Status of alternative angiogenic pathways in glioblastoma resected under and after bevacizumab treatment.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group (p = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group (p = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens (p = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns (p = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

An exploratory prospective phase II study of preoperative neoadjuvant bevacizumab and temozolomide for newly diagnosed glioblastoma.

PURPOSE: This multi-institutional phase I/II study was conducted to confirm the safety and explore the clinical utility of preoperative Bevacizumab (Bev) for newly diagnosed glioblastoma (GB). METHODS: Patients were enrolled based on magnetic resonance imaging (MRI) findings typically suggestive of GB. Preoperative Bev and temozolomide (TMZ) were administered at doses of 10 mg/kg on day 0 and 150 mg/m2 on days 1-5, respectively. Surgical resection was performed between days 21 and 30, inclusive. The safety and efficacy were evaluated in a total of 15 cases by progression-free survival (PFS), changes in tumor volume, Karnofsky Performance Scale (KPS) and Mini-Mental State Examination (MMSE) scores after preoperative therapy. RESULTS: Tumor resection was performed on a mean of day 23.7. Pathological diagnosis was GB, isocitrate dehydrogenase (IDH)-wildtype in 14 cases and GB, IDH-mutant in 1 case. Severe adverse events possibly related to preoperative Bev and TMZ were observed in 2 of the 15 patients, as wound infection and postoperative hematoma and thrombocytopenia. KPS and MMSE scores were significantly improved with preoperative therapy. Tumor volume was decreased in all but one case on T1-weighted imaging with contrast-enhancement (T1CE) and in all cases on fluid-attenuated inversion recovery, with mean volume decrease rates of 36.2% and 54.0%, respectively. Median PFS and overall survival were 9.5 months and 16.5 months, respectively. CONCLUSION: Preoperative Bev and TMZ is safe as long as the instructions are followed. The strategy might be useful for GB in some patients, not only reducing tumor burden, but also improving patient KPS preoperatively. TRIAL REGISTRATION NUMBER: UMIN000025579, jRCT1031180233 https://jrct.niph.go.jp/latest-detail/jRCT1031180233 . Registration Date: Jan. 16, 2017.

Prognostic survival biomarkers of tumor-fused dendritic cell vaccine therapy in patients with newly diagnosed glioblastoma.

Dendritic cell (DC)-based immunotherapy has been applied to glioblastoma (GBM); however, biomarkers informing response remain poorly understood. We conducted a phase I/IIa clinical trial investigating tumor-fused DC (TFDC) immunotherapy following temozolomide-based chemoradiotherapy in patients with newly diagnosed GBM and determined prognostic factors in patients receiving TFDC immunotherapy. Twenty-eight adult patients with GBM isocitrate dehydrogenase (IDH) wild-type (IDH-WT) were enrolled; 127 TFDC vaccine injections (4.5 ± 2.6 times/patient) were administered. Patients with GBM IDH-WT had a respectable 5-year survival rate (24%), verifying the clinical activity of TFDC immunotherapy, particularly against O6-methylguanine-DNA methyltransferase (MGMT) unmethylated GBM (5-year survival rate: 33%). To identify novel factors influencing overall survival (OS) in GBM IDH-WT treated with TFDC immunotherapy, clinical parameters were assessed and comprehensive molecular profiling involving transcriptome and exome analyses was performed. MGMT promoter methylation status, extent of tumor resection, and vaccine parameters (administration frequency, DC and tumor cell numbers, and fusion ratio) were not associated with survival following TFDC immunotherapy. Old age and pre- and post-operative Karnofsky performance status were significantly correlated with OS. Low HLA-A expression and lack of CCDC88A, KRT4, TACC2, and TONSL mutations in tumor cells were correlated with better prognosis. We validated the activity of TFDC immunotherapy against GBM IDH-WT, including chemoresistant, MGMT promoter unmethylated cases. The identification of molecular biomarkers predictive of TFDC immunotherapy efficacy in GBM IDH-WT will facilitate the design of and patient stratification in a phase-3 trial to maximize treatment benefits.

18F-Fluoromisonidazole-Positron Emission Tomography and Immunohistochemistry Verified Tumor Oxygenation, Stemness, and Immunosupportive Microenvironment After Preoperative Neoadjuvant Bevacizumab for Newly Diagnosed Glioblastoma.

