A case of retinoblastoma resulting in phthisis bulbi after proton beam radiation therapy.

Purpose: Proton beam radiation therapy (PBRT) is a treatment option for advanced retinoblastoma (RB) resistant to chemotherapy and focal ophthalmic treatment. Here we report a case of RB with phthisis bulbi following PBRT. Observations: A 16-day-old boy with a family history of RB was referred to our institution. Initial examination revealed an extensive white mass in the right eye and a small tumor near the optic disk of the left eye. The patient was diagnosed with bilateral RB and treated with chemotherapy and focal ophthalmic therapy. The right eye showed shrinkage in the treatment course. The tumor control was not achieved bilaterally, and, therefore, PBRT was performed to preserve the eyes. However, the right eye became significantly phthisical following PBRT and ultimately required enucleation. Conclusions and importance: PBRT for RB may result in phthisis bulbi. Further investigations of its role and possible complications are warranted.

Clinical course of a Japanese girl with Leber congenital amaurosis associated with a novel nonsense pathogenic variant in NMNAT1: a case report and mini review.

Leber congenital amaurosis (LCA), although rare, is one of the most severe forms of early-onset inherited retinal dystrophy (IRD). Here, we review the molecular genetics and phenotypic characteristics of patients with NMNAT1-associated IRD. The longitudinal clinical and molecular findings of a Japanese girl diagnosed with LCA associated with pathogenic variants in NMNAT1 c.648delG, (p.Trp216Ter*) and c.709C>T (p.Arg237Cys) have been described to highlight the salient clinical features of NMNAT1-associated IRD.

New onset or exacerbation of uveitis with infliximab: paradoxical effects?

OBJECTIVE: To report four cases of new onset or exacerbation of uveitis following administration of infliximab. METHODS: This retrospective observational case series includes four patients who developed new onset or exacerbation of uveitis paradoxically during infliximab treatment. RESULTS: Four patients were assessed, including three women, with a mean age of 33 (14-84) years. Infliximab was introduced for the treatment of scleritis associated with rheumatoid arthritis (two cases), chronic anterior uveitis associated with juvenile idiopathic arthritis (JIA) (one case) and Crohn's disease (one case). Anterior scleritis associated with rheumatoid arthritis successfully improved following infliximab administration; however, macular oedema or dense vitritis paradoxically developed in two cases. In one case, infliximab was switched to tocilizumab. In another case, infliximab was discontinued, and additional corticosteroids and immunosuppressive medications were added. In one patient with JIA, new-onset macular oedema and exacerbation of anterior uveitis were observed during infliximab treatment, so the patient was switched to adalimumab. In the patient with Crohn's disease treated with infliximab, severe vasculitis and macular oedema occurred, requiring intravitreal triamcinolone injection. The patient was switched to adalimumab. Given that these reactions were paradoxical effects of infliximab, infliximab treatment was discontinued in all cases, and additional corticosteroids or immunosuppressive medications were added. All cases remained free of ocular inflammation at the last visit. CONCLUSION: Uveitis rarely occurs de novo or is exacerbated during infliximab treatment. Cessation of infliximab led to resolution of this paradoxical adverse effect.

The Effect of Low-dose Cyclosporine (100 mg Once Daily) for Chronic Vogt-Koyanagi-Harada Disease.

Purpose: To determine the effect of low-dose cyclosporine (CyA) treatment for patients with chronic Vogt-Koyanagi-Harada (VKH) disease resistance to systemic corticosteroid treatment. Methods: We retrospectively evaluated patients diagnosed with chronic VKH disease resistance to systemic corticosteroid treatment at Japan Community Health Care Organization (JCHO) Osaka Hospital between March 2013 and March 2016. We followed the observation with systemic low-dose CyA (100 mg once daily) treatment of these patients. The patients were divided into two groups, anterior ocular inflammation group and posterior ocular inflammation group. Demographic data were reviewed, including age, gender, the existence of inflammation at the initial visit and three months after CyA treatment, and side effect. Results: Twenty-three eyes of thirteen patients with chronic VKH disease were included in this study (11 women, 2 men; mean age, 54.6±11.9 years). Nine cases showed anterior ocular inflammation and seven cases showed posterior ocular inflammation (includes overlapping cases). Thirteen of fourteen eyes in the anterior ocular inflammation group subsided at three months after CyA treatment, and ten of thirteen eyes in the posterior ocular inflammation group subsided at three months after treatment. We had to stop the treatment in one patient because of severe increase of serum triglyceride. Conclusions: Low-dose CyA treatment was effective in patients with chronic VKH resistance to systemic corticosteroid treatment. Our results suggest that this treatment was more effective in the anterior ocular inflammation group than in the posterior ocular inflammation group; however, a larger number of patients and longer observation periods are needed to confirm these results.

