A surgical strategy using a fusion image constructed from 11C-methionine PET, 18F-FDG-PET and MRI for glioma with no or minimum contrast enhancement.

The objective of this study was to investigate the distribution of 11C-methionine (MET) and F-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) imaging and the hyperintense area in T2 weighted imaging (T2WI) in glioma with no or poor gadolinium enhancement in magnetic resonance imaging (GdMRI). Cases were also analyzed pathologically. We prospectively investigated 16 patients with non- or minimally enhancing (< 10% volume) glioma. All patients underwent MET-PET and FDG-PET scans preoperatively. After delineating the tumor based on MET uptake, integrated 3D images from FDG-PET and MRI (GdMRI, T2WI or FLAIR) were generated and the final resection plane was planned. This resection plane was determined intraoperatively using the navigation-guided fencepost method. The delineation obtained by MET-PET imaging was larger than that with GdMRI in all cases with an enhanced effect. In contrast, the T2WI-abnormal signal area (T2WI+) tended to be larger than the MET uptake area (MET+). Tumor resection was > 95% in the non-eloquent area in 4/5 cases (80%), whereas 10 of 11 cases (90.9%) had partial resection in the eloquent area. In a case including the language area, 92% resection was achieved based on the MET-uptake area, in contrast to T2WI-based partial resection (65%), because the T2WI+/MET- area defined the language area. Pathological findings showed that the T2WI+/MET+ area is glioma, whereas 6 of 9 T2WI+/MET- lesions included normal tissues. Tissue from T2W1+/MET+/FDG+/GdMRI+ lesions gave an accurate diagnosis of grade in six cases. Non- or minimally enhancing gliomas were classified as having a MET uptake area that totally or partially overlapped with the T2WI hyperintense area. Resection planning with or without a metabolically active area in non- or minimally enhancing gliomas may be useful for accurate diagnosis, malignancy grading, and particularly for eloquent area although further study is needed to analyze the T2WI+/MET- area.

Strategies and Pitfalls of Motor-Evoked Potential Monitoring during Supratentorial Aneurysm Surgery.

BACKGROUND: The aims of this study were to reveal the strategies and pitfalls of motor-evoked potential (MEP) monitoring methods during supratentorial aneurysm surgery, and to discuss the drawbacks and advantages of each method by reviewing our experiences. METHODS: Intraoperative MEP monitoring was performed in 250 patients. Results from 4 monitoring techniques using combinations of 2 stimulation sites and 2 recording sites were analyzed retrospectively. RESULTS: MEP was recorded successfully in 243 patients (97.2%). Direct cortical stimulation (DCS)-spinal recorded MEP (sMEP) was used in 134 patients, DCS-muscle recorded MEP (mMEP) in 97, transcranial electrical stimulation (TES)-mMEP in 11 and TES-sMEP in 1. TES-mMEP during closure of the skull was used in 21 patients. DCS-mMEP was able to detect waveforms from upper and/or lower limb muscles. Alternatively, DCS-sMEP (direct [D]-wave) could accurately estimate amplitude changes. A novel "early warning sign" indicating ischemia was found in 21 patients, which started with a transiently increased amplitude of D-wave and then decreased after proximal interruption of major arteries. False-negative findings in MEP monitoring in 2 patients were caused by a blood insufficiency in the lenticulostriate artery and by a TES-sMEP recording, respectively. CONCLUSIONS: The results of this study suggest that to perform accurate MEP monitoring, DCS-mMEP or DCS-sMEP recording should be used as the situation demands, with combined use of TES-mMEP recording during closure of the skull. DCS-sMEP is recommended for accurate analysis of waveforms. We also propose a novel "early warning sign" of blood insufficiency in the D-wave.

MRI findings and pathological features in early-stage glioblastoma.

