Feasibility of partial-orbit irradiation as a treatment strategy for patients with orbital mucosa-associated lymphoid tissue lymphoma.

OBJECTIVE: For early-stage orbital mucosa-associated lymphoid tissue lymphoma (MALToma), radiotherapy (RT) is known to be the treatment of choice. The classical recommended treatment field is the entire ipsilateral orbit, exposing normal orbital structures such as the lacrimal gland and lens, which are sensitive to moderate doses of radiation, to the full treatment dose. Herein we aimed to evaluate the clinical outcomes and dosimetric values in patients with orbital MALToma who received RT. DESIGN: This study was a retrospective study. PARTICIPANTS: Forty patients with orbital MALToma treated with curative RT. METHODS: The patients were classified into the conjunctival RT (n = 23), partial-orbit RT (n = 10), and whole-orbit RT (n = 7) groups. The treatment outcomes and dosimetric values of the orbital structures were reviewed. RESULTS: We found the 5-year local, contralateral orbit, and overall relapse rates to be 5.0%, 5.9%, and 16.0%, respectively. Local relapse events occurred in 2 patients in the conjunctival RT group. No relapse was observed in the partial-orbit RT group. Whole-orbit RT caused significantly higher rates of dry eyes during treatment. The partial-orbit RT group showed a significantly lower ipsilateral eyeball mean dose and ipsilateral eyelid mean dose than the other groups. CONCLUSION: Partial-orbit RT showed encouraging clinical, toxicity, and dosimetric outcomes in patients with orbital MALToma and has the potential to be a treatment option for such patients.

Longitudinal association of thyroid-stimulating immunoglobulin levels with clinical characteristics in thyroid eye disease.

OBJECTIVES: The clinical course of thyroid eye disease (TED) is heterogeneous and predicting patients who may develop the severe sequelae of the disease is difficult. In this study, we evaluated the longitudinal association between changes in serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb) levels and course of disease activity and severity over time. DESIGN: This was a multicentre, prospective, observational study. SETTING: Fifteen tertiary care oculoplastic service centres in Korea. PARTICIPANTS: Seventy-six patients with newly diagnosed TED were included and followed up for 12 months. METHODS: We evaluated clinical characteristics and serum TRAb levels at baseline, 6 and 12 months of TED diagnosis. Additionally, we analysed longitudinal associations between the serum TRAb levels and clinical activity score (CAS), no signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, sight loss (NOSPECS) score and proptosis. RESULTS: Thyroid-stimulating immunoglobulin (TSI) and TSH-binding inhibitory immunoglobulin (TBII) levels decreased during the 1-year follow-up, whereas disease activity measured using CAS decreased mainly in the first 6 months. Disease severity measured using NOSPECS score and proptosis remained unchanged. Moreover, inter-person differences in TBII levels were associated with CAS, NOSPECS score and proptosis over time, whereas inter-person differences in TSI levels were associated with NOSPECS score. Subgroup analysis of patients with a baseline CAS≥4 demonstrated that within-person changes in TSI levels affected the CAS and NOSPECS score. CONCLUSIONS: Follow-up measurement of serum TSI and TBII levels may help evaluate TED prognosis and enable accurate clinical decision-making.

Ganglioside GT1b increases hyaluronic acid synthase 2 via PI3K activation with TLR2 dependence in orbital fibroblasts from thyroid eye disease patients.

Thyroid eye disease (TED) is a complex autoimmune disease with a spectrum of signs. we previously reported that trisialoganglioside (GT)1b is significantly overexpressed in the orbital tissue of TED patients, and that exogenous GT1b strongly induced HA synthesis in orbital fibroblasts. However, the signaling pathway in GT1b-induced hyaluronic acid synthase (HAS) expression in orbital fibroblasts from TED patients have rarely been investigated. Here, we demonstrated that GT1b induced phosphorylation of Akt/mTOR in a dose-dependent manner in orbital fibroblasts from TED patients. Both co-treatment with a specific inhibitor for PI3K and siRNA knockdown of TLR2 attenuated GT1b-induced Akt phosphorylation. GT1b significantly induced HAS2 expression at both the transcriptional and translational level, which was suppressed by specific inhibitors of PI3K or Akt/mTOR, and by siRNA knockdown of TLR2. In conclusion, GT1b induced HAS2 in orbital fibroblasts from TED patients via activation of the PI3Krelated signaling pathway, dependent on TLR2. [BMB Reports 2021; 54(2): 136-141].

