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Transsphenoidal endoscopic endonasal surgery (EES) provides effective treatment for patients with lesions of the sella turcica. The endoscopic technique requires different instrumentation, which depends on the gross anatomy of the nasal cavity. The treatment of lateral lesions is more challenging in EES.To evaluate the effect of preoperative simulation using multiple anatomic landmarks.Pre- and postoperative tumor volumes were analyzed in 33 patients with nonfunctioning pituitary adenomas who underwent EES (Knosp grades 3 and 4). The surgical working angle and space were three-dimensionally simulated at the plane of the anterior/posterior surgical field (tuberculum sellae/posterior clinoid process) using multiple anatomic landmarks of high-resolution computed tomography scans, such as nasal piriform aperture (proximal surgical corridor), and the width of bilateral vidian canals or lamina perpendicularis of palatine bone (distal surgical corridor). Receiver operating characteristic curves for the removed tumor volume were used to determine the cutoff value for the simulated working angle and space.Simulated working space at the plane of tuberculum sellae using piriform aperture and lamina perpendicularis of palatine bone was associated with the removed tumor volume in the cavernous sinus. Patients with a larger working space (≥42.7 mm) significantly showed a higher removed tumor volume ( P = .023). There was no relationship between other parameters and the removed tumor volume.A new method to predict the surgical field for cavernous sinus lesions around sella turcica was successfully established. Further studies are needed to define and expand applications of this simulation method.

Epilepsy is a neurological disorder with abnormal brain activity. It causes convulsions or periods of unusual behavior, sensations, and sometimes loss of awareness. Drug-resistant epilepsy (DRE) affects an estimated 15%-20% of patients with epilepsy. Vagus nerve stimulation (VNS) is a type of neuromodulation. VNS therapy is an adjunctive neurostimulation treatment for DRE patients who are unsuitable for respective surgery or have experienced unsuccessful surgery. VNS involves the use of a device to stimulate the vagus nerve with electrical impulses. VNS is not a cure for epilepsy, and most epilepsy patients can still experience seizures or use epilepsy medication after the procedure. However, 60%-70% of patients can have over 50% reduction in seizures 5 years after the VNS procedure. Seizure intensity may also reduce. VNS is safe with tolerable side effects in most cases. The mechanism of VNS action against epilepsy is still not accurately verified. Some people believe that VNS therapy improves their mood, memory, or alertness and may also help reduce depression. VNS therapy is also expected to work in other indications, including psychiatric, gastrointestinal, endocrinological, and immunological disorders.

Background Posterior fossa arachnoid cysts are often asymptomatic, but can rarely cause postural headache, the mechanism of which remains unknown. Case Description We present a 40-year-old woman with an asymptomatic supracerebellar arachnoid cyst. Upright computed tomography (CT) showed enlargement of the arachnoid cyst and caudal descent of the cerebellum compared with supine CT with narrowing of the craniocervical junction cerebrospinal fluid space. Conclusions This finding aids in understanding the association of posterior fossa arachnoid cysts with orthostatic headache. Clinicians should be aware of possible posture-related changes in intracranial structures.

