Published papers

Aims Histological invasion into the adjacent brain parenchyma is frequently investigated in meningioma because it is an important morphological criterion for grade II meningioma according to the 2016 WHO classification. However, few studies have focused on dural invasion of meningiomas. Herein, we propose a novel histopathological classification based on dural invasion of meningiomas. Methods Forty-nine cases with WHO grade I meningiomas who underwent Simpson grade I removal were collected. After the meningeal layer (ML) and periosteal layer (PL) of dura mater were visualised by Masson's trichrome stain, we evaluated the depth (to the ML and PL) and the patterns (1, expanding; 2, infiltrating) of dural invasion of meningiomas using serial paraffin sections. Invasion-associated markers, including Ki-67, matrix metalloproteinase (MMP)-1, MMP-9 and MMP-13, aquaporin 1 and Na-K-2Cl cotransporter, were quantitatively analysed by immunohistochemistry. Results Thirty-five cases (71.4%) showed the dural invasion. In 27 of these 35 cases (77.1%), dural invasion was localised in ML. Type 1 (expanding type) and type 2 (infiltrating type) invasions were observed in 23 and 12 cases, respectively. The recurrence rate in cases with type 2 invasion was significantly higher than that in cases with type 1 invasion. The percentage of MMP-1-positive tumour cells was also significantly higher in cases with dural invasion than those without, suggesting involvement of MMP-1 in dural invasion. Conclusions We quantitatively evaluated the depth and patterns of dural invasion in meningiomas. The patterns of dural invasion were associated with meningioma recurrence.

© 2018 Surgical Neurology International | Published by Wolters Kluwer - Medknow. Background: Meningiomas originate from meningothelial cells of the arachnoid membrane. Few cases of meningioma with infiltration of inflammatory cells, such as lymphocytes and plasma cells, have been reported, and the mechanisms underlying meningioma-induced inflammatory reactions have not been fully elucidated. Case Description: In this study, we report an extremely rare case of meningioma with infiltration of both IgG4-positive plasma cells and eosinophils showing extensive dural tail and reactive inflammation of the surrounding arachnoid tissue. The main clinical manifestation was a severe headache, which was improved by surgical excision of the tumor. Conclusion: Only 8 cases of meningioma with IgG4-positive plasma cells have been reported, and only one case exhibited eosinophil infiltration. IgG4-related inflammatory response might mediate inflammation in surrounding tissue, resulting in thickening of the dura adjacent to a meningioma and severe headache. The mechanisms underlying inflammation by meningiomas require further investigation.

Background: The flow dynamics of the intracranial venous channels are fundamentally important for understanding intracranial physiology and pathophysiology. However, the method clinically applicable to the evaluation of the flow dynamics of the intracranial venous system has not been well described in the reported data. We have developed a new method to evaluate intracranial venous flow direction and velocity using 4-dimensional (4D) computed tomography angiography (CTA). The aim of the present study was to verify the accuracy and validity of 4D-CTA in a clinical setting. Methods: We retrospectively analyzed 97 veins from 26 patients (16 cases of arteriovenous shunt disease, 9 intracranial tumor cases, and 1 cerebral aneurysm case) who had undergone both 4D-CTA and conventional digital subtraction angiography (DSA). Using 4D-CTA, we analyzed the time-density curve with gamma distribution extrapolation and obtained the direction of the flow and flow velocity of each vein. The direction of the flow in 4D-CTA was also collated with that obtained using conventional DSA to verify the experimental method. Results: The direction of the flow determined by 4D-CTA was consistent with that of conventional DSA in 94.8% of cases. The average venous flow velocity was 64.3 mm/second and 81.8 mm/second, respectively, in the antegrade and retrograde channels affected by arteriovenous shunts. Conclusions: The present flow analysis using 4D-CTA enabled us to evaluate the direction and velocity of intracranial venous flow. Other than some limitations, the presented method is reliable and its potential for application in clinical settings is promising.