Use of the Bispectral Index to Predict Eye Position of Children during General Anesthesia.

PURPOSE: To assess the relationship between eye position and anesthesia depth using the bispectral index (BIS) value, a parameter derived from electroencephalography data. METHODS: We investigated the relationship between BIS value and eye position in 32 children who underwent surgery for epiblepharon under general anesthesia. BIS values were recorded continuously throughout the procedure (from induction to awakening). Eye positions were video-recorded and analyzed after surgery. The vertical position of each eye was scored according to its height in relation to the medial canthus. An eye position in which the upper eyelid covered one-third of the cornea was defined as a significant ocular elevation. RESULTS: The BIS value correlated inversely with the end-tidal concentration of each anesthetic agent, whereas it correlated positively with the eye elevation score (eye position = 0.014 × BIS + 0.699, p = 0.011). The mean eye position score was significantly greater in patients whose BIS values were over 65. Eleven patients (34.4%) had significant ocular elevation; their mean concurrent BIS value was 61.6. Two of these patients had elevation during surgery and 9 had elevation during emergence from anesthesia. CONCLUSIONS: We found that high BIS values were correlated with low levels of anesthetic concentration and high eye position, suggesting that BIS monitoring may be useful for predicting eye position during anesthesia. Particular attention must be given to eye position during ophthalmic surgery. Anesthesia depth can be maintained by assuring that the BIS value remains below 65.

Identification and Functional Characterization of ST3GAL5 and ST8SIA1 Variants in Patients with Thyroid-Associated Ophthalmopathy.

PURPOSE: This study was conducted to identify and to functionally characterize genetic variants in ST3GAL5 and ST8SIA1 in Korean patients with thyroid-associated ophthalmopathy (TAO). MATERIALS AND METHODS: Genetic analyses were conducted using DNA samples from TAO patients (n=50) and healthy subjects (n=48) to identify TAO-specific genetic variants of ST3GAL5 or ST8SIA1. The effect of each genetic variant on the transcription or expression of these genes was examined. Additionally, correlations between functional haplotypes of ST3GAL5 or ST8SIA1 and clinical characteristics of the patients were investigated. RESULTS: Six promoter variants and one nonsynonymous variant of ST3GAL5 were identified, and four major promoter haplotypes were assembled. Additionally, three promoter variants and two major haplotypes of ST8SIA1 were identified. All ST3GAL5 and ST8SIA1 variants identified in TAO patients were also found in healthy controls. Promoter activity was significantly decreased in three promoter haplotypes of ST3GAL5 and increased in one promoter haplotype of ST8SIA1. Transcription factors activating protein-1, NKX3.1, and specificity protein 1 were revealed as having roles in transcriptional regulation of these haplotypes. The nonsynonymous variant of ST3GAL5, H104R, did not alter the expression of ST3GAL5. While no differences in clinical characteristics were detected in patients possessing the functional promoter haplotypes of ST3GAL5, exophthalmic values were significantly lower in patients with the ST8SIA1 haplotype, which showed a significant increase in promoter activity. CONCLUSION: These results from genotype-phenotype analysis might suggest a possible link between the ST8SIA1 functional promoter haplotype and the clinical severity of TAO. However, further studies with larger sample sizes are warranted.

Electronic enhancement of tear secretion.

