Akitake Mukasa

Oligodendrocyte Progenitor Cells and Macrophages/Microglia Produce Glioma Stem Cell Niches at the Tumor Border

Glioblastoma (GBM) usually develops in adult brain white matter. Even after complete resection, GBM recurs around the tumor removal cavity, where GBM cells acquire chemo-radioresistance. Characterization of the tumor border microenvironment is critical for improving prognosis in patients with GBM. Here, we compared microRNA (miRNA) expression in samples from the tumor, tumor border, and periphery by miRNA microarray. The top three of miRNAs showing higher expression in the tumor border were related to oligodendrocyte differentiation, and pathologically oligodendrocyte lineage cells were increased in the border, where macrophages and microglia also colocalized. Medium cultured with oligodendrocyte progenitor cells (OPCs) and macrophages induced stemness and chemo-radioresistance in GBM cells, similar to that produced by FGF1, EGF and HB-EGF, IL-1β, corresponding to OPCs and macrophages, respectively. Thus, OPCs and macrophages/microglia may form a glioma stem cell niche at the tumor border, representing a promising target for prevention of recurrence.

Usefulness of Oblique Coronal Computed Tomography and Magnetic Resonance Imaging in the Endoscopic Endonasal Approach to Treat Skull Base Lesions

OBJECTIVEnThis report examines the usefulness of the preoperative image to orient the surgeon in the sphenoid sinus during endoscopic endonasal transsphenoidal surgery (ETSS).nnnMETHODSnETSS was performed in 100 cases of sellar lesion and used to classify the sphenoid sinus septum shape. Preoperative computed tomography and magnetic resonance imaging were performed for 2 types of coronal imaging: conventional and oblique. Expected sphenoid sinus septum shape was compared with those from ETSS to estimate concordance. The confirmation rate of anatomic landmarks in the sphenoid sinus by endoscopic observation was compared in various types of septum and the identification rate in oblique coronal imaging was also examined.nnnRESULTSnThe most common septum shape was single type (31%), followed by branched (26%), parallel (18%), none (12%), cross (9%), and bridge (4%) types. In oblique coronal images, preoperative evaluation and endoscopic findings were consistent in 93%-100% of cases. However, with conventional coronal images, the concordance rate was 22.2%-83.9%, and in the none, branched, and cross types, the concordance rate was significantly lower than that for oblique coronal images. Although confirmation of the midline through estimation of landmarks by endoscopic observation was difficult in 33 cases, preoperative computed tomography and magnetic resonance imaging showed landmarks in all cases and oblique coronal images best indicated the midline.nnnCONCLUSIONSnUse of oblique coronal images in addition to conventional images provided good orientation of anatomic structures in the sphenoid sinus. The combination of preoperative imaging and endoscopic observation could allow safer surgery in ETSS.

A Rare Case of Thyrotropin-Secreting Pituitary Adenoma Coexisting with Papillary Thyroid Carcinoma Presenting with Visual Disturbance without Hyperthyroidism

BACKGROUNDnThyroid-stimulating hormone-secreting pituitary adenomas (TSHomas) are uncommon, and majority of the patients present with symptoms of hyperthyroidism. Herein, we report the first case of TSHoma with differentiated thyroid carcinoma (DTC) that presented with visual disturbance without any clinical feature of hyperthyroidism.nnnCASE DESCRIPTIONnA 57-year-old man presented with left temporal hemianopsia of his left eye without any sign of hyperthyroidism. A mass lesion in the sellar and suprasellar region compressing the optic nerves was identified via magnetic resonance imaging. Free thyroxine and free triiodothyronine levels were slightly elevated, whereas the serum level of thyroid-stimulating hormone remained within normal range. Further endocrinologic examination led to the preoperative diagnosis of TSHoma. Ultrasonography and 111In-octreotide scan showed a mass lesion in left lobe of the thyroid gland, and subsequent thyroid aspiration biopsy confirmed the diagnosis of papillary thyroid carcinoma. After administration of short-acting octreotide to prevent thyrotoxic crisis in the perioperative period, the tumor was removed via endoscopic transnasal-transsphenoidal surgery, and the pathologic diagnosis of TSHoma was made. His visual acuity improved, and free triiodothyronine and free thyroxine levels normalized. He underwent thyroidectomy 3 months later after endoscopic transnasal-transsphenoidal surgery.nnnCONCLUSIONSnHerein, we report the first case of TSHoma with DTC that presented with visual disturbance without any clinical feature of hyperthyroidism and reviewed the 13 reported cases of TSHoma coexisting with DTC. The optimal treatment strategy in patients with TSHoma and coexistent DTC has not been established, and individualized therapeutic strategies are needed.