Anti-angiogenic therapy, targeting vascular endothelial growth factor (VEGF)-A/VEGF receptors (VEGFRs), is beneficial for tumor growth prevention in a malignant glioma. A simultaneous blockade using both bevacizumab (Bev), which targets circulating VEGF-A, and a multi-kinase inhibitor on VEGFRs was more effective for advanced solid cancers, including melanoma and renal cell carcinoma. However, previous clinical trials demonstrated a high adverse event rate. Additionally, no studies previously assessed treatment efficacy and safety using both VEGF-A and VEGFR-targeted agents for malignant gliomas. We had conducted clinical trials investigating VEGFRs peptide vaccination in patients with malignant gliomas, in which the treatment exhibited safety and yielded therapeutic effects in some patients. The combined use of Bev and VEGFRs vaccination may enhance the anti-tumor effect in malignant gliomas. In this pilot study, the adverse event profile in patients treated with Bev after the vaccination was investigated to establish this treatment strategy, in comparison to those treated with Bev collected from the published data or treated with the vaccination alone. In our previous clinical studies on patients with malignant gliomas, Bev was administered to 13 patients after VEGFRs vaccinations. One patient had a Grade 4 pulmonary embolism. Two patients had Grade 2 cerebral infarctions. There were no significant differences in the adverse event rates among patients treated with Bev, with the vaccination, or with Bev after the vaccination. Although careful observation is imperative for patients after this combination treatment strategy, VEGFRs-targeted vaccination may coexist with Bev for malignant gliomas.

OBJECTIVE The anterior transpetrosal approach (ATPA) was established in 1984 and has been particularly effective for petroclival tumors. Although some complications associated with this approach, such as venous hemorrhage in the temporal lobe and nervous disturbances, have been resolved over the years, the incidence rate of CSF leaks has not greatly improved. In this study, some varieties of air cell tracts that are strongly related to CSF leaks are demonstrated. In addition, other pre- and postoperative risk factors for CSF leakage after ATPA are discussed. METHODS Preoperative and postoperative target imaging of the temporal bone was performed in a total of 117 patients who underwent ATPA, and various surgery-related parameters were analyzed. RESULTS The existence of air cells at the petrous apex, as well as fluid collection in the mastoid antrum detected by a postoperative CT scan, were possible risk factors for CSF leakage. Tracts that directly connected to the antrum from the squamous part of the temporal bone and petrous apex, rather than through numerous air cells, were significantly related to CSF leak and were defined as “direct tract.” All patients with a refractory CSF leak possessed “unusual tracts” that connected to the attic, tympanic cavity, or eustachian tube, rather than through the mastoid antrum. CONCLUSIONS Preoperative assessment of petrous pneumatization types is necessary to prevent CSF leaks. Direct and unusual tracts are particularly strong risk factors for CSF leaks.

Background: Vascular endothelial growth factor (VEGF)-A and VEGF receptor expression in the peritumoral brain zone (PBZ) differs from that in the tumor core (TC) of glioblastoma. To date, no comparative study has investigated the expression of immunosuppressive cells in the PBZ and TC of glioblastoma. Methods: In 10 patients with newly diagnosed glioblastoma, we used immunohistochemistry to analyze the expression of VEGF-A, hypoxia-inducible factor-1α, programmed cell death-1 (PD-1), Foxp3, CD163, CD4, and CD8 to assess the immunosuppressive microenvironment. Results: The number of Foxp3 and CD163 cells was significantly greater in the TC than in the PBZ and correlated with greater expression of hypoxia-inducible factor-1α and VEGF-A in the TC than in the PBZ. The number of CD8 T cells was lower in the TC than in the PBZ, and the TC had more PD-1 CD8 T cells compared with the PBZ. These results suggest that the hypoxic condition could be associated with PD-1 expression on lymphocytes, the distribution of Foxp3 regulatory T cells and CD163 tumor-associated macrophages. Conclusions: The present study reports the first clinicopathologic features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between the TC and PBZ of glioblastoma. + + + + + + +

Background: Visual field deterioration caused by secondary empty sella after cabergoline therapy for prolactinoma is a rare event. Chiasmapexy is performed to treat empty sella syndrome. Although various materials have been used for the elevation of the optic chasm, the most appropriate material remains to be established. Here, we describe the efficiency of chiasmapexy for empty sella syndrome following dopamine agonist treatment and the utility of septal cartilage and sphenoidal sinus bone as materials for chiasmapexy. Case Description: A 35-year-old male with a history of cabergoline therapy for prolactinoma presented with visual deterioration. His magnetic resonance imaging revealed optic chiasm herniation into the empty sella. Endoscopic endonasal transsphenoidal chiasmapexy was performed using septal cartilage and sphenoidal sinus bone as materials for elevating the chiasm. Visual function improved immediately after operation. Conclusions: Chiasmapexy is an effective surgical method for treating visual deterioration caused by empty sella after cabergoline treatment. Endoscopic endonasal chiasmapexy with septal cartilage and sphenoidal sinus bone is a considerable option because it is minimally invasive and involves decreased risk of infection.