OBJECTIVE: To study electrical stimulation of the lacrimal gland and afferent nerves for enhanced tear secretion, as a potential treatment for dry eye disease. We investigate the response pathways and electrical parameters to safely maximize tear secretion. APPROACH: We evaluated the tear response to electrical stimulation of the lacrimal gland and afferent nerves in isofluorane-anesthetized rabbits. In acute studies, electrical stimulation was performed using bipolar platinum foil electrodes, implanted beneath the inferior lacrimal gland, and a monopolar electrode placed near the afferent ethmoid nerve. Wireless microstimulators with bipolar electrodes were implanted beneath the lacrimal gland for chronic studies. To identify the response pathways, we applied various pharmacological inhibitors. To optimize the stimulus, we measured tear secretion rate (Schirmer test) as a function of pulse amplitude (1.5-12 mA), duration (0.1-1 ms) and repetition rate (10-100 Hz). MAIN RESULTS: Stimulation of the lacrimal gland increased tear secretion by engaging efferent parasympathetic nerves. Tearing increased with stimulation amplitude, pulse duration and repetition rate, up to 70 Hz. Stimulation with 3 mA, 500 µs pulses at 70 Hz provided a 4.5 mm (125%) increase in Schirmer score. Modulating duty cycle further increased tearing up to 57%, compared to continuous stimulation in chronically implanted animals (36%). Ethmoid (afferent) nerve stimulation increased tearing similar to gland stimulation (3.6 mm) via a reflex pathway. In animals with chronically implanted stimulators, a nearly 6 mm increase (57%) was achieved with 12-fold less charge density per pulse (0.06-0.3 µC mm(-2) with 170-680 µs pulses) than the damage threshold (3.5 µC mm(-2) with 1 ms pulses). SIGNIFICANCE: Electrical stimulation of the lacrimal gland or afferent nerves may be used as a treatment for dry eye disease. Clinical trials should validate this approach in patients with aqueous tear deficiency, and further optimize electrical parameters for maximum clinical efficacy.

Hyaluronic acid induces COX-2 expression via CD44 in orbital fibroblasts from patients with thyroid-associated ophthalmopathy.

PURPOSE: The aim of this study was to determine the effect of hyaluronic acid (HA) on cyclooxygenase (COX)-2 expression in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO). METHODS: Primary cultured orbital fibroblasts were obtained from patients with TAO and non-TAO subjects. Dermal and conjunctival fibroblasts were cultured from the eyelid skin of subjects undergoing cosmetic lid surgery or cataract surgery, respectively. The cells were treated with HA and the transcriptional and translational levels of COX-2 were measured. The expression of CD44 on each type of cells was determined, and the involvement of CD44 in the HA-induced COX-2 increase in orbital fibroblasts from patients with TAO was evaluated by using CD44 knockdown cells and by pretreatment with neutralizing antibody. The relevance of the mitogen-activated protein kinase (MAPK) or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated signaling pathway was assessed by immunoblotting for the phosphorylated form of each MAPK or IκB and by using specific inhibitors to these pathways. RESULTS: Hyaluronic acid increased COX-2 expression in orbital fibroblasts from patients with TAO, which was not observed in the cells from non-TAO subjects and conjunctival or dermal fibroblasts. Orbital fibroblasts from patients with TAO expressed significantly higher level of CD44 than non-TAO cells, and the increased COX-2 expression by HA in these cells was attenuated by knockdown or neutralizing of CD44. Hyaluronic acid induced MAPK and IκB phosphorylation; and cotreatment with specific MAPK or NF-κB inhibitors halted HA-induced transcription of COX-2, suggesting the involvement of these signaling pathways. CONCLUSIONS: Hyaluronic acid induced COX-2 expression in orbital fibroblasts from patients with TAO via CD44 through the MAPK and NF-κB-mediated signaling pathways. These results suggest that HA may have a proinflammatory role in the pathogenesis of TAO by inducing COX-2.

Benzylideneacetophenone derivatives attenuate IFN-γ-induced IP-10/CXCL10 production in orbital fibroblasts of patients with thyroid-associated ophthalmopathy through STAT-1 inhibition.

