Masayasu Okada

Chondroitin sulphate N -acetylgalactosaminyl-transferase-1 inhibits recovery from neural injury

Extracellular factors that inhibit axon growth and intrinsic factors that promote it affect neural regeneration. Therapies targeting any single gene have not yet simultaneously optimized both types of factors. Chondroitin sulphate (CS), a glycosaminoglycan, is the most abundant extracellular inhibitor of axon growth. Here we show that mice carrying a gene knockout for CS N-acetylgalactosaminyltransferase-1 (T1), a key enzyme in CS biosynthesis, recover more completely from spinal cord injury than wild-type mice and even chondroitinase ABC-treated mice. Notably, synthesis of heparan sulphate (HS), a glycosaminoglycan promoting axonal growth, is also upregulated in TI knockout mice because HS-synthesis enzymes are induced in the mutant neurons. Moreover, chondroitinase ABC treatment never induces HS upregulation. Taken together, our results indicate that regulation of a single gene, T1, mediates excellent recovery from spinal cord injury by optimizing counteracting effectors of axon regeneration—an extracellular inhibitor of CS and intrinsic promoters, namely, HS-synthesis enzymes.

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.

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.

Observation of the neurohypophysis, pituitary stalk, and adenohypophysis during endoscopic pituitary surgery: Demonstrative findings as clues to pituitary-conserving surgery

BackgroundHigh-definition imaging in endoscopic transsphenoidal pituitary surgery accounts for significantly better identification of anatomic structures. This report presents the clinical images of the adenohypophysis and neurohypophysis under high-definition endoscopic observation, and provides some clues for pituitary-sparing surgery.MethodsTen demonstrative cases of pituitary lesions, including three cases of gonadotropin-producing pituitary adenoma, two cases of somatotropin-secreting pituitary adenoma, and five cases of Rathke’s cleft cysts, were entered in this study. From these cases, we extracted helpful intraoperative findings that affected the surgeon’s decision about surgical procedures and led to favorable results.ResultsThe extracted findings contain the following lessons: (1) to find a boundary plane that separate a lesion from the pituitary; (2) to mark the difference of color between the adenohypophysis and the neurohypophysis; (3) to identify the location of the pituitary stalk connecting to the neurohypophysis; (4) to observe the color change of the pituitary induced by decompression; (5) to know pathological findings of the pituitary surface; (6) to distinguish the parenchyma of the neurohypophysis from pathological tissues; and (7) to recognize the intrasellar findings at the completion of removal. Recognition of these findings led to an excellent result in each case.ConclusionsDespite being shown in a limited number of cases, on the basis of HD endoscopic images, accurate identification of the neurohypophysis and the pituitary stalk as well as adenohypophysis during surgery contributes to pituitary-conserving operations.

Has acromegaly been diagnosed earlier

PURPOSE We investigated whether acromegaly has been diagnosed earlier at the Niigata Medical and Dental University Hospital. METHODS Patients with acromegaly (n = 81) who underwent their first transsphenoidal surgery from 2006 to 2015 were reviewed. Two groups were compared: those who underwent surgery between 2006 and 2010 (n = 35) and those who underwent surgery between 2011 and 2015 (n = 46). We compared clinical features and serum levels of the growth hormone (GH) and insulin-like growth factor-1 (IGF-1), hypertension (HT) and diabetes mellitus (DM) prevalence between the two groups. RESULTS Compared with the early group, microadenomas (<10 mm) were more prevalent in the late group (0% vs. 15.2%, p < .05). Serum IGF-1 standard deviation score (SDS) was significantly lower in the late group (8.57 ± 2.50 vs. 6.44 ± 2.30, p < .001). In both groups, mean IGF-1 SDS was significantly lower in patients without DM than in those with DM (6.9 ± 2.6 vs. 8.3 ± 2.4, p = .02). Logistic regression analysis showed that serum GH and IGF-1 levels were significantly higher in patients with DM than in those without DM. CONCLUSION Regarding operated cases of GH-producing pituitary adenoma, acromegaly clinical manifestations tended to be milder at diagnosis in later years of the decade, and acromegaly was diagnosed at lower IGF-1 levels and in smaller lesions. Further study is mandatory for the generalization of this trend.

Growth Cone Phosphoproteomics Reveals that GAP-43 Phosphorylated by JNK Is a Marker of Axon Growth and Regeneration

Summary Neuronal growth cones are essential for nerve growth and regeneration, as well as for the formation and rearrangement of the neural network. To elucidate phosphorylation-dependent signaling pathways and establish useful molecular markers for axon growth and regeneration, we performed a phosphoproteomics study of mammalian growth cones, which identified >30,000 phosphopeptides of ∼1,200 proteins. The phosphorylation sites were highly proline directed and primarily MAPK dependent, owing to the activation of JNK, suggesting that proteins that undergo proline-directed phosphorylation mediate nerve growth in the mammalian brain. Bioinformatics analysis revealed that phosphoproteins were enriched in microtubules and the cortical cytoskeleton. The most frequently phosphorylated site was S96 of GAP-43 (growth-associated protein 43-kDa), a vertebrate-specific protein involved in axon growth. This previously uncharacterized phosphorylation site was JNK dependent. S96 phosphorylation was specifically detected in growing and regenerating axons as the most frequent target of JNK signaling; thus it represents a promising new molecular marker for mammalian axonal growth and regeneration.

Third Ventricle Germ Cell Tumor Originating from the Infundibulum with Rapidly Expansive Enlargement

We present a pediatric case of a rapidly expanding third ventricle germ cell tumor (GCT). A 14-year-old boy suffered from gradual-onset central diabetes insipidus (DI) and received desmopressin treatment. Magnetic resonance imaging (MRI) showed nonspecific findings of the pituitary-hypothalamic axis. Nine months after the initial DI diagnosis, he developed progressively worsening headache. MRI demonstrated a third ventricle tumor causing noncommunicating hydrocephalus, although an MRI 16 weeks before admission did not show the lesion. We performed gross total resection (GTR) of the tumor in 2 stages: a translamina terminalis approach and an extended transsphenoidal approach. The lesion was histologically diagnosed as immature teratoma with some germinoma. His noncommunicating hydrocephalus resolved after surgery. Through postoperative radiochemotherapy (whole ventricle: 23.4 Gy/13 fractions, tumor bed: 27.0 Gy/15 fractions, and 3 courses of carboplatin-etoposide), he has was in complete remission at the 3-year follow-up and has continued his high school program. This case suggests the following: (1) a mixed GCT originating from the neurohypophysis/infundibulum can show rapidly expansive growth in a child with central DI; (2) GTR and adjuvant radiochemotherapy can result in a good therapeutic outcome in rapidly expanding GCT; and (3) the extended transsphenoidal approach is a complementary approach to transcranial resection of anterior third ventricle GCTs.

MGMT Expression Contributes to Temozolomide Resistance in H3K27M-Mutant Diffuse Midline Gliomas and MGMT Silencing to Temozolomide Sensitivity in IDH-Mutant Gliomas

Histone H3 mutations are frequently found in diffuse midline gliomas (DMGs), which include diffuse intrinsic pontine gliomas and thalamic gliomas. These tumors have dismal prognoses. Recent evidence suggests that one reason for the poor prognoses is that O6-methylguanine-DNA methyltransferase (MGMT) promoter frequently lacks methylation in DMGs. This review compares the epigenetic changes brought about by histone mutations to those by isocitrate dehydrogenase-mutant gliomas, which frequently have methylated MGMT promoters and are known to be sensitive to temozolomide.

Perifocal Inflammatory Reaction with Volume Fluctuation Caused by Diagnostic Radiation-Induced Regression in Germinoma Makes Histological Diagnosis Difficult despite Its Disappearance following Treatment: A Significant Pitfall and Countermeasures to It

We present a pediatric case of neurohypophyseal germinoma with a perifocal inflammatory reaction (PIR) with volume fluctuation caused by diagnostic radiation-induced regression (DRIR). On-target biopsy failed to confirm the histology because PIR hardly contained any germinoma cells. DRIR-related fluctuation of the tumor volume disguised germinoma as inflammation. We analyzed the cerebrospinal fluid (CSF) and detected a high level of placental alkaline phosphatase (PLAP), which demonstrated the neurohypophyseal lesion to be germinoma and brought the patient from successful radiochemotherapy up to complete remission. PIR adjacent to the germinoma (PIRAG) disappeared completely following radiochemotherapy, although it contained almost no germinoma cells. Examination of the CSF-PLAP level can complement the diagnosis of germinoma and will decrease the risk of misdiagnosis. Neurosurgeons should keep in mind PIRAG, DRIR, and the diagnostic value of CSF-PLAP when germinoma is suspected.