Microarray analysis reveals distinct gene set profiles for gastric and intestinal gastrointestinal stromal tumors.

AIM: We sought to address the mechanisms by which intestinal gastrointestinal stromal tumors (GIST) have a markedly higher risk of recurrence than gastric GISTs. MATERIALS AND METHODS: Gene expression levels were compared among six primary gastric, three intestinal and six metastatic liver GISTs using cDNA microarray. Protein levels of Slit homolog 2 (SLIT2) were analyzed by immunohistochemistry in 25 primary gastric and 10 intestinal GIST. RESULTS: Intestinal GIST had gene expression profiles similar to clinically malignant and metastatic GIST. In gene set-enrichment analysis, the gene sets MITOTIC_CELL CYCLE and NEURON_DIFFERENTIATION were up-regulated and down-regulated, respectively, in intestinal GIST compared to gastric GIST. High-risk gastric GISTs and intestinal GIST, expressed similar levels of SLIT2 protein, which were lower than those of low-risk gastric GISTs. CONCLUSION: The gene-expression profile of intestinal GISTs was similar to that of metastatic liver GISTs. Besides higher proliferative activity, down-regulation of SLIT2 might be involved in clinically malignant phenotypes of intestinal GIST.

Long-term outcomes and complications of trabeculectomy for secondary glaucoma in patients with familial amyloidotic polyneuropathy.

OBJECTIVE: Secondary glaucoma is a serious complication in patients with transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP). We assessed the long-term outcomes and complications of trabeculectomy with mitomycin C (MMC) for secondary glaucoma associated with FAP. METHODS: Medical case records of Kumamoto University Hospital were retrospectively reviewed. Twenty-one eyes of 13 patients (10 with FAP ATTR Val30Met; 3 with FAP ATTR Tyr114Cys) underwent trabeculectomy with MMC and follow-up of at least 2 years. The primary outcome measure was Kaplan-Meier survival, with failure of this treatment being defined as an intraocular pressure (IOP) of ≤5 mm Hg or ≥22 mm Hg on two consecutive visits or as additional operations needed to reduce IOP. Secondary outcome measures included complications, bleb characteristics, and additional postoperative interventions required. RESULTS: The mean postoperative follow-up period was 5.7 years (range, 2.2-12.7 years). Kaplan-Meier analysis indicated probabilities of success of 0.76, 0.67, and 0.53 at 1, 2, and 3 years after operation, respectively. Significant complications included ocular decompression retinopathy in 7 eyes (33%) and bleb encapsulation in 10 eyes (48%). Twelve eyes (57%) needed additional surgery, such as bleb revision or trabeculectomy with MMC, to reduce IOP. CONCLUSIONS: Trabeculectomy with MMC may not be optimal for patients with FAP-related glaucoma and may have several significant complications.

Manifestations of transthyretin-related familial amyloidotic polyneuropathy: long-term follow-up of Japanese patients after liver transplantation.

PURPOSE: To observe which symptoms of transthyretin-related familial amyloidotic polyneuropathy (FAP) progressed in the long term after liver transplantation (LT), focusing on cardiac, kidney, and ocular symptoms. METHODS: We reviewed the medical records of 34 Japanese patients with FAP, who underwent LT between 1994 and 2006. The mean follow-up period (± SD) after LT was 9.6 ± 3.4 years. Of the 34 patients, 30 had FAP amyloidogenic transthyretin (ATTR) Val30Met, 1 had FAP ATTR Ser50Ile, and 3 had FAP ATTR Tyr114Cys. RESULTS: The 10-year survival rates from the onset of FAP and from the time of LT were 100% and 91.4%, respectively. Progression of ocular amyloidosis was seen in 17 (50%) patients, 13 of whom had de novo amyloid deposits in the vitreous body; progression of cardiac amyloidosis was seen in 10 (29%) patients, 4 of whom had newly granular sparkling echo on echocardiography, and 9 of whom had newly implanted pacemakers or implantable cardioverter-defibrillators. Although the mean serum creatinine levels did not increase significantly after LT in any of the patients, the estimated glomerular filtration rate had decreased significantly by 7 years after LT. CONCLUSION: Although LT is life-saving for patients with FAP, we observed progression of the ocular and cardiac symptoms of FAP in a significant number of these patients over the long term after LT.