The aim of the present study was to identify a new candidate anti-inflammatory compound for use in the active stage of thyroid-associated ophthalmopathy (TAO). Benzylideneacetophenone compound JC3 [(2E)-3-(4-hydroxy-3-methoxyphenyl)phenylpro-2-en-l-one] was synthesized based on a structural modification of yakuchinone B, a constituent of the seeds of Alpinia oxyphylla, which belongs to the ginger family (Zingiberaceae), has been widely used in folk medicine as an anti-inflammatory phytochemical. Orbital fibroblasts were primarily cultured from patients with TAO, and the potential of JC3 to suppress the interferon (IFN)-γ-induced protein (IP)-10/CXCL10 production in these cells was determined. IFN-γ strongly increased the level of IP-10/CXCL10 in orbital fibroblasts from patients with TAO. JC3 exerted a significant inhibitory effect on the IFN-γ-induced increase in IP-10/CXCL10 in a dose-dependent manner; its potency was greater than that of an identical concentration of yakuchinone B with no toxicity to cells at the concentration range used. Moreover, the constructed dimer and trimer polystructures of JC3, showed greater potency than JC3 in suppressing the IFN-γ-induced production of IP-10/CXCL10. JC3 significantly attenuated the IP-10/CXCL10 mRNA expression induced by IFN-γ, and a gel-shift assay showed that JC3 suppressed IFN-γ-induced DNA binding of signal transducer and activator of transcription-1 (STAT-1) in TAO orbital fibroblasts. Our results provide initial evidence that the JC3 compound reduces the levels of IP-10/CXCL10 protein and mRNA induced by IFN-γ in orbital fibroblasts of TAO patients. Therefore, JC3 might be considered as a future candidate for therapeutic application in TAO that exerts its effects by modulating the pathogenic mechanisms in orbital fibroblasts.

Pirfenidone attenuates the IL-1ß-induced hyaluronic acid increase in orbital fibroblasts from patients with thyroid-associated ophthalmopathy.

PURPOSE: This study aimed to investigate the effect of pirfenidone on the IL-1ß-induced hyaluronic acid (HA) increase in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO). METHODS: Primary cultured orbital fibroblasts were obtained from patients with TAO, and the excreted levels of HA from IL-1ß-treated cells with or without pirfenidone were measured. The effect of pirfenidone on IL-1ß-induced hyaluronic acid synthase (HAS) expression was evaluated. The relevance of the mitogen-activated protein kinase (MAPK)-mediated signaling pathway in IL-1ß-induced HAS expression was assessed using specific inhibitors to p38, extracellular signal-regulated kinase (ERK), or c-Jun N-terminal kinase (JNK). The phosphorylation level of each MAPK in IL-1ß-treated cells with or without pirfenidone and the level of AP-1 DNA binding were measured. The inhibitory potency of pirfenidone on HA production was evaluated using dexamethasone as a reference agent. RESULTS: Pirfenidone strongly attenuated the IL-1ß-induced HA release in a dose-dependent manner. The IL-1ß-induced HAS expression was decreased significantly following cotreatment with pirfenidone at the mRNA and protein levels. The production of mRNAs was halted by cotreatment with inhibitors of ERK and p38, but not by inhibitors of JNK. The IL-1ß-induced ERK and p38 phosphorylation, and AP-1 DNA binding were attenuated in the presence of pirfenidone. Pirfenidone showed greater potency than dexamethasone in inhibiting increases in IL-1ß-induced HA. CONCLUSIONS: Pirfenidone attenuates the IL-1ß-induced HA production in orbital fibroblasts from patients with TAO, at least in part, through suppression of the MAPK-mediated HAS expression. These results support the potential use of pirfenidone for treatment of patients with TAO.

Clinicopathologic features and prognostic factors of malignant eyelid tumors.

