Diffuse Leptomeningeal Glioneuronal Tumor with FGFR1 Mutation in a 29-Year-Old Male.

This study reports on diffuse leptomeningeal glioneuronal tumor (DL-GNT) in a 29-year-old male. DL-GNT is a rare central nervous system (CNS) tumor mostly seen in children and only few cases have been reported in adult patients. Our patient presented with a chronic headache that lasted for five months. MR imaging showed mild hydrocephalus, multiple rim-enhancing nodular lesions in the suprasellar cistern, diffuse leptomeningeal enhancement in the lumbosacral area, and multiple small non-enhancing cyst-appearing lesions not suppressed on fluid attenuated inversion recovery (FLAIR) images in the bilateral basal ganglia, thalami, and cerebral hemispheres. Under the impression of germ cell tumor with leptomeningeal seeding, the patient underwent trans-sphenoidal tumor removal. DL-GNT was pathologically confirmed and FGFR1 mutation was detected through a next-generation sequencing test. In conclusion, a combination of leptomeningeal enhancement and multiple parenchymal non-enhancing cyst-appearing lesions not suppressed on FLAIR images may be helpful for differential diagnosis despite overlapping imaging features with many other CNS diseases that have leptomeningeal enhancement.

Distinct and overlapping features of nodal peripheral T-cell lymphomas exhibiting a follicular helper T-cell phenotype: a multicenter study emphasizing the clinicopathological significance of follicular helper T-cell marker expression.

Nodal peripheral T-cell lymphoma (PTCL) is a heterogeneous category including angioimmunoblastic T-cell lymphoma (AITL), PTCL of follicular helper T-cell (Tfh) phenotype (PTCL-Tfh), and PTCL, not otherwise specified (PTCL-NOS). We explored Tfh marker profiles in nodal PTCL. Nodal PTCLs (n = 129) were reclassified into AITL (58%; 75/129), PTCL-Tfh (26%; 34/129), and PTCL-NOS (16%; 20/129). Histologically, clear cell clusters, high endothelial venules, follicular dendritic cell proliferation, EBV+ cells, and Hodgkin-Reed-Sternberg (HRS)-like cells were more common in AITL than PTCL-Tfh (HRS-like cells, P = .005; otherwise, P < .001) and PTCL-NOS (HRS-like cells, P = .028; otherwise, P < .001). PTCL-NOS had a higher Ki-67 index than AITL (P = .001) and PTCL-Tfh (P = .002). Clinically, AITL had frequent B symptoms (versus PTCL-Tfh, P = .010), while PTCL-NOS exhibited low stage (versus AITL + PTCL-Tfh, P = .036). Positive Tfh markers were greater in AITL (3.5 ± 1.1) than PTCL-Tfh (2.9 ± 0.9; P = .006) and PTCL-NOS (0.5 ± 0.5; P < .001). Tfh markers showed close correlations among them and AITL-defining histology. By clustering analysis, AITL and PTCL-NOS were relatively exclusively clustered, while PTCL-Tfh overlapped with them. Survival was not different among the PTCL entities. By Cox regression, sex and ECOG performance status (PS) independently predicted shorter progression-free survival in the whole cohort (male, P = .001, HR = 2.5; PS ≥ 2, P = .010, HR = 1.9) and in 'Tfh-lymphomas' (ie, AITL + PTCL-Tfh) (male, P = .001, HR = 2.6; PS ≥ 2, P = .016, HR = 2.1), while only PS predicted shorter overall survival (OS) in the whole cohort (P = .012, HR = 2.7) and in 'Tfh-lymphomas' (P = .001; HR = 3.2). ICOS predicted favorable OS in 'Tfh-lymphomas' (log-rank; P = .016). Despite the overlapping features, nodal PTCL entities could be characterized by Tfh markers revealing clinicopathologic implications.

Bcl-6-dependent risk stratification by nuclear expression of Peli1 in diffuse large B-cell lymphoma.