Suppression of choroidal neovascularization by N-acetyl-cysteine in mice.

PURPOSE: N-acetyl-cysteine (NAC) is a potent antioxidant known to be a precursor of glutathione. The purpose of this study was to investigate the role of NAC in the development of choroidal neovascularization (CNV). METHODS: CNV was induced in C57BL/6 mice by laser photocoagulation of the ocular fundus. Mice were injected intraperitoneally with NAC or vehicle alone. The levels of 4-hydoroxy-2-nonenal (4-HNE)-modified protein and nucleus factor (NF)-κB were determined by wester blotting. The recruitment of macrophages and neutrophils after laser injury was analyzed immunohistochemically and in myeloperoxidase (MPO) assays. Enzyme-linked immunosorbent assays (ELISA) were used to measure monocyte chemotactic protein (MCP)-1, CXCL1, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. The extent of CNV was evaluated 7 d after laser injury by lectin staining. RESULTS: In NAC-treated mice with laser-induced injuries, the induction of 4-HNE-modified protein after 3 hr and the activation of NF-κB in nuclear extracts after 6 hr were markedly suppressed compared to vehicle-treated mice. Macrophage and neutrophil recruitment were inhibited and the levels of MCP-1, CXCL1, VEGF, and VEGFR-1 were also lower in NAC-treated mice compared to vehicle-treated mice. Furthermore, the extent of CNV induced was significantly lower in NAC-treated compared to vehicle-treated mice (p = 0.027). CONCLUSIONS: Our results clearly showed that NAC inhibited indicators of oxidative stress and the activation of NF-κB induced by laser injury, and, consequently, suppressed macrophage and neutrophil infiltration and the development of CNV. This suggests novel preventative and interventional therapeutic strategies for age-related macular degeneration.

Photodynamic therapy alone versus combined with intravitreal bevacizumab for neovascular age-related macular degeneration without polypoidal choroidal vasculopathy in Japanese patients.

BACKGROUND: To compare 12-month results of two single initial treatments--photodynamic therapy with verteporfin alone (PDT group), and this therapy combined with intravitreal bevacizumab (IVB) (COMB group)--for neovascular age-related macular degeneration (AMD), not including patients with polypoidal choroidal vasculopathy (PCV) who were presumed to have AMD. METHODS: This retrospective study evaluated 23 eyes in the PDT group and 22 eyes in the COMB group. IVB (1.25 mg) was administered within 2 weeks after PDT. Main outcome measures were best-corrected visual acuity (VA), central foveal thickness by optical coherence tomography, and number of treatments. RESULTS: At month 12, the PDT group had gained 0.7 letter mean VA and the COMB group, 8.8 letters (P = 0.04). Ten eyes (43%) in the PDT group and 19 eyes (86%) in the COMB group received only one treatment, and significant difference was found (P = 0.005). No severe ocular or systemic safety concerns were discovered. CONCLUSIONS: Our 12-month results of PDT combined with IVB for Japanese patients with AMD without PCV appeared to be more effective than those of PDT alone with fewer treatments.

[Spontaneous regression of hepatocellular carcinomas].

We report a rare case of spontaneous regression (SR) of hepatocellular carcinoma (HCC). A 70-year-old man consulted us for general fatigue. Enhanced abdominal computed tomography (CT) showed two HCCs, of 5cm in the posterior segment and 8cm around the right Glissonean pedicle with tumor thrombus in the main portal trunk. He refused to undergo any treatment, but 28 months later, CT showed complete disappearance of the hilar tumor and portal tumor thrombus, and partial regression in the posterior tumor with shrinkage of the right lobe of the liver. His PIVKA-II levels decreased from 23358 to 217mAU/ml. In the present case, tumor infarction of the portal thrombus, and the administration of imidapuril hydrochloride and Hochu-ekki-to may have caused SR.

Impact of liver transplantation on transthyretin-related ocular amyloidosis in Japanese patients.