AIM: To investigate the clinical characteristics and prognosis of patients with malignant eyelid tumors. METHODS: This was a retrospective, non-randomized, clinical reviews. Between January, 2002 and December, 2011, 75 cases with histologically confirmed malignant eyelid tumors were evaluated. Patients' charts were reviewed for clinical information, treatment procedure, and disease course. Survival analysis in terms of recurrence-free survival was performed using age, sex, location of tumor and histopathological type. The follow-up ranged from 1 to 78 months (mean=21 months). RESULTS: The 75 eyelid tumors included 35 basal cell carcinoma (BCC, 46.7%), 22 sebaceous gland carcinoma (SGC, 29.3%), 7 squamous cell carcinoma (SCC, 9.3%), 10 malignant melanoma (MM, 13.3%), and 1 Merkel cell carcinoma (MCC, 1.3%). Recurrence developed in 17 cases (22.7%). The recurrence rate of BCC (4/35, 11.4%) was significant lower than MM (6/10, 60.0%, P<0.001). The mean interval of recurrence was 21 months (range 3-62) for all eyelid tumors. Tumor located at canthus had higher recurrence rate (50%) compared with those located at eyelid (19%, P<0.05). Histological type was independent variable for recurrence by Cox regression analysis. CONCLUSION: It is important to achieve a negative tumor margin in canthus located malignant eyelid tumor. Clinicians should have a high level of suspicion for recurrence according to histological type when treating patients with eyelid tumor.

Pirfenidone attenuates IL-1ß-induced COX-2 and PGE2 production in orbital fibroblasts through suppression of NF-κB activity.

The aim of this study was to determine the effect of pirfenidone on interleukin (IL)-1ß-induced cyclooxygenase (COX)-2 and prostaglandin (PG)E2 expression in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO). Primary cultures of orbital fibroblasts from patients with TAO (n = 4) and non-TAO subjects (n = 4) were prepared. The level of PGE2 in orbital fibroblasts treated with IL-1ß in the presence or absence of pirfenidone was measured using an enzyme-linked immunosorbent assay. The effect of pirfenidone on IL-1ß-induced COX-2 expression in orbital fibroblasts from patients with TAO was evaluated by reverse transcription-polymerase chain reaction (PCR) and quantitative real-time PCR analyses, and verified by Western blot. Activation of nuclear factor-κB (NF-κB) was evaluated by immunoblotting for inhibitor of κB (IκB)α and phosphorylated IκBα, and DNA-binding activity of p50/p65 NF-κB was analyzed by electrophoretic mobility shift assay. In addition, IL-1 receptor type 1 (IL-1R1) expression was assessed by RT-PCR in IL-1ß-treated cells with or without pirfenidone. Pirfenidone significantly attenuated IL-1ß-induced PGE2 release in both TAO and non-TAO cells. IL-1ß-induced COX-2 mRNA and protein expression decreased significantly following co-treatment with pirfenidone. IL-1ß-induced IκBα phosphorylation and degradation decreased in the presence of pirfenidone and led to decreased nuclear translocation and DNA binding of the active NF-κB complex. In our system, neither IL-1ß nor pirfenidone co-treatment influenced IL-1R1 expression. Our results suggest that pirfenidone attenuates the IL-1ß-induced PGE2/COX-2 production in TAO orbital fibroblasts, which is related with suppression of the NF-κB activation.

Pirfenidone inhibits transforming growth factor-ß1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19.

PURPOSE: Transforming growth factor-ß (TGF-ß) plays a key role in transforming retinal pigment epithelial (RPE) cells into mesenchymal fibroblastic cells, which are implicated in proliferative vitreoretinopathy. Herein, we tested the effect of pirfenidone, a novel antifibrotic agent, on TGF-ß1-mediated fibrogenesis in the human RPE cell line ARPE-19. METHODS: The effect of pirfenidone on the TGF-ß1-induced phenotype in ARPE-19 cells was measured with immunocytochemistry as the change in F-actin. Fibronectin and collagen production was measured with enzyme-linked immunosorbent assay, and cell migration activity was investigated using a scratch assay. Immunoblot analyses of cofilin, sma and mad protein (smad) 2/3, p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-related kinase expression were conducted to elucidate the cell signaling networks that contribute to the antifibrotic effect of pirfenidone. RESULTS: Treatment with TGF-ß1 induced typical phenotypic changes such as formation of stress fiber running parallel to the long axis of cells and enhanced migration and production of extracellular matrix components such as collagen type I and fibronectin. This fibroblast-like phenotype induced by TGF-ß1 was significantly inhibited by pretreatment with pirfenidone in a dose-dependent manner. We also elucidated the TGF-ß signaling pathways as the target of the inhibitory effect of pirfenidone. Pirfenidone inhibited TGF-ß signaling by preventing nuclear accumulation of active Smad2/3 complexes rather than phosphorylation of Smad2/3. CONCLUSIONS: These results collectively provide a rational background for future evaluation of pirfenidone as a potential antifibrotic agent for treating proliferative vitreoretinopathy and other fibrotic retinal disorders.