Background/Aim: Peli1 is an E3 ubiquitin ligase involving lymphomagenesis by lysine 63 ubiquitination-mediated stabilization of Bcl-6 with in diffuse large B-cell lymphoma (DLBCL). Materials and Methods: We categorized nuclear expression of Peli1 according to Bcl-6 status by immunohistochemistry in DLBCL (n=100), and analyzed clinicopathologic association with prognosis. Results: We established Bcl-6/Peli1 risk model composed of high risk (Bcl-6+/Peli1+ or Bcl-6-/Peli1-; n=64) and low risk (Bcl-6+/Peli1- or Bcl-6-/Peli1+; n=36). High risk group had more frequent non-GCB subtype (83% vs 64%; p=0.033) and Bcl-6-negativity (69% vs 28%; p<0.001) than low risk group. Univariate survival analysis for progression-free survival (PFS) and overall survival (OS) revealed Bcl-6/Peli1 risk group (p=0.026 and p=0.021) and other conventional variables including international prognostic index (IPI), stage, ECOG performance status, number of extranodal sites were significant prognostic factors, along with B symptoms for OS. In multivariate analysis for PFS, Bcl-6/Peli1 risk group (p=0.032; HR=3.29), IPI (p=0.013; HR=3.39) and ECOG PS (p=0.035; HR=3.08) were independent prognostic factors. In multivariate analysis for OS, Bcl-6/Peli1 risk group (p=0.048; HR=7.87) and IPI (p=0.001; HR=12.15) were associated with prognosis. Conclusions: DLBCL had distinctive risk groups according to pairs of nuclear Peli1 and Bcl-6 expression. These results suggest the potential role of Peli1 and Bcl-6 in risk assessment in DLBCL.

Clinicopathologic implication of PD-L1 gene alteration in primary adrenal diffuse large B cell lymphoma.

BACKGROUND: Primary adrenal (PA) diffuse large B cell lymphoma (DLBCL) was previously reported as an aggressive subset of DLBCL, but its genetic features were not sufficiently characterized. From our previous study of DLBCL with programmed death-ligand 1 (PD-L1) gene alterations, we focused on PD-L1 gene alterations in PA-DLBCL with clinicopathologic implications. METHODS: We performed fluorescence in situ hybridization for PD-L1 gene translocation and amplification in PA-DLBCL (n = 18) and comparatively analyzed clinicopathologic characteristics with systemic non-adrenal (NA)-DLBCL (n = 90). RESULTS: PA-DLBCL harbored distinctive features (vs. NA-DLBCL), including high international prognostic index score (3-5) (72% [13/18] vs. 38% [34/90], p = .007), poor Eastern Cooperative Oncology Group performance score (≥ 2) (47% [7/15] vs. 11% [10/90], p = .003), elevated serum lactate dehydrogenase (LDH) (78% [14/18] vs. 51% [44/87], p = .035) and MUM1 expression (87% [13/15] vs. 60% [54/90], p = .047). Moreover, PA-DLBCL showed frequent PD-L1 gene alterations (vs. NA-DLBCL) (39% [7/18] vs. 6% [5/86], p = .001), including translocation (22% [4/18] vs. 3% [3/87], p = .016) and amplification (17% [3/18] vs. 2% [2/87], p = .034). Within the PA-DLBCL group, PD-L1 gene-altered cases (vs. non-altered cases) tended to have B symptoms (p = .145) and elevated LDH (p = .119) but less frequent bulky disease (≥ 10 cm) (p = .119). In the survival analysis, PA-DLBCL had a poor prognosis for overall survival (OS) and progression-free survival (PFS) (vs. NA-DLBCL; p = .014 and p = .004). Within the PA-DLBCL group, PD-L1 translocation was associated with shorter OS and PFS (p < .001 and p = .012). CONCLUSIONS: PA-DLBCL is a clinically aggressive and distinct subset of DLBCL with frequent PD-L1 gene alterations. PD-L1 gene translocation was associated with poor prognosis in PA-DLBCL.

Tumor spread through air spaces (STAS): prognostic significance of grading in non-small cell lung cancer.

