Yukihiko Fujii

Immunohistochemical profiles of IDH1, MGMT and P53: Practical significance for prognostication of patients with diffuse gliomas

Genetic and epigenetic status, including mutations of isocitrate dehydrogenase (IDH) and TP53 and methylation of O6‐methylguanine‐DNA methyltransferase (MGMT), are associated with the development of various types of glioma and are useful for prognostication. Here, using routinely available histology sections from 312 patients with diffuse gliomas, we performed immunohistochemistry using antibodies specific for IDH1 mutation, MGMT methylation status, and aberrant p53 expression to evaluate the possible prognostic significance of these features. With regard to overall survival (OS), univariate analysis indicated that an IDH1‐positive profile in patients with glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligoastrocytoma and oligodendroglioma, or a MGMT‐negative profile in patients with GBM and AA were significantly associated with a favorable outcome. Multivariate analysis revealed that both profiles were independent factors influencing prognosis. The OS of patients with IDH1‐positive/MGMT‐negative profiles was significantly longer than that of patients with negative/negative and negative/positive profiles. A p53 profile was not an independent prognostic factor. However, for GBM/AA patients with IDH1‐negative/MGMT‐negative profiles, p53 overexpression was significantly associated with an unfavorable outcome. Thus, the immunohistochemical profiles of IDH1 and MGMT are of considerable significance in gliomas, and a combination of IDH1, MGMT and p53 profiles may be useful for prognostication of GBM/AA.

Epstein‐Barr virus‐associated primary central nervous system cytotoxic T‐cell lymphoma

Primary central nervous system lymphoma (PCNSL) expressing T‐cell markers is rare, among which nasal‐type extranodal NK/T‐cell lymphoma is an extremely rare subtype associated with Epstein‐Barr virus (EBV) infection. Here we report the clinicopathologic features of a case of EBV‐associated PCNSL showing a cytotoxic T‐cell phenotype. The patient, a 73‐year‐old woman, presented with rapidly progressive mental deterioration. Brain MRI revealed multiple lesions with swelling in the bilateral cerebral hemispheres, which were hypointense on T1‐weighted images, hyperintense on T2‐weighted and fluid‐attenuated inversion recovery images, and slightly hyperintense on diffusion‐weighted images. Biopsy specimens from the temporal region showed many medium‐sized anaplastic lymphocytic cells with perivascular and angio‐invasive patterns in the cortex. Immunohistochemically, the cells were positive for CD3, CD8, T‐cell‐restricted intracellular antigen‐1 (TIA‐1), granzyme B and perforin, but negative for CD56 and CD20. In situ hybridization revealed EBV‐encoded RNAs in the tumor cell nuclei. A rearrangement study showed T‐cell receptor γ–chain gene rearrangement with a clonal appearance. The patient died 6 months after surgery, and a general autopsy revealed no lymphoma cells outside the brain. These cellular profiles are inconsistent with those of extranodal NK/T‐cell lymphoma, and have not been previously described. This case appears to represent an unusual CNS manifestation of EBV‐associated T‐cell lymphoma.

Early morphological recovery of the optic chiasm is associated with excellent visual outcome in patients with compressive chiasmal syndrome caused by pituitary tumors.