Background: Ossifying fibroma arising in the sinonasal tract is rare. Its treatment includes complete resection; however, this can be challenging to perform due to the well-vascularized nature of the fibroma. Some surgical techniques can control intraoperative hemorrhage; however, to date, no reports have assessed the use of preoperative embolization. Methods: We report a case of a child with ossifying fibroma arising from the ethmoid sinus, which was resected by endoscopic surgery using preoperative transarterial embolization. Conclusions: Embolization was effective in decreasing intraoperative hemorrhage. No complications related to the procedure or operation were encountered. Preoperative embolization should be considered for better control of the bleeding that occurs in ossifying fibromas, similar to that in other well-vascularized tumors.

Background: The pterygovaginal artery (PtVA), a recurrent branch of the internal maxillary artery (IMA), can be a feeder of skull base tumors. Preoperative embolization can help endoscopic resection of hypervascular lesions, which is performed under a narrow surgical space with restricted instrumental maneuverability. Methods: We performed preoperative embolization in five cases with hypervascular skull base lesions supplied by the PtVA, four of which were resected via endoscopic endonasal approach. In two cases, selective PtVA embolization through the distal IMA was successfully conducted. Results: In all the cases, intraoperative bleeding during endoscopic resection was easily controlled. The medial and lateral origins of the PtVA from the IMA were demonstrated by cone-beam CT images reconstructed from three-dimensional rotational angiography, and anastomoses around the eustachian tube and soft palate were visualized by superselective angiography. Conclusions: The PtVA embolization can be an effective strategy before endoscopic skull base tumor resection. When embolizing through the PtVA, clinicians should be aware of its anatomical variations and dangerous anastomoses. Understanding the surrounding angioarchitecture by angiographic techniques helps ensure safe embolization.

The subtemporal approach is applied to the middle cranial fossa and infratemporal fossa in addition to the tentorial incisura, petroclivus, and brain stem lesions. To minimize compression damage to the temporal lobe, it is essential to perform the craniotomy along the middle cranial fossa, to remove the zygomatic arch for supratentorial lesions, and to remove the petrous pyramid for infratentorial lesions. To avoid venous damage, the drainage pathways of the superficial sylvian vein and bridging veins, including Labbé’s vein, should be preoperatively evaluated. Furthermore, with the recent advances in endoscopic surgery, it has become possible to approach the middle cranial fossa and infratemporal fossa endonasally. In the endonasal approach, surgical simulation is important because of the variations in the nasal cavity and paranasal sinus structures. In this article, we outline the surgical anatomy of the middle cranial fossa required for the subtemporal approach, including the endonasal approach, and variations in the venous drainage of the superficial sylvian vein and petrosal vein. Moreover, we describe the treatment of pontine lesions by the subdural subtemporal approach, Meckel cave lesions by the epidural subtemporal approach, petroclival lesions by the anterior transpetrosal approach, and infratemporal lesions by the endonasal approach.

Trigeminal schwannomas can develop anywhere along the course of the trigeminal root, ganglion, and nerve branches. The most frequent tumor site is Meckel’s cave. The tumor, is dumbbell in shape, often extends to the posterior cranial fossa. A series of surgical approaches, which primarily include skull base extradural approaches, used for the management of trigeminal schwannomas has been discussed based on tumor site. More recently, an endoscopic endonasal approach has been used for lesions in Meckel’s cave, pterygoid palatine fossa, and infratemporal fossa. This article describes anatomy‒based surgical approaches for the management of trigeminal schwannoma and surgical approaches aimed at functional preservation.