A number of studies have reported the involvement of the ventral hippocampus (vHip) and the lateral septum (LS) in negative emotional responses. Besides these well‐documented functions, they are also thought to control feeding behavior. In particular, optogenetic and pharmacogenetic interventions to LS‐projecting vHip neurons have demonstrated that the vHip→LS neural circuit exerts an inhibition on feeding behavior. However, there have been no reports of vHip neuronal activity during feeding. Here, we focused on LS‐projecting vCA1 neurons (vCA1→LS) and monitored their activity during feeding behaviors in mice. vCA1→LS neurons were retrogradely labeled with adeno‐associated virus carrying a ratiometric Ca2+ indicator and measured compound Ca2+ dynamics by fiber photometry. We first examined vCA1→LS activity in random food‐exploring behavior and found that vCA1→LS activation seemed to coincide with food intake; however, our ability to visually confirm this during freely moving behaviors was not sufficiently reliable. We next examined vCA1→LS activity in a goal‐directed, food‐seeking lever‐press task which temporally divided the mouse state into preparatory, effort, and consummatory phases. We observed vCA1→LS activation in the postprandial period during the consummatory phase. Such timing‐ and pathway‐specific activation was not observed from pan‐vCA1 neurons. In contrast, reward omission eliminated this activity, indicating that vCA1→LS activation is contingent on the food reward. Sated mice pressed the lever significantly fewer times but still ate food; however, vCA1→LS neurons were not activated, suggesting that vCA1→LS neurons did not respond to habitual behavior. Combined, these results suggest that gastrointestinal interoception rather than food‐intake motions or external sensations are likely to coincide with vCA1→LS activity. Accordingly, we propose that vCA1→LS neurons discriminate between matched or unmatched predictive bodily states in which incoming food will satisfy an appetite. We also demonstrate that vCA1→LS neurons are activated in aversive/anxious situations in an elevated plus maze and tail suspension test. Future behavioral tests utilizing anxious conflict and food intake may reconcile the multiple functions of vCA1→LS neurons.

Since the venous system is affected by gravity, upright computed tomography (CT) in addition to conventional supine CT has great potential for evaluating postural changes in the venous system. We evaluated the morphological differences in the head and neck vessels by performing a contrast CT study in both the supine and the sitting positions. In this study, the 20 included participants (10 men and 10 women) were healthy adults aged 30 to 55 years. The cross-sectional area of the cervical vessels, craniocervical junction veins, and intracranial vessels were obtained quantitatively. Venous sinuses and venous plexuses that were difficult to measure were evaluated qualitatively. The average change in areas from a supine to an upright posture was − 77.87 ± 15.99% (P P P P P P

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.

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. 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. 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). Although the LSO is more widely used for CPA meningiomas, ATPA is also considered for these anterior CPA meningiomas.

Considering that seizure freedom is one of the most important goals in the treatment of epilepsy, repeat epilepsy surgery could be considered for patients who continue to experience drug-resistant seizures after epilepsy surgery. However, the chance of seizure freedom is reported to be below 50% after reoperation for failed epilepsy surgery. This study aimed to elucidate the predictive factors for seizure outcomes after repeat pediatric epilepsy surgery. In all, 39 pediatric patients who underwent repeat curative epilepsy surgery between 2008 and 2020 at our institution were retrospectively studied. The relationship between preoperative clinical factors and postoperative seizure freedom at the last follow-up was statistically evaluated. The mean age at the first surgery was 5.5 years (0-16). The etiology of epilepsy was malformation of cortical development in 33 patients. The average time to seizure recurrence after the first surgery was 6.4 months (range, 0-26 months). In all, 16 patients (41.0%) achieved seizure freedom after the second surgery. Seven patients underwent a third surgery, and three (42.9%) achieved seizure freedom. Overall, 19 patients achieved seizure freedom after repeat epilepsy surgery (48.7%). Female sex, surgical failure due to technical limitations, congruent electroencephalography (EEG) findings, lesional magnetic resonance imaging (MRI) and Rt-sided surgery were predictive of seizure freedom, and surgery limited to the temporal lobe was predictive of residual seizures, as determined in the multivariate analysis. The reoperation of failed epilepsy surgery is challenging. Consideration of the above predictive factors can be helpful in deciding whether to reoperate on pediatric patients whose initial surgical intervention failed.

Chordoma is a rare refractory neoplasm that arises from the embryological remnants of the notochord, which is incurable using any multimodality therapy. Vascular endothelial growth factor (VEGF) is a potent activator of angiogenesis that is strongly associated with the tumor-immune microenvironment. These factors have not been elucidated for chordomas. To evaluate the characteristics of vascular and tumor cells in chordoma, we first analyzed the expression of VEGF receptor (VEGFR) 1, VEGFR2, CD34, and Brachyury in a cell line and 54 tumor tissues. Patients with primary skull base chordomas were divided into the following two groups as per the tumor growth rate: patients with slow progression (SP