Magnetic resonance imaging (MRI) is an important diagnostic tool for glioblastoma, with almost all cases showing characteristic imaging findings such as a heterogeneous-ring enhanced pattern associated with significant edema. However, MRI findings for early-stage glioblastoma are less clear. In this study, a retrospective review of MRI findings in five patients showed slight T2WI signal changes on initial scans that developed into typical imaging findings of a ring-like or heterogeneously enhanced bulky tumor within 6 months. The diagnoses based on initial MRI were low grade glioma in three cases, venous thrombosis in one case, and uncertain in one case. Four cases were treated with gross total resection, while one case underwent biopsy. Immunohistochemical examinations showed that two cases were p53-positive, and that all cases were IDH1 R132H-negative and had overexpression of EGFR. FISH analysis showed that all cases were 1p19q LOH-negative. De novo glioblastoma was the final diagnosis in all cases. Our results show that initial MRI findings in early-stage glioblastoma of small ill-defined T2WI hyperintense lesions with poor contrast develop to bulky mass lesions with typical findings for glioblastoma in as short a period as 2.5 months. The early MRI findings are difficult to distinguish from those for non-neoplastic conditions, including ischemic, degenerative or demyelinating processes. Thus, there is a need for proactive diagnosis of glioblastoma using short-interval MRI scans over several weeks, other imaging modalities, and biopsy or resection, particularly given the extremely poor prognosis of this disease.

Fatty acid binding protein 7 as a marker of glioma stem cells.

Glioblastomas are the most aggressive brain tumors. Glioblastoma stem cells (GSCs) are thought to be responsible for the recurrence, chemoresistance, and poor prognosis of glioblastoma. Fatty acid binding protein 7 (FABP7), which is a cellular chaperone for a variety of omega-3 fatty acids, is a known marker for neural stem cells. In this study, using a newly developed anti-FABP7 antibody and patient-derived GSC lines, we evaluated the expression of FABP7 in GSCs. Using immunocytochemistry, Western blotting, and qPCR analyses, FABP7 was found to be highly enriched in GSCs and its localization was found in cytosol and nuclei. FABP7 expression was significantly downregulated in differentiated GSCs induced by the addition of serum. In the glioma surgical specimens, FABP7 was highly expressed in the majority of glioblastoma. Double immunostaining for FABP7 and Sox2 showed that FABP7(+) Sox2(+) tumor cells were significantly increased in glioblastoma (grade IV) compared with diffuse astrocytoma (grade II) and anaplastic astrocytoma (grade III). Our data introduces FABP7 as a marker for GSCs and further highlights its possible significance for glioma diagnosis and treatment.

Multidrug chemotherapy, whole-brain radiation and cytarabine therapy for primary central nervous system lymphoma in elderly patients with dose modification based on geriatric assessment: study protocol for a phase II, multicentre, non-randomised study.

INTRODUCTION: Multidrug chemoimmunotherapy with rituximab, high-dose methotrexate, procarbazine and vincristine (R-MPV) is a standard therapy for younger patients with primary central nervous system lymphoma (PCNSL); however, prospective data regarding its use in elderly patients are lacking. This multi-institutional, non-randomised, phase II trial will assess the efficacy and safety of R-MPV and high-dose cytarabine (HD-AraC) for geriatric patients with newly diagnosed PCNSL. METHODS AND ANALYSIS: Forty-five elderly patients will be included. If R-MPV does not achieve complete response, the patients will undergo reduced-dose, whole-brain radiotherapy comprising 23.4 Gy/13 fractions, followed by local boost radiotherapy comprising 21.6 Gy/12 fractions. After achieving complete response using R-MPV with or without radiotherapy, the patients will undergo two courses of HD-AraC. All patients will undergo baseline geriatric 8 (G8) assessment before HD-AraC and after three, five and seven R-MPV courses. Patients with screening scores of ≥14 points that decrease to <14 points during subsequent treatment, or those with screening scores <14 points that decrease from the baseline during subsequent treatment are considered unfit for R-MPV/HD-AraC. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, treatment failure-free survival and frequency of adverse events. The results will guide a later phase III trial and provide information about the utility of a geriatric assessment for defining chemotherapy ineligibility. ETHICS AND DISSEMINATION: This study complies with the latest Declaration of Helsinki. Written informed consent will be obtained. All participants can quit the study without penalty or impact on treatment. The protocol for the study, statistical analysis plan and informed consent form have been approved by the Certified Review Board at Hiroshima University (CRB6180006) (approval number: CRB2018-0011). The study is ongoing within nine tertiary and two secondary hospitals in Japan. The findings of this trial will be disseminated through national and international presentations and peer-reviewed publications. TRIAL REGISTRATION: jRCTs061180093.