© 2018 Elsevier Inc. An understanding of the anatomy and function of the skull base venous channels is fundamentally important for safe performance of endoscopic surgery for skull base lesions. This review focuses on 4 skull base venous channels—namely, the intercavernous sinuses, basilar plexus, osseous veins, and inferior petroclival vein—because these have been less recognized by neurosurgeons than other major venous channels such as the inferior petrosal sinus. We reviewed the literature concerning these 4 venous channels and discussed their anatomy and function. The literature review was mainly based on an electronic search in PubMed using the following terms: “intercavernous sinus,” “basilar plexus,” “emissary veins,” “diploic vein,” “basilar plexus,” “intraosseous vein,” “inferior petroclival/petro-occipital vein,” and “transclival.” A total of 50 articles were included in this review. Detailed anatomic features of the 4 structures have been elucidated in the literature. All of these venous channels run along the skull base and have multiple connections with surrounding venous structures. Because of their location, they occasionally obstruct the surgical view and are sometimes implicated in intraoperative hemorrhage, air embolism during endoscopic skull base surgery, and postoperative hematoma. They usually function as a venous reservoir of cranial venous drainage; however, they are less often directly involved in normal brain perfusion. Knowledge about the functional and morphologic anatomy of the skull base venous channels is important for neurosurgeons to avoid unexpected complications during endoscopic skull base surgery.

© 2018 Elsevier Inc. Background: Although there are several surgical approaches for the treatment of tuberculum sellae (TS) meningiomas, clear indications for non–large TS meningiomas are still lacking. Methods: Our case series included 20 patients with TS meningiomas (<3 cm). We classified the tumors into 3 groups based on their radiologic relationship with the optic chiasm: type I, tumor with intact optic chiasm; type II, tumor with superiorly deviated optic chiasm; and type III, tumor with posteriorly deviated optic chiasm. Clinical outcomes, radiologic findings, and surgical approaches for the removal of each tumor type were retrospectively reviewed. Results: Resections using a pterional approach, interhemispheric approach, and an endoscopic endonasal approach were performed in three groups of 6, 7, and 7 patients. The rate of total tumor resection was equivalent across approaches, whereas postoperative visual dysfunction was observed in 1 patient (7.69%) undergoing a transcranial approach. Our evaluation of the sphenoid sinus shape across radiographs revealed that the patterns of bony wall elongation attached to these tumors significantly differed among tumor types, indicating that tumor origin and growth direction might affect the patterns of optic chiasm deviation. In addition, selective elongation of the TS provided a favorable surgical corridor for an endoscopic endonasal approach, especially in type II tumors. These results indicate that this tumor classification influenced surgical approach selection for non–large TS meningiomas. Conclusions: The aim of surgery is maximal tumor resection without causing visual dysfunction. The classification proposed here may predict surgical risk associated with meningioma resection and further inform the selection of a surgical approach.

© 2018 Georg Thieme Verlag KG Stuttgart . New York. Objective The main purpose of this article is to assess the effectiveness and safety of surgery via the endoscopic endonasal approach (EEA) for cavernous sinus (CS) lesion in patients with nonfunctioning pituitary adenomas (NFPA). Design Retrospective study. Setting Keio University Hospital. Participants Thirty patients who underwent CS surgery via the EEA between 2009 and 2017 for Knosp grade 4 NFPA with pre- and postoperative magnetic resonance imaging available for volumetric analysis. Main Outcome Measures Clinical presentation, extent of resection, and surgical complications. Results Gross total and near total resection of CS tumors was achieved in 12/30 (40%) cases of Knosp grade 4 NFPA. The average resection rate of CS lesions in these 30 patients was 73.5%; 77.3% in primary cases and 70.1% in recurrent cases that did not vary significantly. Preoperative visual disturbance and oculomotor nerve palsy improved in 12/19 (63.1%) and - (60%) cases, respectively. Complications associated with CS via the EEA were postoperative cerebrospinal leakage (1/30, 3.3%), meningitis (1/30, 3.3%), and transient cranial nerve palsy (2/30, 6.7%). These complications except a case of mild transient abducens nerve palsy occurred in recurrent cases with subdural lesions. Conclusions Although the optimal management of CS lesions in NFPA is controversial, debulking via the EEA is an effective and safe option that improves neurological symptoms and enables effective adjuvant radiotherapy. Recurrent cases with subdural invasion are technically challenging, even using the EEA, and special care is required to avoid complications.