Tumor spread through air spaces (STAS) is an invasive pattern of lung cancer that was recently described. In this study, we investigated the association between the extent of STAS and clinicopathological characteristics and patient outcomes in resected non-small cell lung cancers (NSCLCs). STAS has been prospectively described from 2008 and graded its extent with a two-tiered system (STAS I: <2500 µm [one field of ×10 objective lens] from the edge of tumor and STAS II: ≥2500 µm from the edge of tumor) from 2011 in Seoul National University Bundang Hospital. We retrospectively analyzed the correlations between the extent of STAS and clinicopathologic characteristics and prognostic significance in 1869 resected NSCLCs. STAS was observed in 765 cases (40.9%) with 456 STAS I (24.4%) and 309 STAS II (16.5%). STAS was more frequently found in patients with adenocarcinoma (ADC) (than squamous cell carcinoma), pleural invasion, lymphovascular invasion, and/or higher pathologic stage. In ADC, there were significant differences in recurrence free survival (RFS), overall survival (OS), and lung cancer specific survival (LCSS) according to the extent of STAS. In stage IA non-mucinous ADC, multivariate analysis revealed that STAS II was significantly associated with shorter RFS and LCSS (p < 0.001 and p = 0.006, respectively). In addition, STAS II was an independent poor prognostic factor for recurrence in both limited and radical resection groups (p = 0.001 and p = 0.023, respectively). In conclusion, presence of STAS II was an independent poor prognostic factor in stage IA non-mucinous ADC regardless of the extent of resection.

Hispidin rescues palmitate­induced insulin resistance in C2C12 myotubes.

Skeletal muscle serves an important role in the utilization of glucose during insulin­stimulated conditions. Excessive saturated fatty acids are considered to be a major contributing factor to insulin resistance in skeletal muscle cells. The present study investigated the effects of hispidin on palmitate­induced insulin resistance in C2C12 skeletal muscle myotubes via an MTT assay, glucose uptake assay, Oil­Red­O staining and western blot analysis. Hispidin reversed the palmitate­induced inhibition of glucose uptake, and inhibited palmitate­induced intracellular lipid accumulation. Hispidin suppressed insulin receptor substrate­1 Ser307 phosphorylation, and significantly promoted the activation of phosphatidylinositol­3­kinase and Akt, via inhibition of protein kinase C theta. Furthermore, hispidin treatment of C2C12 muscle cells increased glucose uptake via activation of adenosine monophosphate­activated protein kinase. These findings indicated that hispidin may improve palmitate­induced insulin resistance in skeletal muscle myotubes, and therefore hispidin treatment may be beneficial for patients with diabetes.

Polysaccharide isolated from the liquid culture broth of Inonotus obliquus suppresses invasion of B16-F10 melanoma cells via AKT/NF-κB signaling pathway.

A number of polysaccharides exhibit pharmacological activities. Polysaccharides derived from Inonotus obliquus (PLIO) appear to have various potential pharmacological properties, including anti­tumor activity. However, the molecular mechanisms underlying these properties remain to be elucidated. The present study investigated the anti­metastatic potential of PLIO and the underlying signaling pathways in B16­F10 murine melanoma cells using the MTT colorimetric assay, in vitro migration and invasion assays, and flow cytometric and western blot analyses. PLIO inhibited the invasion of B16­F10 cells and suppressed the expression of matrix metalloproteinases. PLIO treatment inhibited nuclear factor­κB (NF­κB) nuclear translocation in B16­F10 cells. In addition, PLIO treatment inhibited the phosphorylation of c-Jun N­terminal kinases and AKT. These results suggest that PLIO may suppress the invasion of highly metastatic melanoma cells via inhibition of the AKT/NF-κB signaling pathways.

Mechanism of macrophage activation induced by polysaccharide from Cordyceps militaris culture broth.

Mushroom-derived polysaccharides have been shown to stimulate immune responses. Our previous report showed that the novel polysaccharide PLCM isolated from the culture broth of Cordyceps militaris could induce nitric oxide production in the murine macrophage-like cell line RAW264.7. In this study, we show that PLCM enhances immunostimulatory activities such as the release of toxic molecules (nitric oxide and reactive oxygen species), secretion of the cytokine tumor necrosis factor (TNF)-α, and phagocytic uptake in RAW264.7 macrophages. In addition, all the specific inhibitors against the mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) (SN50, BAY11-7082, PD98059, SP600125 and SB203580) markedly suppressed the nitric oxide production and phagocytic uptake induced by PLCM. Moreover, antibodies specific to the extracellular domain of Toll-like receptor-2, Toll-like receptor-4 or the macrophage receptor Dectin-1 significantly attenuated PLCM-induced secretion of TNF-α. Our results indicate that the C. militaris polysaccharide activates macrophages through the MAPKs and NF-κB signaling pathways via Toll-like receptor 2, Toll-like receptor 4, and Dectin-1.