BACKGROUND: Cancer stemness and immunosuppressive tumor microenvironment (TME) in accordance with tumor oxygenation are variable during bevacizumab (Bev) therapy for glioblastoma (GBM). Positron emission tomography (PET) using 18F-fluoromisonidazole (FMISO) reflects hypoxic TME. The aim of this study was to compare FMISO-PET and immunohistochemical findings of tumor oxygenation in the TME of GBM during Bev treatment. METHODS: Seven patients with newly diagnosed IDH-wildtype GBM underwent FMISO-PET during follow-up. Three patients received preoperative neoadjuvant Bev (neo-Bev) and subsequently underwent surgical resection. Reoperation was performed at the recurrence. FMISO-PET was performed before and after neo-Bev. Four patients who underwent tumor resection without neo-Bev were included as the control group. Expressions of hypoxic markers (carbonic anhydrase; CA9), stem cell markers (nestin, FOXM1), and immunoregulatory molecules (CD163, FOXP3, PD-L1) in tumor tissues were analyzed by immunohistochemistry (IHC). RESULTS: All 3 patients treated with neo-Bev showed decrease in FMISO accumulation in accordance with expressions of CA9 and FOXM1 compared with the control group. Two of these 3 patients at the recurrence showed increase in FMISO accumulation. IHC showed increased CA9-and FOXM1-positive cells in recurrent tumors. Expression of PD-L1 tended to be lower after neo-Bev compared with the control group. CONCLUSIONS: FMISO-PET effectively visualized TME oxygenation after neo-Bev. Increased FMISO accumulation at the time of recurrence, even under Bev treatment, suggests that FMISO-PET might be useful for monitoring the duration of Bev efficacy by reflecting tumor oxygenation.

Real Stiffness and Vividness Reproduction of Anatomic Structures Into the 3-Dimensional Printed Models Contributes to Improved Simulation and Training in Skull Base Surgery.

BACKGROUND: Despite the advancement of 3-dimensional (3D) printing technology with medical application, its neurosurgical utility value has been limited to understanding the anatomy of bones, lesions, and their surroundings in the neurosurgical field. OBJECTIVE: To develop a 3D printed model simulating the surgical technique applied in skull base surgery (SBS), especially to reproduce visually the surgical field together with the mechanical properties of tissues as perceived by the surgeon through procedures performance on a model. METHODS: The Young modulus representing the degree of stiffness was measured for the tissues of anesthetized animals and printing materials. The stiffness and vividness of models were adjusted appropriately for each structure. Empty spaces were produced inside the models of brains, venous sinuses, and tumors. The 3D printed models were created in 7 cases of SBS planned patients and were used for surgical simulation. RESULTS: The Young modulus of pig's brain ranged from 5.56 to 11.01 kPa and goat's brain from 4.51 to 13.69 kPa, and the dura of pig and goat values were 14.00 and 24.62 kPa, respectively. Although the softest printing material had about 20 times of Young modulus compared with animal brain, the hollow structure of brain model gave a soft sensation resembling the real organ and was helpful for bridging the gap between Young moduli values. A dura/tentorium-containing model was practical to simulate the real maneuverability at surgery. CONCLUSION: The stiffness/vividness modulated 3D printed model provides an advanced realistic environment for training and simulation of a wide range of SBS procedures.

Fully-Endoscopic Resection of Deep-Seated Pilocytic Astrocytoma Under 5-Aminolevulinic Acid Fluorescence Guidance: A Technical Note.

AIM: To improve the extent and safety of resecting these deep-seated tumors, we report a novel procedure of minimally invasive endoscopic resection of deep-seated pilocytic astrocytomas under the guidance of 5-aminolevulinic acid (5-ALA) fluorescence undescribed until now. CASE DESCRIPTION: A 53-year-old male presented with a gradually progressing mild right hemiparesis. Imaging studies showed a solid tumor with degenerative cystic formation in the left basal ganglia. The tumor was removed endoscopically via right frontal small craniotomy. The tumor was positive for 5-ALA fluorescence and allowed better detection of the dissection margin of the solid tumor from the surrounding brain tissue. The histopathological diagnosis was pilocytic astrocytoma. No recurrence was observed on follow-up magnetic resonance imaging (MRI) 2 years after surgery, and the patient was fully independent after rehabilitation. CONCLUSION: This minimally invasive technique, enhanced by intraoperative fluorescence, might be a safe and feasible alternative to open surgery in the removal of deeply located gliomas.

