Diffuse infiltrating retinoblastoma invading subarachnoid space

We report herein an unusual case of diffuse infiltrating retinoblastoma involving the brain, which caused a patient’s death 27 months after enucleation. An eight-year-old boy complained of blurred vision in his right eye (OD) in October 2006. Funduscopic examination showed optic disc swelling, dense whitish vitreous opacity, and an orange-colored subretinal elevated lesion adjacent to the optic disc. Fluorescein angiography revealed hyperfluorescence in the peripapillary region at an early-phase OD. Because the size of the subretinal lesion and vitreous opacity gradually increased, he was referred to us. His visual acuity was 20/1000 OD on June 20, 2007. Slit-lamp biomicroscopy showed a dense anterior vitreous opacity. Ophthalmoscopically, the subretinal orange-colored area spread out until reaching the mid peripheral region. A B-mode sonogram and computed tomography showed a thick homogeneous lesion without calcification. Gadolinium-enhanced magnetic resonance imaging showed a markedly enhanced appearance of the underlying posterior retina. Enucleation of the right eye was performed nine months after the initial presentation. Histopathology demonstrated retinal detachment and a huge choroidal mass invading the optic nerve head. The tumor was consistent with diffuse infiltrating retinoblastoma. The patient died due to brain involvement 27 months after enucleation. Ophthalmologists should be aware that diffuse infiltrating retinoblastoma may show an unfavorable course if its diagnosis is delayed

Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells

Immunoglobulin G4-related disease (IgG4-RD) is a systemic disorder characterized by tissue fibrosis and intense lymphoplasmacytic infiltration, causing progressive organ dysfunction. Activation-induced cytidine deaminase (AID), a deaminase normally expressed in activated B-cells in germinal centers, edits ribonucleotides to induce somatic hypermutation and class switching of immunoglobulin. While AID expression is strictly controlled under physiological conditions, chronic inflammation has been noted to induce its upregulation to propel oncogenesis. We examined AID expression in IgG4-related ophthalmic disease (IgG4-ROD; n = 16), marginal zone lymphoma with IgG4-positive cells (IgG4+ MZL; n = 11), and marginal zone lymphoma without IgG4-positive cells (IgG4- MZL; n = 12) of ocular adnexa using immunohistochemical staining. Immunohistochemistry revealed significantly higher AID-intensity index in IgG4-ROD and IgG4+ MZL than IgG4- MZL (p < 0.001 and = 0.001, respectively). The present results suggest that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation, and AID may be a driver of oncogenesis in IgG4-ROD to IgG4+ MZL

A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4+ plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (IL)-4/β-actin, IL-10/β-actin, IL-13/β-actin, transforming growth factor (TGF) β1/β-actin, and FOXP3/β-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis

Phosphorylation of drebrin by cyclin-dependent kinase 5 and its role in neuronal migration.

Cyclin-dependent kinase 5 (Cdk5)-p35 is a proline-directed Ser/Thr kinase which plays a key role in neuronal migration, neurite outgrowth, and spine formation during brain development. Dynamic remodeling of cytoskeletons is required for all of these processes. Cdk5-p35 phosphorylates many cytoskeletal proteins, but it is not fully understood how Cdk5-p35 regulates cytoskeletal reorganization associated with neuronal migration. Since actin filaments are critical for the neuronal movement and process formation, we aimed to find Cdk5 substrates among actin-binding proteins. In this study, we isolated actin gels from mouse brain extracts, which contain many actin-binding proteins, and phosphorylated them by Cdk5-p35 in vitro. Drebrin, a side binding protein of actin filaments and well known for spine formation, was identified as a phosphorylated protein. Drebrin has two isoforms, an embryonic form drebrin E and an adult type long isoform drebrin A. Ser142 was identified as a common phosphorylation site to drebrin E and A and Ser342 as a drebrin A-specific site. Phosphorylated drebrin is localized at the distal area of total drebrin in the growth cone of cultured primary neurons. By expressing nonphosphorylatable or phosphorylation mimicking mutants in developing neurons in utero, the reversible phosphorylation/dephosphorylation reaction of drebrin was shown to be involved in radial migration of cortical neurons. These results suggest that Cdk5-p35 regulates neuronal migration through phosphorylation of drebrin in growth cone processes

Intestinal Mucosa-Associated Lymphoid Tissue Lymphoma Transforming into Diffuse Large B-Cell Lymphoma in a Young Adult Patient with Neurofibromatosis Type 1: A Case Report

Background: Neurofibromatosis type 1 (NF1) is a hereditary cancer syndrome characterized by multiple caf&eacute;-au-lait macules on the skin. Lymphoproliferative malignancies associated with NF1 are limited, although the most common are brain tumors. Case presentation: A 22-year-old woman with NF1 was admitted due to abdominal pain and bloody diarrhea. Her laboratory data exhibited macrocytic anemia and elevated IgA levels. Image studies showed diffuse increased wall thickening in the transverse and descending colon without lymphadenopathy and hepatosplenomegaly. A colonoscopy revealed a hemorrhagic ulcerated mass. Pathological analysis of the tumor tissues confirmed IgA-expressing mucosa-associated lymphoid tissue (MALT) lymphoma with histological transformation. Moreover, whole-exome sequencing in tumor tissues and peripheral blood mononuclear cells identified a somatic frameshift mutation of the A20 gene, which represents the loss of function. The patient responded well to R-CHOP chemotherapy, but the disease relapsed after 1 year, resulting in a lethal outcome. Conclusions: MALT lymphoma in children and young adults is extremely rare and is possibly caused by acquired genetic changes. This case suggests a novel association between hereditary cancer syndrome and early-onset MALT lymphoma