[Insular psammomatous meningioma presenting intractable complex partial seizures].

We describe a 30-year-old female with intractable symptomatic epilepsy caused by an insular calcified mass, which was histologically proved as psammomatous meningioma. Seizures were described as consciousness impairment, motionless stare and automatism. After total removal of the tumor with a neuronavigation system and motor evoked potential (MEP) monitoring, seizures completely disappeared without neurological deficit. We emphasize that insular meningioma presents complex partial seizures which mimic medial temporal lobe epilepsy and seizures are controlled by total resection of the tumor.

Murine embryonic stem cell-derived pyramidal neurons integrate into the cerebral cortex and appropriately project axons to subcortical targets.

Although embryonic stem (ES) cells have been induced to differentiate into diverse neuronal cell types, the production of cortical projection neurons with the correct morphology and axonal connectivity has not been demonstrated. Here, we show that in vitro patterning is critical for generating neural precursor cells (ES-NPCs) competent to form cortical pyramidal neurons. During the first week of neural induction, these ES-NPCs begin to express genes that are specific for forebrain progenitors; an additional week of differentiation produces mature neurons with many features of cortical pyramidal neurons. After transplantation into the murine cerebral cortex, these specified ES-NPCs manifest the correct dendritic and axonal connectivity for their areal location. ES-NPCs transplanted into the deep layers of the motor cortex differentiate into layer 5 pyramidal neurons and extend axons to distant subcortical targets such as the pons and as far caudal as the pyramidal decussation and descending spinal tract and, importantly, do not extend axons to inappropriate targets such as the superior colliculus (SC). ES-NPCs transplanted into the visual cortex extend axons to the dorsal aspect of the SC and pons but avoid ventral SC and the pyramidal tract, whereas cells transplanted deep into the somatosensory cortex project axons to the ventral SC, avoiding the dorsal SC. Thus, these data establish that ES-derived cortical projection neurons can integrate into anatomically relevant circuits.

Benign fibrous histiocytoma of the skull with increased intracranial pressure caused by cerebral venous sinus occlusion.

The authors present a very rare case of benign fibrous histiocytoma of the skull with increased intracranial pressure caused by sinus occlusion. A 33-year-old woman was referred for investigation of a right occipital protrusion with tenderness and double vision. She had only mild divergence insufficiency and bilateral papilledema neurologically. Imaging findings showed that the skull tumor was located at the right occipital bone with bone disruption and a compressed right sigmoid sinus. When planning the resection, caution was required to spare the collateral flow so as to manage the intracranial pressure. Immunohistochemical analysis showed that the tumor was positive for CD68, alpha1-antichymotrypsin, and alpha1-antitrypsin. From these findings, the tumor was diagnosed as a primary benign fibrous histiocytoma of the skull.

Successful treatment of a case of tentorial dural arteriovenous fistula causing subarachnoid hemorrhage with invagination of the brainstem by huge and multiple venous pouches.