Stenotic changes of the posterior cerebral artery are a major contributing factor for cerebral infarction in moyamoya disease

Background: Some patients with moyamoya disease (MMD) show broad infarction with moderate internal carotid artery (ICA) stenosis, whereas others with complete ICA occlusion show no infarction. This suggests that other factors contribute to the occurrence of infarction. Contributing factors predictive of cerebral infarcts must be identified for the prevention of infarction and the consequent neurological deficits. Methods: We examined data from 93 patients with confirmed MMD for the presence of infarction (n = 72), transient ischemic attack (TIA, n = 41), asymptomatic presentation (n = 51), or hemorrhage (n = 22) in 186 bilateral cerebral hemispheres. We analyzed the relationship between the occurrence of infarction and several clinical factors, such as steno-occlusive status or the site of the ICA and posterior cerebral artery (PCA). Results: The incidence of PCA steno-occlusive lesions was significantly higher in infarcted (77.8%) than in non-infarcted hemispheres (TIA, 14.6%; asymptomatic, 9.8%; hemorrhagic 9.1%; P < 0.01). The steno-occlusive site of ICA was also a significant factor (P < 0.05). There was no significant correlation between the occurrence of infarction and the steno-occlusive status of the ICA or grade of the moyamoya vessels. Multivariate statistical analysis demonstrated that the PCA steno-occlusive changes were an important contributing factor for infarction (P < 0.0001). Conclusions: This is the multivariate statistical analysis study identifying PCA steno-occlusive lesions as the most important independent factor that is predictive to cerebral infarction in moyamoya patients. The prediction and inhibition of PCA steno-occlusive changes may help to prevent cerebral infarction.

BCL2 expression is associated with a poor prognosis independent of cellular origin in primary central nervous system diffuse large B-cell lymphoma

PurposePrimary central nervous system diffuse large B-cell lymphoma (CNS-DLBCL) is a distinct clinicopathological entity with a poor prognosis. Concurrent MYC and BCL2 overexpression predicts inferior prognosis in systemic DLBCL, although their prognostic significance remains unclear in primary CNS-DLBCL.MethodsPretreatment diagnostic biopsy samples were retrospectively evaluated for 79 patients with primary CNS-DLBCL who were treated between January 2001 and December 2017. Histological and immunohistochemical testing were performed to evaluate the patients’ statuses for various markers, which were also evaluated for associations with survival outcomes.ResultsAccording to the Hans criteria, 26 patients (32.9%) had the germinal center B-cell subtype and 53 patients (67.1%) had the activated B-cell subtype. Forty-one cases (51.9%) were positive for MYC (expression of ≥u200940%), 33 cases (41.8%) were positive for BCL2 (expression of ≥u200970%), 22 patients (27.8%) were positive for both MYC and BCL2, and 27 patients (34.2%) were negative for both MYC and BCL2. There were no significant differences in survival between the germinal center and activated B-cell subtypes. Furthermore, MYC positivity was not associated with overall survival (pu2009=u20090.369) or progression-free survival (PFS) (pu2009=u20090.253). However, BCL2 positivity was significantly associated with poor overall survival (pu2009=u20090.039) and PFS (pu2009=u20090.036). Co-expression of MYC and BCL2 was not associated with survival.ConclusionOur data suggest that evaluating BCL2 expression may help predict the prognosis in cases of primary CNS-DLBCL.

Machine learning based on multi-parametric magnetic resonance imaging to differentiate glioblastoma multiforme from primary cerebral nervous system lymphoma

PURPOSEnTo evaluate the performance of a machine learning method based on texture features in multi-parametric magnetic resonance imaging (MRI) to differentiate a glioblastoma multiforme (GBM) from a primary cerebral nervous system lymphoma (PCNSL).nnnMATERIALS AND METHODSnWe included 70 patients who underwent contrast enhanced brain MRI at 3u2009T with brain tumors diagnosed as GBM (nu2009=u200945) and PCNSL (nu2009=u200925) in this retrospective study. Twelve histograms and texture parameters were assessed on T2-weighted images (T2WIs), apparent diffusion coefficient maps, relative cerebral blood volume (rCBV) map, and contrast-enhanced T1-weighted images (CE-T1WIs). A prediction model was developed using a machine learning method (univariate logistic regression and multivariate eXtreme gradient boosting-XGBoost) and the area under the receiver operating characteristic curve of this model was calculated via 10-fold cross validation. In addition, the performance of the machine learning method was compared with the judgments of two board certified radiologists.nnnRESULTSnWith the univariate logistic regression model, the standard deviation of rCBV offered the highest AUC (0.86), followed by mean value of rCBV (0.83), skewness of CE-T1WI (0.78), mean value of CET1 (0.78), and max value of rCBV (0.77). The AUC of the XGBoost was significantly higher than the two radiologists (0.98 vs. 0.84; pu2009<u20090.01 and 0.98 vs. 0.79; pu2009<u20090.01, respectively).nnnCONCLUSIONnThe performance of machine learning based on histogram and texture features in multi-parametric MRI was superior to that of conventional cut-off method and the board certified radiologists to differentiate a GBM from a PCNSL.