Abstract Objectives: The study objectives are (1) to identify factors predicting the excellent visual recovery after transsphenoidal removal of pituitary tumors and (2) to describe the association of excellent visual recovery and early restoration of symmetry of the decompressed optic chiasm. Methods: Thirty-five patients with visual symptoms due to pituitary tumors underwent endoscopic endonasal surgery. All patients received perioperative diagnostic magnetic resonance (MR) imaging and ophthalmological assessments within 2 weeks before surgery, within 2 weeks after surgery, and 3 months or later after surgery. Preoperative best-corrected visual acuity (BCVA ≧ 20/20), degree of visual field deficit (VFD, less than half of VF), thickness of retinal nerve fiber layer (RNFL) measured by optical coherence tomography (OCT), and thickness of ganglion cell complex (GCC) measured by OCT were considered for statistical analysis as predictive factors of VF outcome. Multivariate logistic regression models were used in statistical evaluation of data. Results: In the multivariate analysis, RNFL (odds ratio  =  62·137, P < 0·001) and preoperative VFD (odds ratio  =  8·244, P < 0·02) proved to be effective as factors predicting sufficient VF recovery. Postoperative restoration of symmetry of the optic chiasm was related to sufficient VF recovery (P < 0·0001, Fisher’s exact test) and RNFL (P < 0·0001, Fisher’s exact test). Discussion: Early decompression is crucial for sufficient VF recovery, in particular, while RNFL preserves normal or borderline thickness and while VFD keeps within hemianopia. Morphological reversibility is associated with functional reversibility in the optic chiasm compressed by a pituitary tumor. In particular, early morphological recovery suggests functional recovery, which indicates neurocyte reserve in the compressed optic pathway with functional recovery.

Gene expression signature-based prognostic risk score in patients with glioblastoma

The present study aimed to identify genes associated with patient survival to improve our understanding of the underlying biology of gliomas. We investigated whether the expression of genes selected using random survival forests models could be used to define glioma subgroups more objectively than standard pathology. The RNA from 32 non‐treated grade 4 gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array (which contains approximately 47 000 genes). Twenty‐five genes whose expressions were strongly and consistently related to patient survival were identified. The prognosis prediction score of these genes was most significant among several variables and survival analyses. The prognosis prediction score of three genes and age classifiers also revealed a strong prognostic value among grade 4 gliomas. These results were validated in an independent samples set (n = 488). Our method was effective for objectively classifying grade 4 gliomas and was a more accurate prognosis predictor than histological grading.

Suppressed Expression of Autophagosomal Protein LC3 in Cortical Tubers of Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is characterized by benign tumors and hamartomas, including cortical tubers. Hamartin and tuberin, encoded by the TSC 1 and 2 genes, respectively, constitute a functional complex that negatively regulates the mammalian target of rapamycin (mTOR) signaling pathway, eventually promoting the induction of autophagy. In the present study, we assessed the induction of autophagy in cortical tubers surgically removed from seven patients with TSC in comparison with five controls of cortical tissue taken from non‐TSC patients with epilepsy. Immunoblotting demonstrated a marked reduction of LC3B‐I and LC3B‐II in tubers relative to the controls. In tubers, strong, diffuse and dot‐like immunoreactivity (IR) for LC3B was observed in dysmorphic neurons and balloon cells, but LC3B‐IR in other neurons with normal morphology was significantly weaker than that in neurons in the controls. Immunoelectron microscopy revealed diffuse distribution of LC3B‐IR within the cytoplasm of balloon cells. The dot‐like pattern may correspond to abnormal aggregation bodies involving LC3. In an autopsy patient with TSC, we observed that LC3B‐IR in neurons located outside of the tubers was preserved. Thus, autophagy is suppressed in tubers presumably through the mTOR pathway, and possibly a pathological autophagy reaction occurs in the dysmorphic neurons and balloon cells.

Determining the Presence of Thin-Walled Regions at High-Pressure Areas in Unruptured Cerebral Aneurysms by Using Computational Fluid Dynamics.