BACKGROUND: We present a case of tentorial dural arteriovenous fistula (TDAVF) causing subarachnoid hemorrhage with mass effect of large venous pouches, which was struggling to diagnosis and management due to complex vasculature and severe general condition. CASE DESCRIPTION: A 43-year-old man was transferred to our hospital due to sudden consciousness disturbance. A neurological examination revealed tetraparesis and pupil dilatation with no light reflex. Imaging findings showed a large lesion in the brainstem with subarachnoid and intraventricular hemorrhage. Since there were multiple feeding arteries and large and multiple venous pouches on vascular imaging, we diagnosed the patient with TDAVF. Because of a high-flow arteriovenous shunt and the presence of large venous pouches, it appeared to be very difficult to approach the shunting point by direct surgery. Therefore, we first performed transarterial endovascular treatment with 25% n-butyl-2-cyanoacrylate to shrink the venous pouches and to reduce the pressure of the posterior fossa, followed by direct radical interruption of the shunting point using the craniotomy maneuver. Postoperative vascular imaging revealed disappearance of abnormal feeding arteries, draining veins, and venous pouches. The patient was discharged and transferred to a rehabilitation hospital with a modified Rankin Scale Score of 3. Accurate interpretation of the detailed vasculature preoperatively and an appropriate treatment strategy using endovascular and direct surgical technique are required to achieve a satisfactory outcome for difficult-to-treat dural arteriovenous fistulas. CONCLUSIONS: This combined maneuver with endovascular embolism as complementary pretreatment for radical surgery is useful for a case with high-flow shunting and large venous pouches.

Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model.

Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic (DA) neurons. ES cells are currently the most promising donor cell source for cell-replacement therapy in PD. We previously described a strong neuralizing activity present on the surface of stromal cells, named stromal cell-derived inducing activity (SDIA). In this study, we generated neurospheres composed of neural progenitors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, acts synergistically with FGF2 to increase the number of DA neurons in ES cell-derived neurospheres. We also analyzed the effect of transplantation of DA neurons generated from monkey ES cells into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated (MPTP-treated) monkeys, a primate model for PD. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons and attenuated MPTP-induced neurological symptoms.

Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells.

Embryonic stem (ES) cells are a promising donor source for transplantation therapy, but several problems must be solved before they can be clinically useful. One of these is the host immune reaction to allogeneic grafts. In this article, we examine the effect of the host immune reaction on survival and differentiation of grafted ES cell-derived neural precursor cells (NPCs). We induced NPCs from mouse ES cells by stromal cell-derived inducing activity and then transplanted them into mouse brains with or without administering the immunosuppressant cyclosporine A (CsA). Two and 8 weeks following transplantation, the accumulation of host-derived microglia/macrophages and lymphocytes was observed around the graft. This effect was reduced by CsA treatment, although no significant difference in graft volume was observed. These data suggest that an immune response occurs in allografts of ES cell-derived NPCs. Intriguingly, however, the ratio of neurons to astrocytes in the graft was higher in immunosuppressed mice. Because inflammatory or immune cells produce various cytokines, we examined the effect of IL-1beta, IL-6, IFN-gamma, and TNF-alpha on the differentiation of NPCs in vitro. Only IL-6 promoted glial cell fate, and this effect could be reversed by the addition of an IL-6 neutralizing antibody. These results suggest that allogeneic ES cell-derived NPCs can cause an immune response by the host brain, but it is not strong enough to reject the graft. More important, activated microglia and lymphocytes can suppress neuronal differentiation of grafted NPCs in vivo by producing cytokines such as IL-6.

Avoidance of ischemic complications after resection of a brain lesion based on intraoperative real-time recognition of the vasculature using laser speckle flow imaging.

OBJECTIVE To avoid ischemic complications, it is important to consider the arteries in resection planning for lesions such as a vascular intraparenchymal tumor and arteriovenous malformation. Here, the clinical application of laser speckle flow imaging (LSFI) as a complementary method for the management of mass lesion-related arteries during surgery was evaluated. METHODS LSFI was performed in 12 patients with mass lesion-related arteries and brain tumor or arteriovenous malformation. The portable LSFI device was centered over the surgical field, and the relative cerebral blood flow (CBF) before and after the temporary interruption of the arteries was measured through continuous recording. CBF fluctuations permitted the classification of 3 kinds of artery-a feeding artery (FA), a "passing through" artery (PA), and a combined FA and PA (FA+PA)-based on decreased relative CBF in the inner resection area and unchanged CBF in the surrounding area (FA), unchanged CBF in the inner area and decreased CBF in the surrounding area (PA), or decreased CBF in both areas (FA+PA). This information allowed the appropriate management of these arteries and avoidance of postoperative ischemic complications. RESULTS Good visualization of CBF in the surgical field and relative CBF measurements in the regions of interest were achieved in real time with excellent spatiotemporal resolution. In 11 patients (92%) and 20 regions of interest, a decline in CBF was observed after temporary interruption of the FA (n = 8), PA (n = 2), and FA+PA (n = 2) types. There was a significant average reduction in CBF of 15.3% ± 29.0%. There were no ischemic complications, and only 1 patient had a postoperative ischemic lesion caused by resection through an artery that could not be viewed by LSFI due to a positional problem. CONCLUSIONS LSFI permits noninvasive and rapid intraoperative real-time recognition of mass lesion-related vasculature. This information can be used to avoid ischemic complications as a procedure complementary to neurophysiological monitoring.