Background Angiosarcoma often arises as a cutaneous disease in the scalp and the face; however, subdural hematoma (SDH) associated with angiosarcoma is extremely rare. Case Description A 72-year-old woman visited our hospital with gait disorder and progressive consciousness disturbance approximately 3 months after a minor head injury. Initially, on reviewing the results of imaging studies, she was diagnosed with traumatic chronic SDH. Despite repeated operations thereafter, including the embolization of the middle meningeal artery, her general condition progressively worsened, and computed tomography of head repeatedly showed the recurrence of SDH. Based on histopathologic and intraoperative findings, she was finally diagnosed with angiosarcoma originating from the skull. She died shortly thereafter because of aggressive recurrent intracranial SDH caused by leptomeningeal dissemination. Conclusions In addition to cancers metastatic to the skull or dura mater, angiosarcoma should be included in the differential diagnosis for patients with repeated SDH and bone defect. An effective treatment for angiosarcoma with SDH that shows an unfavorable prognosis has not been established; however, an early diagnosis might be useful for a novel treatment.

Implantation of subdural electrodes on the brain surface is still widely performed as one of the “gold standard methods” for the presurgical evaluation of epilepsy. Stereotactic insertion of depth electrodes to the brain can be added to detect brain activities in deep-seated lesions to which surface electrodes are insensitive. This study tried to clarify the efficacy and limitations of combined implantation of subdural and depth electrodes in intractable epilepsy patients. Fifty-three patients with drug-resistant epilepsy underwent combined implantation of subdural and depth electrodes for long-term intracranial electroencephalography (iEEG) before epilepsy surgery. The detectability of early ictal iEEG change (EIIC) were compared between the subdural and depth electrodes. We also examined clinical factors including resection of MRI lesion and EIIC with seizure freedom. Detectability of EIIC showed no significant difference between subdural and depth electrodes. However, the additional depth electrode was useful for detecting EIIC from apparently deep locations, such as the insula and mesial temporal structures, but not in detecting EIIC in patients with ulegyria (glial scar). Total removal of MRI lesion was associated with seizure freedom. Depth electrodes should be carefully used after consideration of the suspected etiology to avoid injudicious usage.

BackgroundMeningiomas are the most common benign intracranial tumors. However, even WHO grade I meningiomas occasionally show local tumor recurrence. Prognostic factors for meningiomas have not been fully established. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor for several solid tumors. The prognostic value of NLR in meningiomas has been analyzed in few studies.Materials and MethodsThis retrospective study included 160 patients who underwent surgery for meningiomas between October 2010 and September 2017. We analyzed the associations between patients’ clinical data (sex, age, primary/recurrent, WHO grade, extent of removal, tumor location, peritumoral brain edema, and preoperative laboratory data) and clinical outcomes, including recurrence and progression-free survival (PFS).ResultsForty-four meningiomas recurred within the follow-up period of 3.8 years. WHO grade II, III, subtotal removal, history of recurrence, Ki-67 labeling index ≥3.0, and preoperative NLR value ≥2.6 were significantly associated with shorter PFS (P < 0.001, < 0.001, 0.002, < 0.001, and 0.015, respectively). Furthermore, NLR ≥ 2.6 was also significantly associated with shorter PFS in a subgroup analysis of WHO grade I meningiomas (P = 0.003). In univariate and multivariate analyses, NLR ≥2.6 remained as a significant predictive factor for shorter PFS in patients with meningioma (P = 0.014).ConclusionsNLR may be a cost-effective and novel preoperatively usable biomarker in patients with meningiomas.