Protective effect of grape seed extract against oxidative stress-induced cell death in a staurosporine-differentiated retinal ganglion cell line.

OBJECTIVE: Grape seed extract (GSE) is a potent antioxidant. We examined the effect of GSE on oxidative stress-induced cell death in a transformed retinal ganglion cell line, RGC-5. METHODS: Staurosporine-differentiated RGC-5 (ssdRGC-5) cells obtained by treating RGC-5 cells with 1 µM staurosporine were incubated with GSE for 2 h and then exposed to buthionine sulfoximine plus glutamate (B/G) for 24 h. Cell death was detected using the LIVE/DEAD viability assay and the type of cell death was evaluated using fluorescein isothiocyanate-conjugated Annexin-V/propidium iodide staining. To investigate the mechanism underlying cell death, we determined the caspase-3 activity and level of reactive oxygen species (ROS) formation. RESULTS: Treatment of ssdRGC-5 cells with B/G increased intracellular ROS and induced apoptosis (not necrosis) with increasing caspase-3 activity. GSE rescued the ssdRGC-5 cells from oxidative stress-induced cell death by inhibiting both intracellular ROS production and caspase-3 activation. CONCLUSION: GSE had a neuroprotective effect against oxidative stress-induced apoptotic death in ssdRGC-5 cells.

Altered ganglioside expression modulates the pathogenic mechanism of thyroid-associated ophthalmopathy by increase in hyaluronic acid.

PURPOSE: The aim of this study was to determine the role of gangliosides in pathogenic mechanisms of thyroid-associated ophthalmopathy (TAO). METHODS: The gangliosides profile and mRNA level of sialyltransferases of the orbital tissues from TAO patients (n = 5) and non-TAO subjects (n = 4) were investigated. In addition, the effect of exogenous gangliosides on the expression of hyaluronic acid was examined in orbital fibroblasts. For in vitro experiments, we used four different strains of cells obtained from non-TAO subjects with at least three replicates for each strain. RESULTS: Trisialoganglioside 1b (GT1b) was significantly overexpressed in the orbital tissue of TAO patients compared with control tissue, whereas no significant difference was observed for either monosialoganglioside 1 (GM1) or disialoganglioside 1a (GD1a) by digital analyses of immunohistochemical images. Moreover, mRNA levels of sialyltransferase (SAT)-I and SAT II were increased in TAO patients compared with control. Exogenous GT1b strongly induced the morphologic changes related to an accumulation of sparse flocculent precipitates in lysosomes and increased the extracellular hyaluronic acid level in orbital fibroblasts with the induction of hyaluronic acid synthase, which were less by GD1a but not by GM1. The GT1b-induced morphologic changes of cells were due, at least in part, to an increase of intracellular hyaluronic acid. Co-treatment of hyaluronidase nicely attenuated the morphologic changes in orbital fibroblasts. Thy-1(+) orbital fibroblasts were more capable of producing hyaluronic acid by exogenous GT1b. CONCLUSIONS: The results suggest that gangliosides, particularly GT1b, may play a role in the pathologic mechanisms of TAO by stimulating an increase in hyaluronic acid.

Antifibrotic effect of Pirfenidone on orbital fibroblasts of patients with thyroid-associated ophthalmopathy by decreasing TIMP-1 and collagen levels.