Background: Anterior transpetrosal approach (ATPA) and lateral suboccipital approach (LSO) are the major surgical approaches for cerebellopontine angle (CPA) meningiomas. Particularly, anterior CPA meningiomas are challenging lesions to be treated surgically. To date, only a few studies have directly compared the outcomes of both approaches focusing on the anterior CPA meningiomas. Methods: For the comparative analysis, anterior CPA meningiomas that were eligible for both APTA and LSO were collected in our hospital from April 2005 to March 2017. Anterior CPA meningiomas targeted for this study were defined as follows: (1) without cavernous sinus, clivus, and middle cranial fossa extension, (2) the posterior edge is 1 cm behind the posterior wall of the internal auditory canal, and (3) the inferior edge is above the jugular tuberculum. Based on these criteria, the operative outcomes of 17 patients and 13 patients who were operated via ATPA and LSO were evaluated. Results: The complication rate of the LSO group was significantly higher than that of the ATPA group (30.7% vs. 0%, p = 0.033). The removal rate did not differ between the ATPA and LSO groups (97.35% vs. 99.23%, p = 0.12). The operative time was significantly shorter in the LSO group than in the ATPA group (304.3 min vs. 405.8 min, p = 0.036). Conclusions: Although the LSO is more widely used for CPA meningiomas, ATPA is also considered for these anterior CPA meningiomas.

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-β and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.

Sinking skin flap syndrome is a craniectomy complication characterized by new neurological dysfunction that typically worsens in the upright position and improves after cranioplasty. We present a 33-year-old man who experienced hemiparesis in the upright position after craniectomy. Upright computed tomography (CT) before cranioplasty showed a remarkable shift of the brain compared to supine CT. After cranioplasty, both symptoms and brain shift on CT resolved. Upright CT enables detection and objective evaluation of paradoxical herniation and midline shift that is not obvious on supine imaging modalities. Clinicians need to be aware of positional brain shift in postcraniectomy patients.

Background: Lateral ventricular meningioma (LVM) is a rare entity, accounting for 0.5%–5% of all intracranial meningiomas. This type of meningioma arises from meningothelial inclusion bodies in the tela choroidea and/or mesenchymal stroma of the choroid plexus. Although not yet fully characterized, a membranous structure is frequently observed around LVMs. This study analyzed quiescent and activated fibroblast phenotypes in LVMs with focus on the relationship between tumor growth and development of the membranous structure. Methods: This retrospective study analyzed 9 LVM cases for which gross total removal was achieved. Expression of the ependymal cell marker (Forkhead Box J1 [FoxJ1]) was histopathologically evaluated. The distribution of quiescent and activated fibroblasts was also analyzed using anti-fibroblast-specific protein-1 (FSP1)/S100A4 antibody and anti-α-smooth muscle actin (αSMA) antibody, respectively. The control group was 5 cases with primary convexity meningioma for which Simpson grade I removal was achieved. Results: Small LVMs (≤30 mm) were covered by a FoxJ1-positive(+) ependymal cell monolayer; no αSMA(+) cells were detected in the tumor; and a thick membrane capsule was not observed. None of the convexity meningiomas showed FoxJ1(+) cells. Large LVMs (>30 mm) had thick membrane capsules without an ependymal cell monolayer, which resembled dura mater. The FSP1/S100A4(+) and αSM(+) cells were clearly concentrated in the peripheral area just below the thick dura mater-like membrane capsules. Conclusions: This study found an association between activated fibroblasts and dura mater–like membrane capsules in LVMs. The characteristics of membranous structure in LVMs may differ depending on tumor size.

Malignant glioma, which is characterized by diffuse infiltration into the normal brain parenchyma, is the most aggressive primary brain tumor with dismal prognosis. Over the past 40 years, the median survival has only slightly improved. Therefore, new therapeutic modalities must be developed. In the 1990s, suicide gene therapy began attracting attention for the treatment of malignant glioma. Some clinical trials used a viral vector for suicide gene transduction; however, it was found that viral vectors cannot cover the large invaded area of glioma cells. Interest in this therapy was recently revived because some types of stem cells possess a tumor-tropic migratory capacity, which can be used as cellular delivery vehicles. Immortalized, clonal neural stem cell (NSC) line has been used for patients with recurrent high-grade glioma, which showed safety and efficacy. Embryonic and induced pluripotent stem cells may be considered as sources of NSC because NSC is difficult to harvest, and ethical issues have been raised. Mesenchymal stem cells are alternative candidates for cellular vehicle and are easily harvested from the bone marrow. In addition, a new type of nonlytic, amphotropic retroviral replicating vector encoding suicide gene has shown efficacy in patients with recurrent high-grade glioma in a clinical trial. This replicating viral capacity is another possible candidate as delivery vehicle to tackle gliomas. Herein, we review the concept of suicide gene therapy, as well as recent progress in preclinical and clinical studies in this field.