BACKGROUND Thin-walled regions (TWRs) of cerebral aneurysms are at high risk of rupture, and careful attention should be paid during surgical procedures. Despite this, an optimal imaging technique to estimate TWRs has not been established. Previously, pressure elevation at TWRs was reported with computational fluid dynamics (CFD) but not fully evaluated. OBJECTIVE To investigate the possibility of predicting aneurysmal TWRs at high-pressure areas with CFD. METHODS Fifty unruptured middle cerebral artery aneurysms were analyzed. Spatial and temporal maximum pressure (Pmax) areas were determined with a fluid-flow formula under pulsatile blood flow conditions. Intraoperatively, TWRs of aneurysm domes were identified as reddish areas relative to the healthy normal middle cerebral arteries; 5 neurosurgeons evaluated and divided these regions according to Pmax area and TWR correspondence. Pressure difference (PD) was defined as the degree of pressure elevation on the aneurysmal wall at Pmax and was calculated by subtracting the average pressure from the Pmax and dividing by the dynamic pressure at the aneurysm inlet side for normalization. RESULTS In 41 of the 50 cases (82.0%), the Pmax areas and TWRs corresponded. PD values were significantly higher in the correspondence group than in the noncorrespondence group (P = .008). A receiver-operating characteristic curve demonstrated that PD accurately predicted TWRs at Pmax areas (area under the curve, 0.764; 95% confidence interval, 0.574-0.955; cutoff value, 0.607; sensitivity, 66.7%; specificity, 82.9%). CONCLUSION A high PD may be a key parameter for predicting TWRs in unruptured cerebral aneurysms. ABBREVIATIONS CFD, computational fluid dynamicsMCA, middle cerebral arteryPave, average pressurePD, pressure differencePmax, maximum pressureTWR, thin-walled regionWSS, wall shear stress.

Intraspinal lesions associated with sacrococcygeal dimples.

UNLABELLED OBJECT.: Sacrococcygeal dimples in the gluteal fold, also known as coccygeal pits, are observed in 2%-4% of newborns. Sacrococcygeal dimples are not generally considered to be associated with a significant risk of intraspinal anomalies and therefore are not thought to require further radiographic evaluation. Accordingly, the precise incidence and nature of intraspinal lesions that may be associated with sacrococcygeal dimples is unclear. This study was conducted to determine the incidence of intraspinal lesions in patients with intergluteal dimples. METHODS In this study, the authors used MRI to evaluate 103 children who were seen at the Niigata University Medical and Dental Hospital between 2006 and 2011 because of skin abnormalities in the lumbosacral region. Of these children, 14 were excluded as having a subcutaneous fatty mass, and 5 were excluded because the dimples were above the gluteal fold or did not end at the coccyx. The remaining 84 patients were classified according to whether the bottom of the dimple was visible (shallow) or not (deep). The authors also retrospectively examined other skin abnormalities and coexisting anomalies. RESULTS The mean age at the time of MRI evaluation was 11.7 months. Magnetic resonance imaging led to the identification of fibrolipoma of the terminal filum (FTF) in 14 cases (16.7%); 6 of these patients also had a low conus. Classified by depth, there were 58 cases with shallow and 26 with deep dimples. Fibrolipoma of the terminal filum was found in significantly more patients with deep dimples (9 [34.6%]) than in those with shallow dimples (5 [8.6%]). The frequency of other congenital anomalies was significantly higher in patients with FTF-associated dimples (6 [42.9%] of 14) than in those with dimples that were not associated with FTF (9 [12.9%] of 70). CONCLUSIONS Fibrolipoma of the terminal filum was identified by MRI in 16.7% of patients with sacrococcygeal dimples. The risk of FTF increased when the dimples were deeply excavated or were accompanied by congenital anomalies. Magnetic resonance imaging should be performed to identify intraspinal lesions when there are high risk factors for intraspinal abnormalities, or when an ultrasound screening suggests intraspinal abnormalities.

Detectability of Neural Tracts and Nuclei in the Brainstem Utilizing 3DAC‐PROPELLER