PURPOSE: The aim of this study was to determine the antifibrotic effects of pirfenidone in orbital fibroblasts of patients with thyroid-associated ophthalmopathy (TAO). METHODS: The effects of interleukin (IL)-1beta and of fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-beta on the induction of tissue inhibitors of metalloproteinases (TIMP)-1 were assessed in orbital fibroblasts of TAO patients. TIMP-1 protein levels were measured by ELISA and Western blot analyses, and TIMP-1 activity was assessed by reverse zymography. The effect of pirfenidone on TIMP-1 induction in orbital fibroblasts was evaluated with the same methods using dexamethasone as a reference agent. A hydroxyproline assay was used to determine the effect of pirfenidone and dexamethasone on collagen production in orbital fibroblasts, and the tetrazolium-based MTT assay was used to assess pirfenidone cytotoxicity. RESULTS: IL-1beta strongly and dose dependently increased the level of active TIMP-1 protein, whereas FGF, PDGF, and TGF-beta did not significantly induce TIMP-1 protein. Pirfenidone was more effective than dexamethasone in inhibiting IL-1beta-induced increases in TIMP-1, reducing TIMP-1 levels to less than those in untreated controls at a minimal concentration (5 mM). Moreover, pirfenidone effectively decreased hydroxyproline levels in orbital fibroblasts, whereas dexamethasone had no effect on hydroxyproline levels. Pirfenidone exhibited no toxicity in orbital fibroblasts at the concentrations used. CONCLUSIONS: These results indicate that nontoxic concentrations of pirfenidone have significant antifibrotic effects on orbital fibroblasts from patients with TAO.

A case of congenital orbital malignant rhabdoid tumor: systemic metastasis following exenteration.

A newborn girl presented with massive proptosis of the right eye. Physical and radiologic examination disclosed that the primary orbital mass was confined to the site. A diagnosis of malignant rhabdoid tumor was made by histopathologic examination of an incisional biopsy specimen. Exenteration was performed, and the resection margins were free from tumor cells. However, distant metastasis developed in the liver 1 month after surgery. Despite chemotherapy, the patient died 2 months later due to tumor invasion into the central nervous system, which was confirmed by autopsy. To the best of our knowledge, this is the first case of congenital orbital malignant rhabdoid tumor showing systemic metastasis after exenteration, which suggests the need for aggressive systemic treatment rather than exenteration, even in a case of locally confined tumor.

The use of autogenous sclera as wrapping material in hydroxyapatite implantation.

PURPOSE: To report postoperative results and effectiveness using autogenous sclera as a wrapping material for hydroxyapatite orbital implant. METHODS: A chart review of 78 patients (78 eyes) undergoing primary enucleation or a secondary procedure using autogenous sclera as a wrapping material from March 1997 to October 2004 was undertaken. Primary enucleation was performed in 54 eyes and secondary implantation in 24. In severely constricted eyes or eviscerated eyes with small implants, the sclera was unfolded and used for wrapping only on the anterior surface of the implant. RESULTS: The average size of implants was 19.7 mm in diameter, and all the 78 implants were over 18 mm. During an average postoperative follow-up of 18 months, complications such as implant exposure, infection or extrusion did not occur in any case. CONCLUSION: This study shows that autogenous sclera is a safe, effective wrapping material for hydroxyapatite orbital implants with no serious complications.

Bone marrow-derived progenitor cells promote corneal wound healing following alkali injury.