OBJECTIVE: To evaluate the long-term impact of liver transplantation on ocular manifestations of familial amyloid polyneuropathy (FAP) in Japanese patients. METHODS: Medical records were retrospectively reviewed in a long-term follow-up study. Of 52 patients with FAP amyloidogenic transthyretin Val30Met, 22 patients underwent liver transplantation. We assessed ocular manifestations, including amyloid deposition at the pupillary border, pupillary border with irregularity, vitreous opacities, and glaucoma, in patients who underwent liver transplantation. In addition, we compared the clinical characteristics of vitreous opacities-the most common ocular manifestation of FAP-in patients who underwent liver transplantation and those who did not to determine the effect of transplantation on the progression of ocular amyloidosis. RESULTS: Mean time after FAP onset was 10 years and after liver transplantation was 7 years in patients who underwent liver transplantation. All ocular manifestations increased with time after transplantation. Eight patients (36%) developed vitreous opacities and 4 patients (18%) developed glaucoma during follow-up. Mean time from FAP onset to vitreous opacities onset was significantly shorter in patients with early-onset disease who underwent liver transplantation than in those who did not. CONCLUSIONS: Patients with FAP who undergo liver transplantation continue to have a long-term risk of severe ocular manifestations, especially vitreous opacities and glaucoma, which can restrict their daily lives, even after liver transplantation.

Novel therapy for transthyretin-related ocular amyloidosis: a pilot study of retinal laser photocoagulation.

OBJECTIVE: The occurrence of ocular complications associated with transthyretin-related familial amyloidotic polyneuropathy increases with time, even after liver transplantation, which leads to a halt in the progression of systemic neurologic complications. This study investigated a new strategy to prevent ocular involvements. DESIGN: Two interventional case reports. PARTICIPANTS: Two patients with familial amyloidotic polyneuropathy who had progressive ocular manifestations. METHODS: We used panretinal laser photocoagulation, which damages the retinal pigment epithelium, the main location for synthesis of amyloidogenic transthyretin in ocular tissues, to treat 1 eye of each patient. After laser photocoagulation, we performed general ophthalmic examinations every 3 months for 3 years. MAIN OUTCOME MEASURES: Fundus photography, visual acuity, and intraocular pressure. RESULTS: Panretinal laser photocoagulation clearly prevented progression of amyloid deposition in the vitreous and on the retinal surface in both cases during 3 years of follow-up. No serious complications occurred. CONCLUSIONS: Panretinal laser photocoagulation is a safe and well-known procedure that offers a new treatment option to mitigate ocular manifestations in patients with transthyretin-related familial amyloidotic polyneuropathy.

Suppression of choroidal neovascularization in lectin-like oxidized low-density lipoprotein receptor type 1-deficient mice.

PURPOSE: To elucidate the role of the scavenger receptor, lectin-like oxidized low-density lipoprotein receptor type 1 (LOX-1), in the formation of choroidal neovascularization (CNV). METHODS: CNV was induced by laser photocoagulation of the ocular fundus in mice. The expression of LOX-1 mRNA and protein after laser injury was determined by real-time RT-PCR and Western blot analysis. Gelatin zymography was used to measure the activity of matrix metalloproteinase (MMP)-2 and pro-MMP-9, and ELISA was used to determine monocyte chemoattractant protein (MCP)-1 and vascular endothelial growth factor (VEGF) levels. At 14 days after laser injury, the extent of CNV was evaluated by fluorescein angiography and lectin staining using confocal microscopy. RESULTS: In wild-type mice, the relative expression level of LOX-1 mRNA compared with the control increased significantly 6 hours after laser injury and peaked 12 hours after laser injury (P = 0.011 and P = 0.0006, respectively), and the expression of LOX-1 protein was also detected 1 and 3 days after laser injury. Increases in MMP-2, pro-MMP2, and pro-MMP-9 after laser injury were reduced in LOX-1-deficient mice compared with wild-type mice. At 3 days after laser injury, increases in MCP-1 and VEGF significantly decreased in LOX-1-deficient mice compared with wild-type mice (P = 0.014 and P = 0.001, respectively). Morphometric analyses revealed that the induction of CNV formation was significantly inhibited in LOX-1-deficient mice. CONCLUSIONS: These results suggest that LOX-1 plays an important role in the formation of CNV. This scavenging system might thus be a novel therapeutic target for CNV.

Long-term relationship between intraocular pressure and visual field loss in primary open-angle glaucoma.