Despite clinical importance of identifying exact anatomical location of neural tracts and nuclei in the brainstem, no neuroimaging studies have validated the detectability of these structures. The aim of this study was to assess the detectability of the structures using three‐dimensional anisotropy contrast‐periodically rotated overlapping parallel lines with enhanced reconstruction (3DAC‐PROPELLER) imaging. Forty healthy volunteers (21 males, 19 females; 19‐53 years, average 23.4 years) participated in this study. 3DAC‐PROPELLER axial images were obtained with a 3T‐MR system at four levels of the brainstem: the lower midbrain, upper and lower pons, and medulla oblongata. Three experts independently judged whether five tracts (corticospinal tract, medial lemniscus, medial longitudinal fasciculus, central tegmental and spinothalamic tracts) and 10 nuclei (oculomotor and trochlear nuclei, spinal trigeminal, abducens, facial, vestibular, hypoglossal, prepositus, and solitary nuclei, locus ceruleus, superior and inferior olives) on each side could be identified. In total, 240 assessments were made. The five tracts and eight nuclei were identified in all the corresponding assessments, whereas the locus ceruleus and superior olive could not be identified in 3 (1.3%) and 16 (6.7%) assessments, respectively. 3DAC‐PROPELLER seems extremely valuable imaging method for mapping out surgical strategies for brainstem lesions.

Novel devices for intraoperative monitoring of glossopharyngeal and vagus nerves during skull base surgery

Background: Swallowing disturbance is among the most burdensome complications suffered by patients with glossopharyngeal and vagus nerve involvement in lesions adjacent the jugular foramen. For monitoring these nerves, we have developed new devices that comprised four contacts adhering to the surface of the cuff of an endotracheal tube, with attachment the posterior pharyngeal wall. To determine whether these devices are useful for monitoring the glossopharyngeal and vagus nerves and predicting postoperative swallowing dysfunction in patients undergoing removal of skull base tumors involving these nerves. Methods: We studied 10 patients. Compound muscle action potentials (CMAPs) were recorded from the posterior pharyngeal wall by stimulating the glossopharyngeal or vagus nerve in order to identify the nerve course, especially in patients showing severe nerve distortion due to the tumor. Pharyngeal motor evoked potential (PhMEP) elicited by transcranial electrical stimulation were recorded in all patients. The correlation between the final to baseline PhMEP ratio and postoperative swallowing function was examined. Results: Responses were obtained in six of the seven patients in whom CMAP monitoring was performed. Deterioration of swallowing function postoperatively was demonstrated in six of seven (86%) patients with intraoperative PhMEP ratios <50%. None of the three patients with intraoperative PhMEP ratios >50% showed deterioration of swallowing function after surgery, although the one patient already had severe swallowing dysfunction requiring preoperative tracheostomy. Conclusions: Our novel devices were useful for monitoring the glossopharyngeal and vagus nerves in patients undergoing removal of skull base tumors involving these nerves.

Advantages of Dose-dense Methotrexate Protocol for Primary Central Nervous System Lymphoma: Comparison of Two Different Protocols at a Single Institution

The efficacy and toxicity of high-dose methotrexate (HD-MTX)-based chemotherapy were retrospectively reviewed in patients with primary central nervous system lymphoma (PCNSL). All immunocompetent patients with histologically or radiographically diagnosed PCNSL treated between 2006 and 2012 at Niigata University Hospital were enrolled. Thirty-eight patients with a diagnosis of PCNSL were treated with one of two regimens during different time periods. During the first period, from 2006 to 2009, three 3-week cycles of MPV (MTX + procarbazine + vincristine) were administered (MPV3 group). In the second period, from 2010 to 2012, five 2-week cycles of MTX were administered (MTX5 group). High-dose cytarabine was used in both groups following HD-MTX-based chemotherapy. Whole-brain radiotherapy was used for patients who did not attain a complete response (CR) based on magnetic resonance images. In the MPV3 group, 20 out of 23 patients (87%) completed the planned treatment. The CR rate after chemotherapy was 30%, and 57% after radiation therapy. Thirteen out of 15 patients (87%) in the MTX5 group completed the planned treatment. The CR rates after chemotherapy and radiation therapy were 53% and 93%, respectively. Renal dysfunction was assessed by measuring creatinine clearance rates, which were very similar in both groups. In terms of hematologic toxicity and other adverse reactions, there was no significant difference between the two groups. In conclusion, dose-dense MTX chemotherapy improved outcome with acceptable toxicity compared with the treatment schedule for three cycles of MPV treatment.