Is hemifacial spasm affected by changes in the heart rate? A study using heart rate variability analysis

OBJECTIVEnHemifacial spasm (HFS) is caused by arterial conflict at the root exit zone of the facial nerve. As the offending artery is pulsatile in nature, this study investigated the association of heart rate fluctuation with HFS.nnnMETHODSnTwenty-four preoperative patients underwent simultaneous recordings of facial electromyogram and electrocardiogram overnight. Series of R-wave to R-wave intervals (RRIs) in the electrocardiogram were analyzed across subjects in relation to HFS. The degree of heart rate fluctuation was quantified by analyzing the heart rate variability (HRV). The sleep stage was evaluated during the period of HFS.nnnRESULTSnA 0.1u202fHz fluctuation in RRIs by 5% compared to the baseline preceded a few seconds the onset of the HFS, indicating that a significant increase in the heart rate coincided with HFS. HRV analysis demonstrated that fluctuations in the heart rate were significantly enhanced during HFS. Wake or light sleep stages were more often accompanied by HFS, suggesting an association with autonomic activities.nnnCONCLUSIONnOur findings suggest that the etiology of HFS is more than just a mechanical compression of the facial nerve and may involve changes in pulsatile frequency in offending arteries.nnnSIGNIFICANCEnWe propose the etiology of HFS from a unique standpoint.

IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis

IDH‐mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II‐IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next‐generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH‐mutated gliomas, 12 were 1p‐intact/19q‐intact (anaplastic astrocytomas [AA]), 7 were 1p‐intact/19q‐loss (AA), and 23 showed 1p/19q‐codeletion (anaplastic oligodendrogliomas). Of the 88 IDH‐wild type glioblastomas (GBMs), 14 showed 1p‐intact/19q‐loss status. All of the seven 1p‐intact/19q‐loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q‐loss AAs had regions presenting oligodendroglioma‐like morphology, and were associated with significantly longer overall survival compared to 19q‐intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q‐loss GBM and 19q‐intact GBM (P = .4). In a case of 19q‐loss AA, both oligodendroglial morphology and 19q‐loss disappeared after recurrence, possibly indicating correlation between 19q‐loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH‐mutated astrocytomas harboring 19q‐loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q‐intact astrocytomas.

CSF TACI and BAFF levels in patients with primary CNS lymphoma as novel diagnostic biomarkers

We used an enzyme‐linked immunosorbent assay to measure pretreatment B cell‐activating factor belonging to the tumour necrosis factor family (BAFF) and transmembrane activator and CAML‐interactor (TACI) levels in CSF and serum collected from patients with primary central nervous system lymphoma (PCNSL) and control groups. The decision tree analysis of CSF TACI and BAFF levels for patients with a PCNSL diagnosis showed 100% sensitivity and 100% specificity when we attempted to differentiate PCNSL from glioblastoma and CNS inflammatory diseases. The combination of CSF TACI and BAFF levels may thus be a novel and useful diagnostic biomarker of PCNSL.

Clinical significance of polyglutamylation in primary central nervous system lymphoma

The therapeutic response to high-dose methotrexate (HD-MTX) therapy for primary central nervous system lymphoma (PCNSL) varies. Polyglutamylation is a reversible protein modification with a high occurrence rate in tumor cells. MTX incorporated into cells is polyglutamylated and strongly binds to dihydrofolate reductase without competitive inhibition by leucovorin (LV). Tumor cells with high polyglutamylation levels are selectively killed, whereas normal cells with lower polyglutamylation are rescued by LV. We hypothesized that the extent of polyglutamylation in tumor cells determines treatment resistance. Here, we investigated the therapeutic response of PCNSL to HD-MTX therapy with LV rescue based on polyglutamylation status. Among 113 consecutive PCNSL patients who underwent HD-MTX therapy in our department between 2001 and 2014, polyglutamylation was evaluated by immunostaining in 82 cases, with relationships between polyglutamylation and therapeutic response retrospectively examined. Human malignant lymphoma lines were used for in vitro experiments, and folpolyglutamate synthetase (FPGS), which induces polyglutamylation, was knocked down with short-hairpin RNA, and a stable cell line with a low rate of polyglutamylation was established. Cell viability after MTX treatment with LV rescue was evaluated using sodium butyrate (NaBu), a histone-deacetylase inhibitor that induces polyglutamylation by elevating FPGS expression. The complete response rate was significantly higher in the group with polyglutamylation than in the non-polyglutamylation group [58.1% (25/43) and 33.3% (13/39), respectively] (pu2009<u20090.05), and progression-free survival was also significantly increased in the group with polyglutamylation (pu2009<u20090.01). In vitro, the relief effect of LV after MTX administration was significantly enhanced after FPGS knockdown in al cell lines, whereas enhancement of FPGS expression by NaBu treatment significantly reduced this relief effect. These findings suggested that polyglutamylation could be a predictor of therapeutic response to HD-MTX therapy with LV rescue in PCNSL. Combination therapy with HD-MTX and polyglutamylation-inducing agents might represent a promising strategy for PCNSL treatment.