PURPOSE: To investigate the dependence upon intraocular pressure (IOP) of the progression of visual field defects in eyes with primary open-angle glaucoma (POAG), in which the mean IOP was maintained at < or =21 mm Hg. METHODS: This study involved 100 eyes with POAG, which were followed up for > or =5 years. The mean IOP levels were maintained at < or =21 mm Hg during the follow-up period. The relationship between the IOP and the progression of visual field defects, which was scored using the Advanced Glaucoma Intervention Study criteria, was investigated retrospectively. RESULTS: Compared with the baseline scores, the visual field defect scores had significantly worsened by the end of the follow-up period (P<0.0001, Wilcoxon paired signed rank test). The change in the visual field defect score (2.5+/-0.5) in eyes with average IOP levels of > or =16 mm Hg (n=36) was significantly greater (P=0.031, Mann-Whitney U test) than the change (1.3+/-0.3) in eyes with average IOP levels of <16 mm Hg (n=64). Moreover, IOP of > or =18 mm Hg made a major contribution to the aggravation of visual field defects in eyes with POAG. CONCLUSIONS: Eyes with POAG and with mean IOP levels maintained at < or =21 mm Hg underwent IOP-dependent progression of their visual field defects. Our results suggest that further IOP lowering would be beneficial in such cases.

Desmoid tumor presenting as a superior sulcus tumor: a unique bone change in the vertebral body.

Desmoid tumor, also referred to as aggressive fibromatosis, is a relatively rare, locally infiltrative, histologically benign tumor. This report details a case of desmoid tumor presented as a superior sulcus tumor, which showed a unique manifestation in the vertebral bodies on computed tomography.

[Clinical results of amniotic membrane transplantation in Miyata Eye Hospital according to surgical methods].

PURPOSE: To evaluate clinical results of amniotic membrane transplantation according to three methods : graft, patching, and stuffing. SUBJECT AND METHODS: We retrospectively reviewed 65 patients(65 eyes) who received amniotic membrane transplantation by the three methods, graft, patching or stuffing during the period of March 1998 to May 2003 in the Miyata Eye Hospital. Application of surgery was determined as follows : graft with limbal transplantation for limbal dysfunction, patching for prolonged epithelial defect, and stuffing for corneal perforation. The criteria of success were defined as corneal and conjunctival epithelialization and prevention of invasion of proliferative tissues beyond the limbus for graft, corneal epithelialization for patching, and occlusion of perforated cornea at first use for stuffing, respectively.

Limbal allograft, amniotic membrane transplantation, and intraoperative mitomycin C for recurrent pterygium.

OBJECTIVE: To conduct a pilot study evaluating the efficacy and safety of limbal allograft, preserved amniotic membrane transplantation, and intraoperative mitomycin C treatment for recurrent pterygium. DESIGN: Prospective, noncomparative, interventional case series. PARTICIPANTS: Twelve eyes of 11 patients with recurrent pterygium. The mean number of previous surgeries for pterygium was 1.9+/-1.4 (range, 1-6). INTERVENTION: All subjects received limbal allograft, preserved amniotic membrane transplantation, and intraoperative mitomycin C. MAIN OUTCOME MEASURES: Pterygium recurrence and complications. RESULTS: The mean follow-up period was 21.6+/-5.6 months (range, 16-36 months). There was no pterygium recurrence in any of the eyes. Symblepharon reappeared in 3 eyes and diplopia recurred in 2 eyes. There were no other surgical complications and there was no graft rejection. CONCLUSIONS: Limbal allograft, preserved amniotic membrane transplantation, and intraoperative mitomycin C may be a safe and effective procedure for recurrent pterygium.

Hepatocellular carcinoma associated with autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a disorder of unknown etiology, which often progresses to cirrhosis and carries a high mortality, even though its treatment with corticosteroids has become common. Hepatocellular carcinoma (HCC) has been reported as a rare complication of AIH. We describe herein a patient with HCC associated with AIH, in whom microwave coagulation therapy provided a means of definitive management, and we also review the literature. Male sex and longstanding cirrhosis seem to be the risk factors for hepatocarcinogenesis in AIH. The prognosis of this disease is extremely poor because of the low resectability caused by poor hepatic reserve. It is important to pay attention to hepatic disorders and the possible development of HCC at the time of diagnosis of AIH. Surgeons should select suitable treatment, without undue surgical stress, whenever the diagnosis of HCC has been established. Microwave coagulation therapy is a preferred option for the treatment of high-risk patients with poor hepatic reserve or unresectable multiple HCCs.