Inonotus obliquus-derived polysaccharide inhibits the migration and invasion of human non-small cell lung carcinoma cells via suppression of MMP-2 and MMP-9.

Polysaccharides isolated from the fruiting body of Inonotus obliquus (PFIO) are known to possess various pharmacological properties including antitumor activity. However, the anti-metastatic effect and its underlying mechanistic signaling pathway involved these polysaccharides in human non-small cell lung carcinoma remain unknown. The present study therefore aimed to determine the anti-metastatic potential and signaling pathways of PFIO in the highly metastatic A549 cells. We found that PFIO suppressed the migration and invasive ability of A549 cells while decreasing the expression levels and activity of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, PFIO decreased the phosphorylation levels of mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) as well as the expression level of COX-2, and inhibited the nuclear translocation of nuclear factor κB (NF-κB) in A549 cells. These results suggested that PFIO could suppress the invasion and migration of human lung carcinoma by reducing the expression levels and activity of MMP-2 and MMP-9 via suppression of MAPKs, PI3K/AKT, and NF-κB signaling pathways.

Cordyceps militaris extract protects human dermal fibroblasts against oxidative stress-induced apoptosis and premature senescence.

Oxidative stress induced by reactive oxygen species (ROS) is the major cause of degenerative disorders including aging and disease. In this study, we investigated whether Cordyceps militaris extract (CME) has in vitro protective effects on hydrogen peroxide-induced oxidative stress in human dermal fibroblasts (HDFs). Our results showed that the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of CME was increased in a dose-dependent manner. We found that hydrogen peroxide treatment in HDFs increased ROS generation and cell death as compared with the control. However, CME improved the survival of HDFs against hydrogen peroxide-induced oxidative stress via inhibition of intracellular ROS production. CME treatment inhibited hydrogen peroxide-induced apoptotic cell death and apoptotic nuclear condensation in HDFs. In addition, CME prevented hydrogen peroxide-induced SA-ß-gal-positive cells suggesting CME could inhibit oxidative stress-induced premature senescence. Therefore, these results suggest that CME might have protective effects against oxidative stress-induced premature senescence via scavenging ROS.

Polysaccharide from Inonotus obliquus inhibits migration and invasion in B16-F10 cells by suppressing MMP-2 and MMP-9 via downregulation of NF-κB signaling pathway.

Polysaccharides derived from Inonotus obliquus (PIO) are known to possess multiple pharmacological activities including antitumor activity. However, the possible molecular mechanisms of these activities are unknown. In the present study, we determined the anti-metastatic potential and signaling pathways of PIO in the highly metastatic B16-F10 mouse melanoma cell line in vitro. We found that PIO suppressed the migration and invasive ability of B16-F10 cells and decreased the expression levels and activities of matrix metalloproteinase (MMP)-2 and MMP-9. In addition, PIO decreased the phosphorylation levels of extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK); PIO also decreased the expression level of cyclooxygenase (COX)­2 and inhibited the nuclear translocation of nuclear factor κB (NF-κB) in B16-F10 melanoma cells. These results suggest that PIO could suppress the invasion and migration of B16-F10 melanoma cells by reducing the expression levels and activities of MMP-2 and MMP-9 through suppressing MAPK, COX-2 and NF-κB signaling pathways.

Effects of mulberry ethanol extracts on hydrogen peroxide-induced oxidative stress in pancreatic ß-cells.

Reactive oxygen species (ROS) are key mediators of mammalian cellular damage and are associated with diseases such as aging, arteriosclerosis, inflammation, rheumatoid arthritis and diabetes. Type 1 diabetes develops upon the destruction of pancreatic ß-cells, which is partly due to ROS activity. In this study, we investigated the cytoprotective and anti-oxidative effects of fractionated mulberry extracts in mouse insulin-producing pancreatic ß-cells (MIN6N cells). Treatment with hydrogen peroxide (H2O2) induced significant cell death and increased intracellular ROS levels, lipid peroxidation and DNA fragmentation in the MIN6N cells. Fractionated mulberry extracts significantly reduced the H2O2-dependent production of intracellular ROS, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and lipid peroxidation. In addition, mulberry extracts inhibited DNA fragmentation induced by H2O2. Thus, the antioxidant properties of mulberry extracts in pancreatic ß-cells may be exploited for the prevention or treatment of type 1 diabetes.