Metastatic cerebellar tumor of papillary thyroid carcinoma mimicking cerebellar hemangioblastoma.

INTRODUCTION: Well-differentiated papillary thyroid carcinoma generally (PTC) have a favorable prognosis. This metastasis is rare in the central nervous system. Brain metastasis has a relatively poor prognosis. We present a rare case of cerebellar metastasis, one that mimics a solid type cerebellar hemangioblastoma and because of which it was very hard to reach accurate preoperative diagnosis. Accurate diagnosis was challenging because of the similar imaging and histopathological findings for these two tumors. CASE DESCRIPTION: A brain lesion was detected by routine medical checkup of the brain with MRI in a 49-year-old woman 2 years after thyroidectomy for well-differentiated PTC. Gadolinium-enhanced MRI showed a homogeneous prominently enhanced lesion with surrounding enhanced dilated vessels in the left cerebellar hemisphere. Digital subtraction angiography showed a strongly stained lesion fed by the peripheral branch of the left posterior inferior cerebellar artery with drainage into the inferior vermian vein, revealing arteriovenous shunting. The most like likely preoperative diagnosis was felt to be that of a solid cerebellar hemangioblastoma. Gross total resection of the tumor was achieved by bilateral suboccipital craniotomy, and intraoperative pathological analysis suggested hemangioblastoma. Histopathological findings showed proliferation of vacuolated sheeted tumor cells with clear and eosinophilic cytoplasm and numerous thin-walled microvessels, consistent with hemangioblastoma. However, the final diagnosis was brain metastasis of the follicular variant of PTC due to a partial thyroid follicle-like pattern including eosinophilic fluid pathologically and positive TTF-1 immunostaining. DISCUSSION AND EVALUATION: Since presented rare case of cerebellar metastasis of PTC was very similar to solid type cerebellar hemangioblastoma on imaging and histopathological findings, accurate diagnosis was challenging. Moreover, it is extremely rare for a cerebellar metastasis to occur as an initial distant metastasis of PTC, and hemangioblastoma is the most common primary cerebellar neoplasm in adults. This epidemiological data was also one of the reason of difficulty to reach preoperative accurate diagnosis. CONCLUSIONS: To the best of our knowledge, there are no other reports of challenging diagnosis case of these two tumors in the literature. Brain metastasis of a well-differentiated PTC could be a relatively poor prognostic factor, and accurate diagnosis and suitable surgical therapy or radiotherapy are needed.

Epithelioid/rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma.

Epithelioid glioblastoma (GBM) and rhabdoid GBM are rare variants that are morphologically similar, but there is no consensus on the characteristics of each disease. These tumors have aggressive features of early recurrence and leptomeningeal dissemination and tend to develop in younger patients compared to typical GBM. The prognosis is normally worse than typical GBM, even with intensive chemoradiotherapy after surgical resection. Thus, accurate diagnosis and effective therapy for epithelioid/rhabdoid GBM are required. Four consecutive patients aged 16-48 years were diagnosed with epithelioid/rhabdoid GBM by pathological and immunohistochemical analysis at Yamaguchi University Hospital from 2006 to 2012. Two of these patients had relatively long-term survival (19 and 23 months after diagnosis). Two cases had a BRAF V600E mutation, whereas no ATRX mutation was present in any cases. All patients suffered leptomeningeal and/or spinal dissemination that worsened their prognosis. These results illustrate the need for a new therapeutic approach, such as molecular targeted drug therapy like BRAF inhibition, in addition to standard chemoradiotherapy for typical GBM.

