization. The downregulated genes were particularly involved in the functions of single-organism process, binding, cellular process, metabolic process and catalytic activity, and associated with the pathways including ECM-receptor interaction, focal adhesion, cardiac muscle contraction and oxidative phosphorylation. The expression of six differentially expressed genes involved in the GnRH signaling pathway was all downregulated. In addition, several important functional genes related to gonadal development after GnRHa immunization were screened. This study confirmed the expression of corresponding genes was affected by GnRHa on the gonad development in tilapia at the molecular level, and laid a foundation for elucidating the mechanism of GnRHa immunization.

Effects of BMPER, CXCL10, and HOXA9 on Neovascularization During Early-Growth Stage of Primary High-Grade Glioma and Their Corresponding MRI Biomarkers.

Neovascularization is required in high-grade glioma (HGG). The objective of this study was to explore neovascularization-related genes and their corresponding MRI biomarkers during the early-growth stage of HGG. Tumor tissues from 30 HGG patients underwent perfusion MRI scanning prior to surgery were used to establish orthotopic xenograft models, pathologically analyze the tumor vasculature and perform transcriptome sequencing. The cases were divided into two groups based on whether the xenograft was successfully established. Microvascular density and BMPER, CXCL10, and HOXA9 expression of surgical specimens in the xenograft-forming group was significantly elevated and the microvascular diameter was significantly reduced, in vitro inhibition of BMPER, CXCL10, or HOXA9 in the glioma stem cell significantly suppressed its tube formation abilities. The in vivo experiment showed that BMPER was highly expressed in the early tumor growth phase (20 days), CXCL10 and HOXA9 expression was elevated with tumor progress, and spatially associated with tumor vasculature. Perfusion weighted MRI (PWI-MRI) derived parameters, rCBV, rCBF, Ktrans, and Vp, were also increased in the xenograft-forming group. In conclusion BMPER, CXCL10, and HOXA9 promote early tumor growth and progression by stimulating neovascularization of primary HGG. The rCBV, rCBF, Ktrans, and Vp can be used as imaging biomarkers to predict the expression statuses of these genes.

Vascular habitat analysis based on dynamic susceptibility contrast perfusion MRI predicts IDH mutation status and prognosis in high-grade gliomas.

OBJECTIVE: The current study aimed to evaluate the clinical practice for hemodynamic tissue signature (HTS) method in IDH genotype prediction in three groups derived from high-grade gliomas. METHODS: Preoperative MRI examinations of 44 patients with known grade and IDH genotype were assigned into three study groups: glioblastoma multiforme, grade III, and high-grade gliomas. Perfusion parameters were analyzed and were used to automatically draw the four reproducible habitats (high-angiogenic enhancing tumor habitats, low-angiogenic enhancing tumor habitats, infiltrated peripheral edema habitats, vasogenic peripheral edema habitats) related to vascular heterogeneity. These four habitats were then compared between inter-patient with IDH mutation and their wild-type counterparts at these three groups, respectively. The discriminating potential for HTS in assessing IDH mutation status prediction was assessed by ROC curves. RESULTS: Compared with IDH wild type, IDH mutation had significantly decreased relative cerebral blood volume (rCBV) at the high-angiogenic enhancing tumor habitats and low-angiogenic enhancing tumor habitats. ROC analysis revealed that the rCBVs in habitats had great ability to discriminate IDH mutation from their wild type in all groups. In addition, the Kaplan-Meier survival analysis yielded significant differences for the survival times observed from the populations dichotomized by low (< 4.31) and high (> 4.31) rCBV in the low-angiogenic enhancing tumor habitat. CONCLUSIONS: The HTS method has been proven to have high prediction capabilities for IDH mutation status in high-grade glioma patients, providing a set of quantifiable habitats associated with tumor vascular heterogeneity. KEY POINTS: • The HTS method has a high accuracy for molecular stratification prediction for all subsets of HGG. • The HTS method can give IDH mutation-related hemodynamic information of tumor-infiltrated and vasogenic edema. • IDH-relevant rCBV difference in habitats will be a great prognosis factor in HGG.

Microvascular characteristics of lower-grade diffuse gliomas: investigating vessel size imaging for differentiating grades and subtypes.