We aimed to use upright computed tomography (CT) to depict posture-related changes in the brain tissue under normal gravity. Thirty-two asymptomatic volunteers underwent upright CT in the sitting position and conventional CT in the supine position on the same day. We compared the shift of the pineal body, cerebellar tonsil, the length of pituitary stalk, optic nerve sheath area and perimeter (ONSA and ONSP, respectively), and lateral ventricular volume between the supine and sitting positions. We also compared shape changes of the cerebrospinal fluid (CSF) spaces at different sites between both positions. In the sitting position, the pineal body shifted 0.68 ± 0.27 mm in the ventral direction and 0.76 ± 0.24 mm in the caudal direction, the length of pituitary stalk decreased by 1.23 ± 0.71 mm, the cerebellar tonsil descended by 2.10 ± 0.86 mm, the right ONSA decreased by 15.21 ± 6.54%, the left ONSA decreased by 15.30 ± 7.37%, the right ONSP decreased by 8.52 ± 3.91%, the left ONSP decreased by 8.20 ± 4.38%, and the lateral ventricular volume decreased by 5.07 ± 3.24% (all P

The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2.

The anti-VEGF antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Theoretically, vascular endothelial growth factor receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. Here we show an exploratory clinical study of VEGFRs peptide vaccine in seven patients with progressive NF2-derived schwannomas. Hearing improves in 2/5 assessable patients (40%) as determined by international guidelines, with increases in word recognition scores. Tumor volume reductions of ≥20% are observed in two patients, including one in which bevacizumab had not been effective. There are no severe adverse events related to the vaccine. Both VEGFR1-specific and VEGFR2-specific CTLs are induced in six patients. Surgery is performed after vaccination in two patients, and significant reductions in the expression of VEGFRs in schwannomas are observed. Therefore, this clinical immunotherapy study demonstrates the safety and preliminary efficacy of VEGFRs peptide vaccination in patients with NF2., The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Here, the authors show that VEGFRs peptide vaccination can improve hearing and reduce tumor volume in NF2 patients, including in previously bevacizumab resistant tumors.

Neurofibromatosis type 2 (NF2) patients uniformly develop multiple schwannomas. The tumor-microenvironment (TME) is associated with hypoxia and consists of immunosuppressive cells, including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). The hypoxic TME of NF2 schwannomas remains unclear. In addition, no comparative study has investigated immunosuppressive cells in NF2 and sporadic schwannomas. In 22 NF2 and 21 sporadic schwannomas, we analyzed the immunohistochemistry for Ki-67, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR2, platelet derived growth factor receptor-beta (PDGFR-β), programmed cell death-1 (PD-1)/ programmed cell death ligand-1 (PD-L1), Foxp3, CD163, CD3, and CD8 to assess the immunosuppressive TME. Most vessels in sporadic schwannomas exhibited slight or negative VEGFR1 and 2 expressions with pericytes coverage. In contrast, large vessels in NF2 schwannomas exhibited strong VEGFR1 and 2 expressions without pericytes. The number of CD3+, CD8+, and CD163+ cells was significantly higher in NF2 schwannomas than in sporadic ones. The expression of PD-L1 and nestin positive cell ratio was higher in NF2 schwannomas than that in sporadic ones. The number of CD163+ cells, nestin positive cell ratio, and HIF-1α expression were significantly associated with shorter progression-free survival in NF2 schwannomas. This study presents the clinicopathological features of the differences in immunosuppressive cells and the expression of immune checkpoint molecules between NF2 and sporadic schwannomas. Hypoxic TME was first detected in NF2-schwannomas, which was associated with the tumor progression.

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 ⅗ (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: Endoscopic endonasal transsphenoidal surgery (EES) is the gold standard for pituitary adenoma (PA) resection. The sphenoid sinus (SS), a highly variable anatomic structure, is located in the center of the cranial base. It has previously been reported that poor pneumatization of the lateral recess of the SS (LRSS) increases the difficulty level of the surgery and the risk of neural and vascular injury. However, to date no studies have evaluated the association between LRSS volume and PAs removal rate by EES. Methods: The present study analyzed 23 consecutive patients with new-onset PAs categorized as Knosp Grades 3 and 4 who underwent EES. A retrospective radiographic analysis was conducted on patients undergoing magnetic resonance imaging and high-resolution computed tomography scans. Results: Among PA cases categorized as Knosp 3 and 4, no significant association was found between the whole tumor’s resection rate and LRSS volume (R = 0.08, P = 0.70). However, a significant association was found between cavernous sinus (CS) tumors’ removal rate and LRSS volume (R = 0.52, P = 0.011). The same results were achieved in PAs with a Knosp Grade 4, with a stronger correlation (R = 0.60, P = 0.014). Conclusion: The development of LRSS pneumatization affects the removal rate of CS tumors in PAs. Preoperative analysis of LRSS development should be considered when planning EES against PA with CS invasion.