Vaccine therapy for murine glioma using tumor cells genetically modified to express B7.1.

OBJECTIVE: In a syngeneic mouse brain tumor model, we tested the hypothesis that vaccination with tumor cells genetically modified to express B7.1 molecules induces tumor-specific T cells and immunological antitumor effects. METHODS: Malignant glioma cells (RSV-MG) derived from a C3H/He mouse induced by Schmidt-Ruppin Rous sarcoma virus (RSV) were infected with an adenovirus encoding the B7.1 gene (AdB7). To investigate the effects of B7.1 expression on the tumorigenicity of RSV-MG cells, infected cells were implanted subcutaneously into C3H/He mice. The C3H/He mice were vaccinated with AdB7 transfectants injected subcutaneously and 2 weeks later were challenged intracerebrally with wild-type RSV-MG cells to determine whether or not the expression of B7.1 would enhance the immunogenicity of RSV-MG cells. RESULTS: Immunocytochemistry confirmed the expression of B7.1 and major histocompatibility complex Class I antigen on the infected cells. The growth of subcutaneous tumors was markedly retarded in the AdB7 group, whereas tumors had formed and progressively increased in size in the other control groups. In the vaccine experiments, the mice immunized with AdB7 transfectants survived longer than did the mice of the other groups, and a significant difference in survival times was noted. Immunocytochemistry revealed that brain tumors in mice previously vaccinated with AdB7 infectants had been infiltrated by a larger number of CD3(+) lymphocytes and that these CD3(+) lymphocytes contained not only CD4(+) and CD8(+) T cells but also CD25(+)-activated T cells. In addition, a cytotoxicity assay confirmed that vaccination with the AdB7 transfectants induced tumor-specific cytotoxicity. CONCLUSION: These results demonstrate the therapeutic potential of vaccination with tumor cells expressing B7.1 for the treatment of malignant glioma.

Ictal onset and spreading of seizures of parietal lobe origin.

The characteristics of seizures associated with parietal lobe epilepsy were investigated in six consecutive patients with medically intractable epilepsy due to parietal lobe lesions. Intracranial electrode recordings were retrospectively reviewed to investigate the seizure onset symptoms and spreading patterns associated with the disorder. All six patients underwent implantation of subdural or depth electrodes and subsequent video/electroencephalography monitoring. Common symptoms included motionless stare, contralateral eye deviation, and head turn. Tonic posturing, contralateral sensory disturbance, and motor weakness were also seen. Asymmetrical generalized tonic and clonic seizures were seen in all six patients. All seizure activities began in the parietal lobe harboring the lesions, and then spread immediately to the adjacent lobes in most seizures, where the clinical symptoms were produced. The parietal lobe is a pure generator of seizures, whereas most clinical symptoms originate from adjacent lobes following seizure onset. No apparent specific symptoms other than sensory disturbance arising from the parietal lobe proper were recognized. Regardless of clinical symptoms, the seizure onset occurred in the parietal lobe harboring the lesion.

[A case of a ruptured dermoid cyst in the sylvian fissure].

A 22-year-old woman was admitted to our department after developing a headache. The neurological findings were unremarkable on her first visit, but CT demonstrated a lot of low-density masses in the subarachnoid space. The largest mass was in the right sylvian fissure. These lesions appeared hyper-intense in T1, T2 and diffusion-weighted MR images. A right frontotemporal craniotomy was performed to remove the main mass lesion in the right sylvian fissure. During surgery, thickening of the arachnoid membrane and floating oily globules were seen in the subarachnoid space. The histopathological examination revealed that the tumor was a dermoid cyst. Follow-up MRI revealed that some of the small lesions had moved since the operation. These findings suggested that the tumor was a ruptured dermoid cyst. The patient's postoperative course was uneventful and her headache disappeared completely.