Steroid Resistant Vogt-Koyanagi-Harada Disease Treated Effectively with Cyclosporine.

Purpose: To report two cases of Vogt-Koyanagi-Harada disease (VKH) resistant to systemic corticosteroid therapy, effectively treated with systemic cyclosporine. Case 1: A 52-year-old man diagnosed as VKH was administered oral corticosteroids (40 mg/day), following steroid pulse therapy. Since there was no significant improvement, he underwent a second course of steroid pulse therapy and oral corticosteroid administration (40 mg/day). However, there was still no improvement, and a combination therapy of both oral corticosteroids (40 mg/day) and cyclosporine 200 mg (3 mg/kg) was administered. As a result, the inflammation subsided and the dosage of the drugs was tapered successfully. Case 2: A 50-year-old man diagnosed as VKH underwent two courses of steroid pulse therapy, which did not improve significantly. We performed combination therapy of both corticosteroids and cyclosporine, similar to the case described above and obtained good results. Conclusion: Our experience of these two cases indicates that systemic cyclosporine treatment was effective in the management of VKH patients resistant to conventional systemic corticosteroid therapy.

Simultaneous analyses of vitreous levels of 27 cytokines in eyes with retinopathy of prematurity.

PURPOSE: To determine the vitreous levels of 27 types of cytokines in eyes with retinopathy of prematurity (ROP). DESIGN: Retrospective case-control study. PARTICIPANTS: Twenty-seven eyes of 19 infants with stage 4 ROP were studied. Six eyes of 5 patients with congenital cataract who underwent lensectomy were used as controls. METHODS: The ROP eyes were divided into 2 groups according to vascular activity: 12 eyes with vascularly active ROP and 15 eyes with vascularly inactive ROP. Undiluted vitreous samples were collected, and the vitreous concentrations of 27 types of cytokines were determined by a multiplex bead analysis system: interleukin (IL)-1b, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, fibroblast growth factor (FGF) basic, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interferon-r, interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)-1a, MIP-1b, platelet-derived growth factor bb, regulated on activation, normal T cell expressed and secreted (RANTES), tumor necrosis factor alpha, and vascular endothelial growth factor (VEGF). MAIN OUTCOME MEASURES: The vitreous levels of the 27 types of cytokines and a comparison of the levels in the 3 groups. RESULTS: The postmenstrual age at vitrectomy was significantly younger in the vascularly active ROP eyes than in vascularly inactive ROP eyes. The cytokines that had significantly different vitreous levels among the 3 groups were: IL-6, IL-7, IL-10, IL-15, Eotaxin, FGF basic, G-CSF, GM-CSF, IP-10, RANTES, and VEGF (P<0.05). The vitreous levels of IL-6, IL-7, IL-15, Eotaxin, G-CSF, IP-10, and RANTES were significantly higher (P<0.05) in both vascularly active and inactive ROP eyes than in control eyes, whereas the vitreous level of VEGF was significantly higher (P<0.05) only in vascularly active ROP eyes than in control eyes. There was a significantly negative correlation (r = -0.382; P = 0.0495) between the VEGF level and the postmenstrual age at vitrectomy. CONCLUSIONS: These results indicate that, although cytokines other than VEGF may be involved in the pathologic changes in eyes with ROP, VEGF is likely to have the strongest correlation with the vascular activity in ROP eyes among these cytokines.

Vitreous levels of erythropoietin and vascular endothelial growth factor in eyes with retinopathy of prematurity.