Cavernous sinus (CS) invasion is an aggressive behavior exhibited by pituitary neuroendocrine tumors (PitNETs). The cause of CS invasion in PitNETs has not been fully elucidated. The tumor immune microenvironment, known to promote aggressive behavior in various types of tumors, has not been examined for PitNETs. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is strongly associated with the tumor immune microenvironment. In the present study, these molecular and histopathological characteristics were examined in invasive non-functional PitNETs (NF-PitNETs). Twenty-seven patients with newly diagnosed NF-PitNETs (with CS invasion: 17, without CS invasion: 10) were analyzed by immunohistochemistry for VEGF-A/VEGFR1 and 2, hypoxia-inducible Factor (HIF), tumor-infiltrating lymphocytes, immunosuppressive cells including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and immune checkpoint molecules. Previously validated tumor proliferation markers including mitotic count, Ki-67 index, and p53 were also analyzed for their expressions in NF-PitNETs. VEGF-A and VEGFR1 were expressed on not only vascular endothelial cells, but also on tumor cells. The expressions of VEGF-A and VEGFR1 were significantly higher in NF-PitNETs with CS invasion. The number of TAMs and the expression of PD-L1 were also significantly higher in NF-PitNETs with CS invasion than in NF-PitNETs without CS invasion. The high expression of VEGF-A and VEGFR1 and associated immunosuppressive microenvironment were observed in NF-PitNETs with CS invasion, suggesting that a novel targeted therapy can be applied.

Objectives It is difficult to treat cavernous sinus (CS) meningiomas because of their complex vascular and neurological structures. Recently, immunotherapy has become an attractive therapeutic modality, but the role of tumor immune microenvironment is yet to be investigated for CS meningiomas. In the current study, these molecular and histopathological characteristics were examined in CS meningiomas. Methods The present study used twenty-eight meningioma tissues arising in two different locations (8 CS and 20 convexity meningiomas). Immunohistochemical analyses were performed with CD3, CD4, CD8, Foxp3, CD163, PDGFR-β, VEGF receptors 1 & 2 (VEGFR-1, VEGFR-2), VEGF-A and HIF-1α. Quantitative polymerase chain reaction (qPCR) was performed to assess the expression of Foxp3, VEGF-A, CD163, VEGFRs-1 & 2 and HIF-1α. Results The numbers of different tumor-infiltrating immune cells, such as immunosuppressive cells, were significantly lower in CS meningiomas compared with convexity meningiomas. Analysis of the vascular characteristics showed the vessels in the CS meningiomas were covered with PDGFR-β-positive pericytes and were negative or had only very low amounts of VEGFR-1 and VEGFR-2. However, most vessels in convexity meningiomas showed high VEGFRs expression and were not covered with pericytes. Immunohistochemical and qPCR analyses revealed that the expression of HIF-1α, VEGF-A and VEGFRs-1 & 2 was lower in CS meningiomas. Conclusion Fewer immunocompetent cells were observed in CS meningiomas compared with convexity meningiomas. Lower expression of VEGF-A, VEGFRs-1 and 2, and the vascular structure may contribute to this specific immune microenvironment.

Although most pituitary neuroendocrine tumors (PitNETs) show benign behavior, a significant number of PitNETs exhibit an aggressive course including cavernous sinus (CS) invasion. To date, the cause of CS invasion has not been fully elucidated. In this study, we analyzed the relationship between CS invasion in PitNETs and the expression of PITX2 and SNAIL1, which are the transcription factors associated with the morphogenesis of pituitary gland. Sixty cases with non-functional PitNETs were classified into four types: type 1a, none of CS invasion and suprasellar expansion; type 1b, suprasellar expansion without CS invasion; type 2a, CS invasion without suprasellar expansion; and type 2b, CS invasion with suprasellar expansion. We analyzed the expression of PITX2 and SNAIL1 employing quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry. Other parameters such as mitotic count, Ki-67 index, and p53 expression were also analyzed, which were previously reported as potential tumor proliferative markers in PitNETs. PITX2 expression was significantly higher in PitNETs with CS invasion than PitNETs without CS invasion (P = 0.019). Expression of SNAIL1 was significantly elevated in PitNETs with suprasellar expansion compared with PitNETs without suprasellar expansion (P = 0.02). There was no apparent relationship between CS invasion and mitotic count, Ki-67 index, and p53 expression (mitotic count, P = 0.11; Ki-67 index, P = 0.61; p53, P = 0.66). High PITX2 expression was observed in non-functional PitNETs with CS invasion, suggesting that PITX2 may be involved in CS invasion of PitNETs.

Background: There is no established therapy for neurofibromatosis type 2 (NF2). Bevacizumab has recently proved efficacious for the treatment of NF2, presumably because vascular endothelial growth factor (VEGF) is essential for NF2 tumor growth. Theoretically, VEGF receptors (VEGFRs)-specific cytotoxic T lymphocytes (CTLs) can kill both tumor vessel cells and tumor cells expressing VEGFRs. The aim of the current study was to evaluate the safety and efficacy of a VEGFRs peptide vaccine in NF2 patients. Methods: An exploratory clinical study of VEGFRs peptide vaccine was conducted in 7 patients with progressive NF2-derived schwannomas. Tumor volume and blood flow were analyzed via magnetic resonance imaging and computed tomography perfusion, and hearing was evaluated via word recognition scores (WRSs) and pure-tone audiograms. To investigate the therapeutic mechanisms involved in this novel therapy, CTL responses and VEGFRs expression in schwannomas were analyzed. Findings: Hearing improved in 3 of the 6 assessable patients (50%), with WRS increases of more than 10%. Reductions of > 20% in more than one tumor were observed in 2 patients, including a case in which bevacizumab had not been effective (case 6). There were no severe adverse events related to the vaccine. Both VEGFR1 specific and VEGFR2-specific CTLs were induced in 6 patients, and in the remaining patient VEGFR1-specific CTLs were induced. Histological analysis of schwannomas revealed high VEGFRs expression both in tumor vessels and in tumor cells. Surgery was performed after vaccination in two patients, and significant reductions in VEGFRs expression in schwannomas were observed. Interpretation: This is the first clinical immunotherapy study demonstrating the safety and efficacy of VEGFRs peptide vaccination in patients with NF2. Trial Registration Number: The trial was registered at UMIN (UMIN000023565). Funding Statement: The authors state: "None." Declaration of Interests: The authors have no personal financial or institutional interests in any of the drugs, materials, or devices mentioned in this article. Ethics Approval Statement: All protocols were approved by the Keio University Ethics Committee, and conducted in accordance with the Helsinki declaration on experimentation on human subjects.

Background There have been a few previous reports of trigeminal neuralgia caused by bony structures. We report a rare case of trigeminal neuralgia caused by petrous bone deformity. Case Description A-43-year-old man with facial pain in the left maxillary and mandibular divisions of the trigeminal nerve was referred to our hospital. Computed tomography showed bone hyperplasia protruding into the left cerebellopontine cistern, compressing the left trigeminal nerve. Administration of carbamazepine ameliorated facial pain, but the effect was unsatisfactory, and microvascular decompression was performed through the anterior transpetrosal approach. The protruding petrous bone was drilled out to release compression of the trigeminal nerve, thus straightening the deviated trajectory of the nerve. The superior cerebellar artery adjacent to the thickened petrosal bone seemed to have compressed the trigeminal nerve and was also transposed. The facial pain disappeared completely after microvascular decompression surgery. Conclusions The anterior transpetrosal approach is an appropriate and essential strategy for trigeminal neuralgia caused by petrous bone deformity of the petrous apex.

