Despite advances in surgical technique and postoperative care, fibrosis remains the major impediment to a marked reduction of intraocular pressure without the need of additional medication (complete ...success) following filtering glaucoma surgery. Several aspects specific to filtering surgery may contribute to enhanced fibrosis. Changes in conjunctival tissue structure and composition due to preceding treatments as well as alterations in interstitial fluid flow and content due to aqueous humor efflux may act as important drivers of fibrosis. In light of these pathophysiological considerations, current and possible future strategies to control fibrosis following filtering glaucoma surgery are discussed.
•Growth factors, structural and biomechanical stimuli interact to drive scarrring following filtering glaucoma surgery.•Changes in interstitial fluid flow may have a major, yet undefined role in fibrosis following filtering glaucoma surgery.•A broad spectrum of signaling pathways can be addressed to modulate wound healing.
IMPORTANCE: Giant cell arteritis (GCA) is the most common systemic vasculitis in elderly individuals. Diagnosis is confirmed by temporal artery (TA) biopsy, although biopsy results are often ...negative. Despite the use of corticosteroids, disease may progress. Identification of causal agents will improve outcomes. Biopsy-positive GCA is associated with TA infection by varicella-zoster virus (VZV). OBJECTIVE: To analyze VZV infection in TAs of patients with clinically suspected GCA whose TAs were histopathologically negative and in normal TAs removed post mortem from age-matched individuals. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study for VZV antigen was performed from January 2013 to March 2015 using archived, deidentified, formalin-fixed, paraffin-embedded GCA-negative, GCA-positive, and normal TAs (50 sections/TA) collected during the past 30 years. Regions adjacent to those containing VZV were examined by hematoxylin-eosin staining. Immunohistochemistry identified inflammatory cells and cell types around nerve bundles containing VZV. A combination of 17 tertiary referral centers and private practices worldwide contributed archived TAs from individuals older than 50 years. MAIN OUTCOMES AND MEASURES: Presence and distribution of VZV antigen in TAs and histopathological changes in sections adjacent to those containing VZV were confirmed by 2 independent readers. RESULTS: Varicella-zoster virus antigen was found in 45 of 70 GCA-negative TAs (64%), compared with 11 of 49 normal TAs (22%) (relative risk RR = 2.86; 95% CI, 1.75-5.31; P < .001). Extension of our earlier study revealed VZV antigen in 68 of 93 GCA-positive TAs (73%), compared with 11 of 49 normal TAs (22%) (RR = 3.26; 95% CI, 2.03-5.98; P < .001). Compared with normal TAs, VZV antigen was more likely to be present in the adventitia of both GCA-negative TAs (RR = 2.43; 95% CI, 1.82-3.41; P < .001) and GCA-positive TAs (RR = 2.03; 95% CI, 1.52-2.86; P < .001). Varicella-zoster virus antigen was frequently found in perineurial cells expressing claudin-1 around nerve bundles. Of 45 GCA-negative participants whose TAs contained VZV antigen, 1 had histopathological features characteristic of GCA, and 16 (36%) showed adventitial inflammation adjacent to viral antigen; no inflammation was seen in normal TAs. CONCLUSIONS AND RELEVANCE: In patients with clinically suspected GCA, prevalence of VZV in their TAs is similar independent of whether biopsy results are negative or positive pathologically. Antiviral treatment may confer additional benefit to patients with biopsy-negative GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.
PURPOSE:Ocular chronic graft-versus-host disease (cGVHD) is one of the most frequent long-term complications after hematopoietic stem cell transplantation and is often associated with significant ...morbidity and reduced quality of life.
METHODS:The German/Austrian/Swiss Consensus Conference on Clinical Practice in cGVHD aimed to summarize the currently available evidence for diagnosis and (topical) treatment and to summarize different treatment modalities of ocular cGVHD. The presented consensus was based on a review of published evidence and a survey on the current clinical practice including transplant centers from Germany, Austria, and Switzerland.
RESULTS:Ocular cGVHD often affects the lacrimal glands, the conjunctiva, the lids (including meibomian glands), and the cornea but can also involve other parts of the eye such as the sclera. Up to now, there have been no pathognomonic diagnostic features identified. The main therapeutic aim in the management of ocular cGVHD is the treatment of inflammation and dryness to relieve patientsʼ symptoms and to maintain ocular integrity and function. Therapy should be chosen in the context of the patientʼs overall condition, systemic immunosuppressive therapy, symptoms, ocular surface integrity, and inflammatory activity. The consensus conference proposed new grading criteria and diagnostic recommendations for general monitoring of patients with graft-versus-host-disease for use in clinical practice.
CONCLUSION:The evidence levels for diagnosis and treatment of ocular cGVHD are low, and most of the treatment options are based on empirical knowledge. Topical immunosuppression, for example, with cyclosporine, represents a promising strategy to reduce inflammation and dryness in ocular cGVHD. Further clinical trials are necessary to elucidate risk factors for eye manifestation, complications, and visual loss and to evaluate staging criteria and diagnostic and therapeutic measures for ocular cGVHD.
PURPOSE:To evaluate tear film osmolarity (TFO) as a diagnostic tool for detecting chronic ocular graft-versus-host disease (GVHD) in patients after hematopoietic stem cell transplantation and to ...assess its correlation with the new international chronic ocular GVHD score.
METHODS:A group of 204 consecutive patients who underwent hematopoietic stem cell transplantation at University Hospital Wuerzburg in Germany received an ophthalmologic examination after transplantation. TFO was measured and the chronic ocular GVHD score was calculated based on the Schirmer test, corneal fluorescein staining, conjunctival injection, Ocular Surface Disease Index questionnaire, and presence of systemic GVHD.
RESULTS:A total of 172 patients showed no chronic ocular GVHD. Of the remaining 32 patients using the international chronic ocular GVHD score, 21 were classified as “probably” and 11 as “definite” chronic ocular GVHD. TFO was positively correlated with the new chronic ocular GVHD score (P < 0.01, r = 0.35). TFO differed significantly between patients with no ocular GVHD (300 ± 16.5 mOsm/L) and definite ocular GVHD (337 ± 36 mOsm/L)—a receiver operating characteristic analysis showed high discrimination capability (area under the curve0.91 ± 0.04) and suggested a threshold level of the TFO value of 312 mOsm/L yielding a sensitivity of 91% and a specificity of 82%.
CONCLUSIONS:TFO can be used for detecting chronic ocular GVHD with high sensitivity and specificity as a noninvasive objective test in addition to traditional dry eye tests. It correlates positively with the diagnostic criteria of a recently established international consensus score for diagnosing the disease.
Oncocytomas are benign tumors most often occurring in salivary or lacrimal glands and thyroid tissue. As cutaneous oncocytoma is exceptionally rare, this tumor is uncommonly encountered by ...dermatopathologists. