A Pediatric Case of Extraneural Subcutaneous Metastasis of Ependymoma.

Ependymoma is the third most common brain tumor in children. Extracranial metastases of ependymomas are uncommon. A 21-month-old Japanese boy was diagnosed to be brain dead due to a posterior fossa (PF) brain tumor. Surgical resection of the tumor was not performed. Twenty-seven months later, he developed a truncal subcutaneous tumor, which was pathologically diagnosed as PF ependymoma group A. We observed the intracranial recurrence of the brain tumor, an invasion to the left orbit, and a neoplasm in his liver before he died. This case suggests that PF ependymoma group A can metastasize extracranially to various organs.

Hyperplasia of Arachnoid Trabecular Cells: A Hitherto Undescribed Lesion Observed in the Setting of Neurofibromatosis Type 1.

Central nervous system manifestations, a variety of benign and malignant tumors as well as non-neoplastic abnormalities, are found in over 70% of neurofibromatosis type 1 (NF1) patients. Herein, we report hitherto undescribed space-occupying lesions in the setting of NF1. We aimed to clarify their characteristics, especially whether they represent neoplastic or non-neoplastic (hyperplastic) lesions. All 3 cases were preoperatively assessed as non-neoplastic; 2 and 1 cases were suspected to be arachnoid cysts and dilation of subarachnoid space, respectively. However, all lesions were revealed to be whitish jelly-like masses by operation, and the histology composed of spindle cells resembling arachnoid trabecular cells with moderate cellularity and cellular uniformity gave an impression that these lesions may be neoplastic. In contrast, electron microscopic analysis showed that the characteristics of these cells were compatible with those of normal arachnoid trabecular cells. Furthermore, whole-exome sequencing and array comparative genomic hybridization did not show any obvious alterations suggestive of their neoplastic nature. DNA methylation analysis demonstrated that these lesions were epigenetically distinct not only from meningiomas but also from normal healthy meninges. In conclusion, considering the clinicopathologic aspects of the present lesions and the results of the molecular analysis that failed to suggest their neoplastic nature, they may represent previously unrecognized rare hyperplasia of arachnoid trabecular cells, which may be associated with NF1.

Identification and characterization of diacylglycerol kinase ζ as a novel enzyme producing ceramide-1-phosphate.

Ceramide-1-phosphate (C1P) is a sphingolipid formed by the phosphorylation of ceramide; it regulates various physiological functions, including cell survival, proliferation, and inflammatory responses. In mammals, ceramide kinase (CerK) is the only C1P-producing enzyme currently known. However, it has been suggested that C1P is also produced by a CerK-independent pathway, although the identity of this CerK-independent C1P was unknown. Here, we identified human diacylglycerol kinase (DGK) ζ as a novel C1P-producing enzyme and demonstrated that DGKζ catalyzes the phosphorylation of ceramide to produce C1P. Analysis using fluorescently labeled ceramide (NBD-ceramide) demonstrated that only DGKζ among ten kinds of DGK isoforms increased C1P production by transient overexpression of the DGK isoforms. Furthermore, an enzyme activity assay using purified DGKζ revealed that DGKζ could directly phosphorylate ceramide to produce C1P. Furthermore, genetic deletion of DGKζ decreased the formation of NBD-C1P and the levels of endogenous C18:1/24:1- and C18:1/26:0-C1P. Interestingly, the levels of endogenous C18:1/26:0-C1P were not decreased by the knockout of CerK in the cells. These results suggest that DGKζ is also involved in the formation of C1P under physiological conditions.

N-butyldeoxynojirimycin (miglustat) ameliorates pulmonary fibrosis through inhibition of nuclear translocation of Smad2/3.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. The disease involves excessive accumulation of fibroblasts and myofibroblasts, and myofibroblasts differentiated by pro-fibrotic factors promote the deposition of extracellular matrix proteins such as collagen and fibronectin. Transforming growth factor-ß1 is a pro-fibrotic factor that promotes fibroblast-to-myofibroblast differentiation (FMD). Therefore, inhibition of FMD may be an effective strategy for IPF treatment. In this study, we screened the anti-FMD effects of various iminosugars and showed that some compounds, including N-butyldeoxynojirimycin (NB-DNJ, miglustat, an inhibitor of glucosylceramide synthase (GCS)), a clinically approved drug for treating Niemann-Pick disease type C and Gaucher disease type 1, inhibited TGF-ß1-induced FMD by inhibiting the nuclear translocation of Smad2/3. N-butyldeoxygalactonojirimycin having GCS inhibitory effect did not attenuate the TGF-ß1-induced FMD, suggesting that NB-DNJ exerts the anti-FMD effects by GCS inhibitory effect independent manner. N-butyldeoxynojirimycin did not inhibit TGF-ß1-induced Smad2/3 phosphorylation. In a mouse model of bleomycin (BLM)-induced pulmonary fibrosis, intratracheal or oral administration of NB-DNJ at an early fibrotic stage markedly ameliorated lung injury and deterioration of respiratory functions, such as specific airway resistance, tidal volume, and peak expiratory flow. Furthermore, the anti-fibrotic effects of NB-DNJ in the BLM-induced lung injury model were similar to those of pirfenidone and nintedanib, which are clinically approved drugs for the treatment of IPF. These results suggest that NB-DNJ may be effective for IPF treatment.

Endoscopic Extended Transsphenoidal Approach for Sellar and Suprasellar Xanthogranuloma: Potential Implications for Surgical Strategies in Adult Craniopharyngioma.

OBJECTIVE: Differentiation of suprasellar xanthogranuloma (XG) from adult craniopharyngioma (CP) can be problematic in endoscopic extended transsphenoidal surgery. METHODS: We reviewed the clinical data, preoperative imaging, intraoperative endoscopic findings, and intraoperative frozen section pathology in newly diagnosed adult CPs (19 patients) and XGs (6 patients). RESULTS: Intracystic signal intensity was often high on T1-weighted magnetic resonance images in the XGs but low in the CPs (P = 0.015). Capsular intensity was low on T2-weighted imaging in XGs but iso to high in CPs (P < 0.001). Capsular gadolinium enhancement was often seen in CPs and not in XGs (P < 0.001). CPs often had a solid component with contrast enhancement but none in XGs (P < 0.001). Intraoperative endoscopic observations frequently found a whitish solid component in the CPs but yellow to brown fibrous granulomatous lesions in XGs (P < 0.001). The tumor capsule was dark grayish and soft in CPs, whereas it was fibrously hard in XGs (P = 0.002). Yellowish hemosiderin deposits were seen in all XGs (P = 0.003). Intraoperative pathologic diagnosis of CP was all verified whereas no evidence of tumor was found in XGs (P < 0.001). Partial removal was performed in 4 patients with XGs. No recurrence was observed in these patients during the follow-up period (1.5-8 years). CONCLUSIONS: Careful interpretation of preoperative magnetic resonance imaging, intraoperative endoscopic findings, and intraoperative frozen section diagnosis may be important for the differential diagnosis between XG and CP. In endoscopic-extended transsphenoidal surgery, intentional partial removal can be effective for XG after careful diagnosis.

Diffusely infiltrating glioma with CREBBP-BCORL1 fusion showing overexpression of not only BCORL1 but BCOR: A case report.

BCORL1 encodes a transcriptional corepressor homolog to BCOR. BCORL1 rearrangements have been previously described as rare events, and among them, CREBBP-BCORL1 has been reported only in 2 cases of ossifying fibromyxoid tumors. Herein, we present the first case of diffusely infiltrating glioma with CREBBP-BCORL1 involving a 17-year-old female patient. Histologically, the tumor was composed of a diffusely infiltrative proliferation of small tumor cells with moderate cellularity showing prominent microcystic formation. DNA methylation analysis revealed that the current case and a previously reported anaplastic ependymoma with EP300-BCORL1 were clustered together in close proximity to but distinct from methylation class high-grade neuroepithelial tumor with BCOR alteration. RNA sequencing demonstrated high mRNA expression of not only BCORL1 but BCOR, and the latter was compatible with diffuse nuclear expression of BCOR detected by immunohistochemistry. Our findings suggest that central nervous system tumors with CREBBP/EP300-BCORL1 may exhibit diverse morphologies but form a distinct DNA methylation group and that BCORL1 fusion genes may lead to upregulation of both BCOR and BCORL1.

An autopsy case of granulomatous amebic encephalitis caused by Balamuthia mandrillaris involving prior amebic dermatitis.

An 82-year-old man, who was healthy and had worked as a farmer, experienced worsening neurological symptoms over a seven-month period, which eventually caused his death. Multiple fluctuating brain lesions were detected radiographically. Clinically, sarcoidosis was ranked high among the differential diagnoses because of the presence of skin lesions showing granulomatous inflammation, confirmed by biopsy. The patient's cerebrospinal fluid was also examined, but no definitive diagnosis was made while he was alive. An autopsy revealed multiple granulomatous amebic encephalitis lesions in the brain. Genetic and immunohistochemical analyses identified Balamuthia (B.) mandrillaris, a free-living ameba, which resides in soil and fresh water, as the causative organism. A retrospective examination revealed B. mandrillaris in the biopsied skin as well as cerebrospinal fluid, strongly suggesting that the ameba had spread into the brain percutaneously. Few studies have detailed the cutaneous pathology of B. mandrillaris infections. In general, granulomatous amebic encephalitis is extremely difficult to diagnose without autopsy, but the present case provides a clue that could allow similar cases to be diagnosed earlier; that is, the presence of skin lesions.