Impact of Neoadjuvant Bevacizumab on Neuroradiographic Response and Histological Findings Related to Tumor Stemness and the Hypoxic Tumor Microenvironment in Glioblastoma: Paired Comparison Between Newly Diagnosed and Recurrent Glioblastomas.

Background: Previously, we reported that bevacizumab (Bev) produces histological and neuroradiographic alterations including changes in tumor oxygenation, induction of an immunosupportive tumor microenvironment, and inhibition of stemness. To confirm how those effects vary during Bev therapy, paired samples from the same patients with newly diagnosed glioblastoma (GBM) who received preoperative neoadjuvant Bev (neoBev) were investigated with immunohistochemistry before and after recurrence. Methods: Eighteen samples from nine patients with newly diagnosed GBM who received preoperative neoBev followed by surgery and chemoradiotherapy and then autopsy or salvage surgery after recurrence were investigated. The expression of carbonic anhydrase 9 (CA9), hypoxia-inducible factor-1 alpha (HIF-1α), nestin, and Forkhead box M1 (FOXM1) was evaluated with immunohistochemistry.For comparison between neoBev and recurrent tumors, we divided the present cohort into two groups based on neuroradiographic response: good and poor responders (GR and PR, respectively) to Bev were defined by the tumor regression rate on T1-weighted images with gadolinium enhancement (T1Gd) and fluid-attenuated inversion recovery images. Patterns of recurrence after Bev therapy were classified as cT1 flare-up and T2-diffuse/T2-circumscribed. Furthermore, we explored the possibility of utilizing FOXM1 as a biomarker of survival in this cohort. Results: A characteristic "pseudo-papillary"-like structure containing round-shaped tumor cells clustered adjacent to blood vessels surrounded by spindle-shaped tumor cells was seen only in recurrent tumors. Tumor cells at the outer part of the "pseudo-papillary" structure were CA9-positive (CA9+)/HIF-1α+, whereas cells at the inner part of this structure were CA9-/HIF-1α+ and nestin+/FOXM1+. CA9 and HIF-1α expression was lower in T1Gd-GR and decreased in the "T2-circumscribed/T2-diffuse" pattern compared with the "T1 flare-up" pattern, suggesting that tumor oxygenation was frequently observed in T1Gd-GR in initial tumors and in the "T2-circumscribed/T2-diffuse" pattern in recurrent tumors. FOXM1 low-expression tumors tended to have a better prognosis than that of FOXM1 high-expression tumors. Conclusion: A "pseudo-papillary" structure was seen in recurrent GBM after anti-vascular endothelial growth factor therapy. Bev may contribute to tumor oxygenation, leading to inhibition of stemness and correlation with a neuroimaging response during Bev therapy. FOXM1 may play a role as a biomarker of survival during Bev therapy.

Avoidance and Improvement in Visual Field Defect After Surgery for Metastatic Brain Tumors in the Parietal and the Occipital Lobe.

OBJECTIVE: Visual field defects occasionally occur secondary to tumors in the parietal and the occipital lobes. The aim of this study was to analyze the efficacy of improvement in hemianopsia after surgery for metastatic brain tumors involving or adjacent to the optic radiation (OR). METHODS: The study included 49 patients with brain metastasis in the parietal and occipital lobes in the present study. Preoperative and postoperative neurological assessments included visual field, Mini-Mental State Examination, and Karnofsky performance scale. RESULTS: Of 49 patients, 33 (67.3%) presented with preoperative homonymous hemianopsia. Of these 33 patients, the visual field was improved postoperatively in 17 patients (51.5%). In all patients regardless of preoperative hemianopsia, postoperative visual fields did not deteriorate. Tractography demonstrated that the OR was split by the tumor (n = 6) and fanning of fibers expanded along the lateral side of the tumor (n = 11). All tumors were removed via surgical access toward the medial side of the tumor. Gross total resection was achieved in most tumors in the group with visual improvement (n = 16/17; 94.1%). Improvement in the visual field was attributed to tumor location in the subcortical white matter, removal rate of the tumor, and higher postoperative Karnofsky performance scale score. CONCLUSIONS: The OR tended to deviate to the lateral side of the tumor in the parieto-occipital junction. The postoperative visual field improved even in cases of an occipital tumor. Based on the present study, total resection via an appropriate surgical route should be considered to preserve the OR, leading to improvement in the postoperative visual field.

Differentiating between glioblastomas with and without isocitrate dehydrogenase gene mutation by findings on conventional magnetic resonance images.