PURPOSE: To determine the vitreous levels of erythropoietin and vascular endothelial growth factor (VEGF) in eyes with retinopathy of prematurity (ROP) and to study the correlation between the 2 levels. DESIGN: Retrospective case-control study. PARTICIPANTS: Forty eyes of 27 infants with stage 4 ROP (4A, 30 eyes; 4B, 10 eyes) were studied. Five eyes of 4 patients with congenital cataract were used as controls. METHODS: The eyes with ROP were classified by the vascular activity into 3 groups: highly vascular-active ROP (n = 16), moderately vascular-active ROP (n = 10), and mildly vascular-active ROP (n = 14). Eyes with highly vascular-active ROP initially received an intravitreal injection of 0.5 mg bevacizumab and underwent vitrectomy approximately 1 week after the injection. The eyes in the other groups underwent vitrectomy without bevacizumab. Undiluted vitreous samples were obtained at the beginning of vitrectomy, and the vitreous concentrations of erythropoietin and VEGF were measured by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: The vitreous concentrations of erythropoietin and VEGF were determined and compared among the 4 groups. RESULTS: The vitreous level of erythropoietin was significantly higher (P<0.05) in the highly and moderately vascular-active ROP eyes than in control eyes. The median concentration of erythropoietin was 744.6 mIU/ml in the highly vascular-active ROP eyes, 729.9 mIU/ml in the moderately vascular-active ROP eyes, 478.0 mIU/ml in the mildly vascular-active ROP eyes, and 0 mIU/ml in control eyes. The vitreous VEGF level was significantly higher (P<0.05) in the moderately vascular-active ROP eyes than in control eyes. The median concentration of VEGF was 44.7 pg/ml in the highly vascular-active ROP eyes that had received an intravitreal bevacizumab injection, 360.8 pg/ml in the moderately vascular-active ROP eyes, 0 pg/ml in the mildly vascular-active ROP eyes, and 11.4 pg/ml in control eyes. There was a significant positive correlation (r = 0.410; P = 0.047) between the erythropoietin and VEGF levels in moderately and mildly vascular-active ROP eyes. CONCLUSIONS: The elevated level of erythropoietin and its correlation with the VEGF level in eyes with stage 4 ROP suggest that not only VEGF but also erythropoietin may contribute to the pathogenesis of ROP. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Effect of transcorneal electrical stimulation in patients with nonarteritic ischemic optic neuropathy or traumatic optic neuropathy.

PURPOSE: To determine whether transcorneal electrical stimulation (TES) can improve the visual function of patients with nonarteritic ischemic optic neuropathy (NAION) or traumatic optic neuropathy (TON). METHODS: Eight consecutive patients at the Osaka University Hospital were studied. TES (600-800 microA, 20 Hz, 30 min) was applied once each to three eyes with NAION and to five eyes with TON, using a contact lens-type stimulating electrode. The primary outcome measurement was the change in visual acuity at 1 to 3 months after TES. An improvement in visual acuity was defined as a change of > or =0.3 log (minimum angle of resolution) (logMAR) units. The side effects of TES were also investigated. RESULTS: After TES application, the visual acuity improved in two patients with NAION and in four patients with TON. Visual acuity did not worsen in any of the eyes. Only a mild superficial punctuate keratopathy was observed in all eyes immediately after TES, and it healed by the next day. CONCLUSIONS: Visual acuity can be improved after TES without major complications in some patients with NAION or TON. These results suggest that TES should be considered as a new treatment for eyes with optic neuropathy.

Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.

Patients with chronic hepatitis C virus (HCV) infection often develop liver cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection. Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at random into two groups. Forty-four patients were treated with alpha-tocopherol (Vit E group) while the other 39 were followed as controls. The clinical background (gender, age, and laboratory data) was similar in the two groups. Serum levels of alpha-tocopherol, albumin, alanine aminotransferase (ALT), and total cholesterol and platelet count were measured serially over a period of five years. The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment. Platelet count, serum albumin, ALT, and total cholesterol were not different between the two groups during the five-year period. Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls, albeit statistically insignificant. The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV. Although the administration of alpha-tocopherol normalized the level one month later, it could neither improve liver function, suppress hepatocarcinogenesis, nor improve cumulative survival. Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant.

Expression and purification of a small cytokine growth-blocking peptide from armyworm Pseudaletia separata by an optimized fermentation method using the methylotrophic yeast Pichia pastoris.

A small multifunctional cytokine, growth-blocking peptide (GBP), from the armyworm Pseudaletia separata larvae was expressed as a soluble and active recombinant peptide in the methylotrophic yeast Pichia pastoris. An expression vector for GBP secretion was constructed using vector pPIC9, and GBP was expressed under the control of the alcohol oxidase (AOX1) promoter. Although we first tried to cultivate GBP in shake flask cultures, the yield was low, probably due to proteolysis of the recombinant protein. To overcome this problem, we utilized a high-density fermentation method. The pH of the medium in the fermenter was kept at 3.0, and the medium was collected within 48h post methanol shift to minimize exposure of the target peptide to proteases. Recombinant GBP was purified through three reverse-phase HPLC columns. We characterized the 25 amino acid GBP by molecular mass spectrometry and amino acid sequencing. Plasmatocyte spreading, one of the activities of GBP, was similar between chemically synthesized GBP and purified recombinant GBP. Up to 50mg GBP was recovered per 1L of yeast culture supernatant.