Idiopathic Orbital Inflammation Appearing on the Affected Side of Preceding Myasthenia Gravis.

The patient was a 70-year-old man with idiopathic orbital inflammation (IOI) that appeared on the severely affected side of preceding myasthenia gravis (MG). The patient was diagnosed with MG 5 years prior to the onset of IOI. When IOI was diagnosed, an edrophonium test was negative. IOI was considered because he complained of left orbital pain, eyelid swelling, and cerebral MRI exhibited the enhanced lesions along the left orbital periosteum. A biopsy specimen revealed pathological findings compatible with IOI. The administration of corticosteroids was effective for improving the ocular symptoms. IOI should be considered when ocular symptoms deteriorated with soft tissue swelling/pain in MG patients.

Long-term complete response in a patient with postoperative recurrent ALK-rearranged lung adenocarcinoma treated with crizotinib: A case report.

Anaplastic lymphoma kinase (ALK) gene rearrangements are identified in approximately 5% of patients with non-small cell lung cancer (NSCLC). Despite initial dramatic responses to ALK inhibitors, the majority of patients relapse within 1 year, owing to the development of resistance. Herein we present a case of variant type 2 ALK-rearranged lung adenocarcinoma recurrence with multiple lung metastasis that maintained complete response over 5 years with crizotinib, which is the first approved ALK inhibitor. The efficacy of crizotinib may vary among ALK fusion variants and thus, variant type may represent an important factor in guiding the treatment strategy for ALK-rearranged lung adenocarcinoma.

Clinicopathological characteristics of circumscribed high-grade astrocytomas with an unusual combination of BRAF V600E, ATRX, and CDKN2A/B alternations.

We report four cases of high-grade astrocytoma with a BRAF V600E mutation, ATRX inactivation, and CDKN2A/B homozygous deletion. Children to young adults aged 3-46 presented with a well demarcated contrast-enhancing mass in the supratentorial area. Pathological examination revealed packed growth of short spindle to round polygonal cells including some pleomorphic cells. The tumors had less ability to infiltrate into the adjacent brain parenchyma and presented a circumscribed growth pattern. Mitosis was readily found, accompanied by focal necrosis and/or microvascular proliferation. Tumors were histologically similar in part to pleomorphic xanthoastrocytoma (PXA) or anaplastic PXA, but did not fit criteria for either neoplasm. A BRAF V600E mutation and homozygous deletion of CDKN2A/B were observed, which is similar to the genetic features of PXA or epithelioid glioblastoma, but the additional loss of ATRX nuclear immunoreactivity and absence of TERT promoter mutation were unusual findings, indicating a novel genetic profile. Despite their malignant histological features, all patients had a favorable clinical course and remained alive for 6 months to 28 years under standard medical treatment for malignant glioma. In summary, high grade astrocytomas with BRAF V600E, ATRX, and CDKN2A/B alternations had unique clinicopathological features and may be a novel subset of high grade glioma.

Role of bypass surgery and balloon occlusion test for the endovascular management of fusiform dissecting aneurysms. Report of two cases.

Fusiform intracranial aneurysm is one of the most difficult pathologies to treat. The role and efficacy of recent advanced endovascular technique and conventional bypass surgery are discussed.

Purification of NADPH-P450 reductase (NPR) from Xenopus laevis and the developmental change in NPR expression.

NADPH-P450 reductase (NPR) was purified from hepatic microsomes of Xenopus laevis. The electron transfer activity of purified NPR was 23.8 units/min/mg with horse cytochrome c. The aminopyrine demethylation activity of rat CYP2B1 with Xenopus NPR was 58.1 nmol/min/nmol. The corresponding cDNA was isolated from Xenopus liver. The homology in amino acid sequence deduced from NPR cDNA isolated from Xenopus liver was 80%, 78%, and 81% with human, rat, and rabbit NPR, respectively. Antibody against Xenopus NPR was prepared. The expression of NPR was investigated in various tissues and in early development by Western blotting. NPR was most abundantly expressed in the kidney, followed by the liver, lung, and heart. The brain had very low levels of NPR. The level of NPR protein was almost the same at all stages, 2-cell stage (st. 2), blastula (st. 8), gastrula (st. 12), tail bud (st. 26) and larva (st.35), examined in this study. We further investigated the distribution of NPR using whole-mount in situ hybridization. NPR mRNA was expressed in cement gland, lens placode, ear vesicle, mesencephalon, rhombencephalon, lymphatic vessel, and heart anlage in the embryo at stage 29. Xenopus NPR has similar properties to mouse and rat NPRs. Localization of NPR in Xenopus embryo was consistent with the abnormal region caused by NPR deficiency in mice.