Various studies using advanced techniques have estimated the isocitrate dehydrogenase (IDH) gene mutation status in glioblastoma (GBM) from preoperative images. However, it is important to be able to predict mutation status using conventional MRI, which is more widely used in clinical practice. In this study, we examined the features of GBM with and without IDH gene mutation on conventional MRI. Twenty-three patients with GBM in whom IDH gene mutation status had been pathologically and molecularly confirmed in tumor specimens were included. The cases were divided into an IDH-wildtype group (n = 17) and an IDH-mutant group (n = 6). We retrospectively compared the following imaging parameters between the two groups: tumor location (superficial or deep), borders on T2-weighted images (regular or irregular), borders of enhancing lesions (regular or irregular), number of lesions showing contrast enhancement (solitary or multiple), presence or absence of intralesional bleeding, and presence or absence of a low-grade glioma in the background around the enhancing lesion. IDH-wildtype tumors were significantly more likely to be superficial than were IDH-mutant tumors (p < 0.05). Enhancing lesions in the IDH-wildtype group were less likely to have an irregular border (p = 0.059). Low-grade glioma was a background lesion in 5 patients (83.3%) in the IDH-mutant group and 9 (52.9%) in the IDH-wildtype group. The IDH mutation status is likely to be wildtype in patients with superficial GBM in which the enhancing lesion has a regular border and when low-grade glioma is not found as a background lesion on MRI.

Anticancer Non-narcotic Opium Alkaloid Papaverine Suppresses Human Glioblastoma Cell Growth.

BACKGROUND: Glioblastoma (GBM) is the most aggressive type of primary malignant brain tumour. The interaction between high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) is important for tumour cell growth. Previously, we identified an anticancer candidate, papaverine, that inhibited the HMGB1-RAGE interaction. MATERIALS AND METHODS: Our study assessed the anticancer effects of papaverine alone or in combination with temozolomide on U87MG and T98G human GBM cells using clonogenicity assays, as well as in a U87MG xenograft mouse model. The radiosensitizing efficacy of papaverine was measured based on the clonogenicity of T98G cells. RESULTS: Papaverine significantly inhibited the clonogenicity of U87MG and T98G cells. Compared with single treatment, the combination of papaverine and temozolomide more highly suppressed the clonogenicity of T98G cells and delayed tumour growth in the U87MG xenograft mouse model. Furthermore, papaverine increased the radiosensitivity of T98G cells. CONCLUSION: Papaverine is a potential anticancer drug in GBM treatment.

The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications.

The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological "cold tumors" into the "hot tumors". Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.

Anticancer effects of a non-narcotic opium alkaloid medicine, papaverine, in human glioblastoma cells.

The interaction between high-mobility group box 1 protein (HMGB1) and receptor for advanced glycation end products (RAGE) is important for tumor cell growth. We investigated the tumor biological effects of HMGB1 and RAGE interaction. Previously, we identified an inhibitor of HMGB1/RAGE interaction, papaverine (a non-narcotic opium alkaloid), using a unique drug design system and drug repositioning approach. In the present study, we examined the anticancer effects of papaverine in human glioblastoma (GBM) temozolomide (TMZ; as a first-line anticancer medicine)-sensitive U87MG and TMZ-resistant T98G cells. HMGB1 supplementation in the culture medium promoted tumor cell growth in T98G cells, and this effect was canceled by papaverine. In addition, papaverine in T98G cells suppressed cancer cell migration. As an HMGB1/RAGE inhibitor, papaverine also significantly inhibited cell proliferation in U87MG and T98G cells. The effects of papaverine were evaluated in vivo in a U87MG xenograft mouse model by determining tumor growth delay. The results indicate that papaverine, a smooth muscle relaxant, is a potential anticancer drug that may be useful in GBM chemotherapy.

Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab.

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post-Bev recurrent tumors from 9 patients were included. The expression of programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD-L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD-1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post-Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long-term Bev therapy.

Dual role of macrophage in tumor immunity.

Macrophages are significant in immune responses, assuming a defensive role. In contrast, macrophages often cause undesirable changes. These reactions are processes by which macrophages express different functional programs in response to microenvironmental signals, defined as M1/M2 polarization. Tumor immunity has been acknowledged for contributing to the elucidation of the mechanism and clinical application in cancer therapy. One of the mechanisms for the refractoriness to cancer immunotherapy is the production of inhibitory cytokines by tumor cells or macrophages. Therefore, therapeutic strategy targeting macrophage or macrophage-derived cytokines may be effective and attractive. This review aims to investigate macrophage-associated pathophysiology and biological behavior in cancers, especially related to microenvironment, such as hypoxia, and current topics regarding some therapies involving macrophages.