Highlights • Corpus callosotomy (CC) was performed in 3 pediatric patients with refractory epileptic encephalopathy with ESES. • IQ was improved after CC with complete resolution of ESES in one patient. • Developmental regression ceased after CC with worthwhile seizure reduction and temporary improvement of ESES in 2 patients. • Epileptiform discharges disappeared or became lateralized after CC., Epileptic encephalopathy with electrical status epilepticus during sleep (ESES) is often refractory to medical treatment and leads to poor cognitive outcomes. Corpus callosotomy may be an effective treatment option for drug-resistant ESES with no focal etiology. We retrospectively identified three patients who underwent corpus callosotomy for drug-resistant ESES in our institution. Electroencephalography (EEG) findings and cognitive functions were evaluated before surgery, at 3 months, 6 months, 1 year, and 2 years after surgery. Age at surgery was 6 years 10 months, 7 years 9 months, and 8 years 4 months, respectively. Period between the diagnosis of ESES and surgery ranged from 7 to 25 months. All patients had no obvious structural abnormalities and presented with cognitive decline despite multiple antiseizure medications and steroid therapies. One patient showed complete resolution of ESES and an improvement of intelligence quotient after surgery. Epileptiform EEG was lateralized to one hemisphere after surgery and spike wave index (SWI) was decreased with moderate improvement in development and seizures in the other 2 patients. SWI re-exacerbated from 6 months after surgery, but without subsequent developmental regression in these 2 patients. Corpus callosotomy may become an important treatment option for drug-resistant ESES in patients with no structural abnormalities.

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.

Following publication of the original article [1], the authors reported an error in the author group.

Skull base meningiomas (SBMs) are considered to be less aggressive and have a slower growth rate than non-SBMs. However, SBMs often develop local recurrences after surgical resection. Gross total removal is difficult because SBMs are deep-seated tumors and involve critical neurovascular structures. The treatment strategy for recurrent SBMs remains controversial. The present study aimed to evaluate the long-term clinical course and prognostic factors associated with shorter progression-free survival (PFS) of recurrent SBMs. This retrospective study included 85 recurrent SBMs from 65 patients who underwent surgery from January 2005 to September 2018. Overall survival (OS) and PFS were evaluated, and the associations among shorter PFS and age, sex, tumor size, lesions, World Health Organization (WHO) grading, removal rate, and time since prior surgery were analyzed. The median follow-up period for PFS was 68 months. The 2-, 5-, and 10-year PFS rates were 68.0%, 52.8%, and 22.7%, respectively. WHO grade II or III, multiple lesions, and tumor size were significantly associated with shorter PFS (p &lt, 0.0001, p = 0.030, and p = 0.173, respectively). Although, radiotherapy did not improve PFS and OS for overall patients, PFS of the patients with subtotal and partial removal for WHO grade II SBMs was significantly improved by the radiotherapy. Multivariate analysis identified WHO grade II or III and multiple lesions as independent prognostic factors for shorter PFS (p &lt, 0.0001 and p = 0.040, respectively). It is essential to estimate the risks associated with shorter PFS for patients with recurrent SBMs to aid in the development of appropriate postoperative strategies.

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: Intra or peritumoral hemorrhage of brain and skull tumors sometimes presents as stroke. Skull metastasis of chondrosarcoma is relatively rare, and furthermore, a case of intratumoural hemorrhage of skull metastasis of chondrosarcoma has not been reported. Case Description: A 73-year-old man underwent right lower leg amputation in the past because of chondrosarcoma and was operated for a skull metastasis. He presented with a sudden headache, and head computed tomography revealed a right acute subdural hematoma (SDH) adjacent to the recurrent skull metastatic tumor. The removal of the SDH and tumor resection were performed emergently. The intraoperative findings included metastatic invasion beyond the dura mater to as deep as the subdural space, and the histological diagnosis was metastatic chondrosarcoma. His postoperative course was uneventful. Conclusion: In the event of subdural invasion of a metastatic lesion, intratumoral hemorrhage may induce acute SDH, as in the present case. Similar to our case, most previous reports of intracranial chondrosarcoma hemorrhage have had an unclear etiology. Despite the rarity of this event, a patient with a history of malignancy presenting with nontraumatic acute SDH should be examined for the intratumoral hemorrhage of skull metastasis in the differential diagnosis.