PURPOSE: To determine whether bone marrow-derived progenitor cells can be stimulated by inflammatory mediators and play a role in corneal wound healing following alkali injury. METHODS: Sixty rabbits were divided into two groups (Group I and Group II). Group I served as a bone marrow-suppression model, and received 200 mg/kg cyclophosphamide. Corneal alkali injury was created in one eye of each rabbit in each group; the other eye served as control. Three days after corneal burn, inflammatory cells in peripheral blood were counted. At the end of 4 weeks follow-up, corneas of all rabbits were subjected to histochemical examination to assess infiltrated CD34 and C-kit positive cells. Clinical outcome was determined at the end of 4 weeks. RESULTS: Cyclophosphamide suppressed bone marrow function in Group I by reducing cellularity by more than 30% and neutrophil distribution by 3.18 +/- 1.83%. The number of bone marrow hematopoietic and mesenchymal progenitor cells were all suppressed by cyclophophamide, as demonstrated by statistically significant differences between Group I and Group II of CD34+ cells (t = -21.62, P < 0.01) and C-Kit cells (t = -21.62, P < 0.01). Fewer inflammatory cells were released into circulation in Group I (14.42 +/- 5.70%) than in Group II (44.36 +/- 8.64%). Clinical observation revealed that Group II rabbits had much greater reepithelization (t = 6.999, P < 0.01) and clearer corneas (X(2) = 4.417, P < 0.01) than Group I. CONCLUSIONS: Corneal alkali injury is a stimulus that induces a rapid bone marrow reaction to release not only inflammatory cells but also progenitor cells into circulation. Migrated bone marrow-derived progenitor cells can home to local sites to promote wound healing.

Evaluation of computer-based volume measurement and porous polyethylene channel implants in reconstruction of large orbital wall fractures.

PURPOSE: To describe the use of computer-based orbital volume measurement as a predictor of late enophthalmos, and to assess the effectiveness of the MedPor (Porex Surgical Products Group, Newnan, GA) porous polyethylene channel implant to restore orbital volume in repairing large orbital wall fractures. METHODS: Sixteen patients with unilateral large orbital fractures were included. Computed tomographic (CT) scans were used to obtain computer-based orbital volume measurement to predict the likelihood of late enophthalmos and to assess the change in orbital volume before and after surgery. The effectiveness of a channel implant was evaluated by the orbital volume and postoperative exophthalmetric measurement. RESULTS: The average time interval between injury and surgery was 17.4 +/- 10 days, and the mean follow-up was 9 months. The orbital volume of the injured orbit was significantly increased (mean, 4.22 +/- 2.61 cm2) compared with the unaffected orbit before surgery (t = 3.046, P = 0.005). There was not a significant difference in orbital volume between the two orbits after orbital reconstruction (t = 0.069, P = 0.945). The orbital volume change after reconstructive surgery was significantly positively correlated with the decrease of enophthalmos (r = 0.715, P = 0.001; enophthalmos [E] = 0.72; volume increment [V] = 0.06). To resolve 2 mm enophthalmos, more than 2.9 cm3 orbital volume augmentation is recommended for early reconstructive surgery. Postoperative CT scan showed most of the channel implants to be well positioned. CONCLUSIONS: Computer-based orbital volume measurement from a CT scan is useful in the posttraumatic evaluation of orbital fractures, and it can help predict the degree of late enophthalmos that can be expected. Orbital reconstruction with the MedPor channel implant (Porex Surgical Products Group), when indicated, is recommended, especially for large orbital wall fractures.

Temporary amniotic membrane patch for the treatment of primary pterygium: mechanisms of reducing the recurrence rate.

PURPOSE: The purpose of the study was to evaluate the outcome of the use of the temporary amniotic membrane patch (TAMP) for the treatment of primary pterygium and to investigate the mechanisms of reducing the recurrence rate. METHODS: Twenty eyes in 20 patients with primary pterygium underwent pterygium excision followed by TAMP for 5 days. Removed amniotic membrane (AM) was immunostained with primary antibodies CD34, c-Kit, STRO-1 and AC133. RESULTS: Within the period of follow-up (53.3+/-13.8 months), all the eyes showed a smooth ocular surface without recurrence of pterygium. Different grades of CD34, c-Kit, STRO-1and AC133 positive stem and progenitor cells infiltrated or attached to the stroma of patched AM, with more spindle-shaped c-Kit cells than ovoid-shaped CD34 and AC133 cells. CONCLUSION: The temporary amniotic membrane patch is an effective and safe procedure for the treatment of primary pterygium. Absorbing excessive stem and progenitor cells may be one of the mechanisms of reducing the recurrence rate using AM.