"Paradoxical" findings of tumor vascularity and oxygenation in recurrent glioblastomas refractory to bevacizumab.

Anti-angiogenic therapy induces the apparent normalization of vascular structure, decreases microvessel density (MVD), and improves tumor oxygenation in glioblastomas (GBMs). Six initial and recurrent tumor pairs after bevacizumab (Bev) treatment were compared with GBMs from nine patients resected under neoadjuvant Bev treatment with regard to histological characteristics; MVD; MIB-1 index; and expression of vascular endothelial growth factor (VEGF) and its receptors, hypoxia markers (hypoxia-inducible factor 1 alpha, carbonic anhydrase 9), and nestin as a marker of glioma stem-like cells. In recurrent tumors post-Bev treatment, while the MVD remained low compared with the paired initial tumors (pre-Bev tumors), the expression of hypoxic markers were increased and were even higher in expression compared with the paired pre-Bev tumors in three of the six cases. MIB-1 indices were similar among the initial GBMs, neoadjuvant group, and recurrent tumors post-Bev treatment. The nestin-positive cell ratio of the post-Bev recurrent tumors was as high as that of the pre-Bev tumors. The expression of VEGF and VEGFR1 was increased in the post-Bev recurrent tumors in three and four cases, respectively, compared with the paired pre-Bev tumors. In the majority of Bev-refractory GBMs, tumor hypoxia was present with a paradoxical decrease in MVD. These findings suggest that re-activation of tumor angiogenesis is not initially involved in the acquisition of resistance to Bev.

[A Case of Amusia Following Right Temporal Subcortical Hemorrhage].

A woman in her 60s presented with amusia due to a localized subcortical hemorrhage of the right temporal lobe. No other symptoms of higher brain dysfunction or body paralysis were observed. One characteristic symptom in this case was rhythm impairment. Few cases of this impairment have been previously reported, and the responsible lesion and underlying mechanisms are still a matter of speculation. However, in this case, a relationship with the right temporal lobe was indicated.

Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma.

BACKGROUND: This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM). METHOD: GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient's PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays. RESULTS: FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays. CONCLUSIONS: The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

Imaging alterations due to squamous metaplasia in intracranial neurenteric cysts: A report of two cases.

Intracranial neurenteric cysts are rare congenital abnormalities with a broad imaging spectrum, and therefore are occasionally mistaken for other common intracranial cysts such as epidermoid and arachnoid cysts. We report two cases of neurenteric cysts in the posterior cranial fossa that were initially mistaken for other types of cysts. They exhibited signal intensity alterations in magnetic resonance imaging with significant volume expansion during their long-term observation. Both cases received surgical treatment because of clinical deterioration. Histologically, the cysts were lined by flattened or cuboidal epithelium, occasionally showing squamous metaplasia. Xanthogranulomatous inflammation and accumulation of cholesterol clefts, dry keratin and proteinaceous substance were observed in the cysts. These findings may indicate that chronic inflammation in neurenteric cysts induces squamous metaplasia, keratinization and high proteinaceous content, and causes MRI signal intensity alterations and volume expansion. We propose that MRI signal intensity alterations in neurenteric cysts may be a warning sign of their volume expansions, and thus require closer follow-up imaging and eventually surgical treatment.

BRAF V600E-mutated diffuse glioma in an adult patient: a case report and review.

Recent advances in genomic technology and genome-wide analysis have identified key molecular alterations that are relevant to the diagnosis and prognosis of brain tumors. Molecular information such as mutations in isocitrate dehydrogenase (IDH) genes or 1p/19q co-deletion status will be more actively incorporated into the histological classification of diffuse gliomas. BRAF V600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM. This mutation is relatively rare in other types of diffuse gliomas, especially in adult onset cases. Here, we present an adult onset case of IDH wild-type/BRAF V600E-mutated diffuse glioma, evolving from grade III to grade IV. The tumor displayed atypical exophytic growth and had unusual histological features not fully compatible with, but indicative of PXA and E-GBM. We discuss differential diagnosis of the tumor, and review previously described diffuse gliomas with the BRAF V600E mutation.