OBJECTIVES: Vessel size imaging (VSI) could reveal average microvessel diameter. The aim was to investigate microvascular characteristics and the efficacy of VSI in lower-grade glioma (LGG) grading and subtype differentiation based on 2016 classification of central nervous system tumours. METHODS: Fifty-seven LGG (grade II/III, 36/21) patients who received VSI examination before surgery were retrospectively analysed. The average (Rmean) and maximum (Rmax) vessel size indexes were obtained. The long (VDmax) and short (VDmin) vascular diameter, microvascular area (MVA) and density (MVD) were obtained using paraffin specimens. The patients were divided into grades II and III, and histological and molecular subtypes. The differences among microvascular parameters of different subtypes and grades were compared. Two-sample t-test, analysis of variance test, Mann-Whitney test, the Kruskal-Wallis test and Pearson correlation analysis were used for statistics. RESULTS: Rmean, Rmax, VDmin, VDmax, and MVA were higher in grade-III than in grade-II LGGs (p < 0.05) in each type except the isocitrate dehydrogenase (IDH) mutant with 1p/19q-intact type. For grade II, the IDH mutant with 1p/19q co-deleted and IDH wildtype possessed more dominant angiogenesis than IDH mutant with 1p/19q-intact type, revealed by lower Rmean, Rmax and VDmin while higher MVD for the former (p < 0.05), the same as oligodendroglioma versus astrocytoma. Rmean and Rmax correlated with VDmin (r = 0.804, 0.815, p < 0.05), VDmax (r = 0.766, 0.774, p < 0.05) and MVA (r = 0.755, 0.759, p < 0.05), respectively, while they had no correlation with MVD (r = -0.085, -0.080, p > 0.05). CONCLUSIONS: VSI holds great potential for non-invasively revealing microvascular characteristics of LGGs pre-surgery and differentiating their grades and molecular subtypes. KEY POINTS: • VSI can assist in differentiating grade-II and -III gliomas. • The IDH gene and 1p/19q chromosome may influence the angiogenesis in grade-II gliomas. • VSI is valuable for differentiating the molecular subtypes of grade-II gliomas.

Aberrant glioblastoma neovascularization patterns and their correlation with DCE-MRI-derived parameters following temozolomide and bevacizumab treatment.

Glioblastoma (GBM) is a highly angiogenic malignancy, and its abundant, aberrant neovascularization is closely related to the proliferation and invasion of tumor cells. However, anti-angiogenesis combined with standard radio-/chemo-therapy produces little improvement in treatment outcomes. Determining the reason for treatment failure is pivotal for GBM treatment. Here, histopathological analysis and dynamic contrast-enhanced MRI (DCE-MRI) were used to explore the effects of temozolomide (TMZ) and bevacizumab (BEV) on GBM neovascularization patterns in an orthotopic U87MG mouse model at 1, 3 and 6 days after treatment. We found that the amount of vascular mimicry (VM) significantly increased 6 days after BEV treatment. TMZ inhibited neovascularization at an early stage, but the microvessel density (MVD) and transfer coefficient (Ktrans) derived from DCE-MRI increased 6 days after treatment. TMZ and BEV combination therapy slightly prolonged the inhibitory effect on tumor microvessels. Sprouting angiogenesis was positively correlated with Ktrans in all treatment groups. The increase in VM after BEV administration and the increase in MVD and Ktrans after TMZ administration may be responsible for treatment resistance. Ktrans holds great potential as an imaging biomarker for indicating the variation in sprouting angiogenesis during drug treatment for GBM.

Increasing of Blood-Brain Tumor Barrier Permeability through Transcellular and Paracellular Pathways by Microbubble-Enhanced Diagnostic Ultrasound in a C6 Glioma Model.

Most of the anticancer agents cannot be efficiently delivered into the brain tumor because of the existence of blood-brain tumor barrier (BTB). The objective of this study was to explore the effect of microbubble-enhanced diagnostic ultrasound (MEUS) on the BTB permeability and the possible mechanism. Glioma-bearing rats were randomized into three groups as follows: the microbubble-enhanced continued diagnostic ultrasound (MECUS) group; the microbubble-enhanced intermittent diagnostic ultrasound (MEIUS) group and the control group. The gliomas were insonicated through the skull with a diagnostic ultrasound and injected with microbubbles through the tail veins. Evans Blue (EB) and dynamic contrast-enhanced-MRI were used to test changes in the BTB permeability. Confocal laser scanning microscopy was used to observe the deposition of the EB in the tumor tissues. The distribution and expression of junctional adhesion molecule-A (JAM-A) and calcium-activated potassium channels (KCa channels) were detected by a Western blot, qRT-PCR, and immunohistochemical staining. In the MEUS groups, the EB extravasation (11.0 ± 2.2 µg/g in MECUS group and 17.9 ± 2.3 µg/g in MEIUS group) exhibited a significant increase compared with the control group (5.3 ± 0.9 µg/g). The MEIUS group had more EB extravasation than the MECUS group. The Ktrans value of the dynamic contrast-enhanced-MRI in the MEUS groups was higher than that of the control group and correlated strongly with the EB extravasation in the tumor (R2 = 0.97). This showed that the Ktrans value might be a non-invasive method to evaluate the BTB permeability in rat glioma after microbubble-enhanced ultrasound treatment.Western blot, qRT-PCR and immunohistochemical staining revealed that MEUS increased the KCa channels expression and reduced JAM-A expression in glioma. This change was more obvious in the MEIUS group than in the MECUS group. The results demonstrated that MEUS effectively increased the BTB permeability in glioma. The mechanisms might involve the up-regulation of KCa channels expression and affecting the formation of tight junctions in the BTB by a reduction of JAM-A expression. These findings might provide some new guidance for glioma drug therapy.

Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

Application of iron oxide nanoparticles in glioma imaging and therapy: from bench to bedside.

Gliomas are the most common primary brain tumors and have a very dismal prognosis. However, recent advancements in nanomedicine and nanotechnology provide opportunities for personalized treatment regimens to improve the poor prognosis of patients suffering from glioma. This comprehensive review starts with an outline of the current status facing glioma. It then provides an overview of the state-of-the-art applications of iron oxide nanoparticles (IONPs) to glioma diagnostics and therapeutics, including MR contrast enhancement, drug delivery, cell labeling and tracking, magnetic hyperthermia treatment and magnetic particle imaging. It also addresses current challenges associated with the biological barriers and IONP design with an emphasis on recent advances and innovative approaches for glioma targeting strategies. Opportunities for future development are highlighted.

The expression of P2X7 receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas.

In order to use endothelial progenitor cells (EPCs) as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas, how to enhance proliferation and targeting ability of transplanted EPCs is a high priority. Here, we confirmed, for the first time, the expression of P2X7 receptors in rat spleen-derived EPCs. Activation of P2X7 receptors in EPCs by BzATP promoted cells proliferation and migration, rather than apoptosis. In vivo, the homing of transplanted EPCs after long-term suppression of P2X7 receptors by persistent BBG stimulation was evaluated by MRI, immunohistochemistry and flow cytometry. Compared to the group without BBG treatment, less transplanted EPCs homed to gliomas in the group with BBG treatment, especially integrated into the vessels containing tumor-derived endothelial cells in gliomas. Moreover, western blot showed that CXCL1 expression was downregulated in gliomas with BBG treatment, which meant P2X7 receptors suppression inhibited the homing of EPCs to gliomas through down-regulation of CXCLl expression. Further, effects of P2X7 receptors on C6 glioma cells or gliomas were evaluated at the same dose of BzATP or BBG used in EPCs experiments in vitro and in vivo. MTT assay and MRI revealed that P2X7 receptors exerted no significant promoting effect on C6 glioma cells proliferation, gliomas growth and angiogenesis. Taken together, our findings imply the possibility of promoting proliferation and targeting ability of transplanted EPCs to brain gliomas in vivo through P2X7 receptors, which may provide new perspectives on application of EPCs as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas.

A new mosaic pattern in glioma vascularization: exogenous endothelial progenitor cells integrating into the vessels containing tumor-derived endothelial cells.

Emerging evidence suggests that glioma stem-like cells (GSCs) transdifferentiating into vascular endothelial cells (ECs) possibly contributes to tumor resistance to antiangiogenic therapy. Endothelial progenitor cells (EPCs), showing active migration and incorporation into neovasculature of glioma, may be a good vehicle for delivering genes to target GSCs transdifferentiation. Here, we found a new mosaic pattern that exogenous EPCs integrated into the vessels containing the tumor-derived ECs in C6 glioma rat model. Further, we evaluated the effect of these homing EPCs on C6 glioma cells transdifferentiation. The transdifferentiation frequency of C6 glioma cells and the expressions of key factors on GSCs transdifferentiation, i.e. HIF-1α, Notch1, and Flk1 in gliomas with or without EPCs transplantation showed no significant difference. Additionally, magnetic resonance imaging could track the migration and incorporation of EPCs into glioma in vivo, which was confirmed by Prussian blue staining. The number of magnetically labeled EPCs estimated from T2 maps correlated well with direct measurements of labeled cell counts by flow cytometry. Taken together, our findings may provide a rational base for the future application of EPCs as a therapeutic and imaging probe to overcome antiangiogenic resistance for glioma and monitor the efficacy of this treatment.