Background Temozolomide (TMZ) is now standard adjuvant therapy in combination with radiotherapy for patients with newly diagnosed malignant glioma. Treatment-related myelodysplastic syndrome and acute treatment-related leukemia (t-AML) associated with TMZ chemotherapy for patients with glioma is quite a rare complication. Case Description A 43-year-old man with an anaplastic astrocytoma received radiation therapy synchronized with ranimustine and adjuvant TMZ chemotherapy for 15 cycles. Close follow-up magnetic resonance imaging of the head during TMZ chemotherapy showed no evidence of tumor progression. One year after the completion of TMZ chemotherapy, a bone-marrow aspiration was performed because the patient's white blood cell count decreased. He was diagnosed with t-AML based on the bone marrow examination, and then he was referred to the cancer center for the treatment of t-AML. Conclusions In this case study, we continued adjuvant TMZ therapy beyond the recommended 6 cycles. Currently, there is no consensus as to how long the adjuvant TMZ therapy should be continued for the treatment of residual tumor showing no apparent interval change. A new decision-making tool to assess the clinical benefits against the side effects for long-term adjuvant TMZ therapy is needed.

Cette note est le resultat d'une etude analytique des sables eoliens de la region de Shari. 25 echantillons collectionnes de la dune littorale actuelle ont ete examines suivant les methodes d'autrefois, en meme temps que ceux de la plage correspondante.A la granulometrie le principal element est compose habituellement de grains moyens et fins, environ 2.0phi pour Md; et it y a un'egalite quantitatif des fractions, autour de 0.5phi Pd, transportes en reptation et en saltation par l'action de vents forts dominants. On se trouve qu'une forte proportion des mineraux colores tien en taille de grains plus fins.L'indice d'emousse, la morphometrie, montre comme d'habitude plus grande valeur en comparaison des sables marins. Dans la classification de types des grains de sable, il est de toute evidence que l'eolisation au cours de la plage a la dune, a donne lieu a une superiorite des grains qui sont presque l'aspect intermediaire entre le RM-type franc et le EL-type franc.Leurs criteres distinguables dans la table 4 de qui chaque indice des sables eoliens et marins est montre seront appliques partiellement aux recherches de depots anciens.

This report is a part of the study based on writer's theoretical hypothesis that the abrasion benches along the rocky coast are minute-landforms which suggested the earthmovement in recent time (Holocence epoch).There are many kinds of benches, and they are classified as follows: high tide-, storm-, elevated-, submerged-, low, tide-and submarine-benches ; and severally have some properties. In this area these benches have been distributed on a small scale, sujecting many factors which are rock facies, geological structure, ocean-climete or weather, degree of abrasion or wave erosion and etc.At present time the hightide-benches showing the degree of waverosion and the form of earthmovement, conspicuously are characterized by the abrupt slope and the narrow width. I supposed that the elevated benches were formed by the elevation of land or the lowering of sea-level (before 3000 and 4000 years), and then gradually are changing into the storm bench by a storm-wave, but they have been remained at 4 to 5 M. height front of the sea cliff. The heights of storm benches, showing it of the storm-wave, become higher as approching the promontory.In the sea bottom (shallower than 50 to 60 M. depth), the eroded surfaces belonging to the submarine and lowtide-benches divided into three steps or more. The submarine benches, periodecally, would be formed by the submergence of land or uplifting of sea-level at the early stage of alluvial, and the low tide-benches (shallower than 10 M depth) would be done by the present wave erosion. These eroded surfaces have been in discordance with the depositional surfaces.In consequence, I guessed the northward area of Miyako is rising and the southward is sinking at present time.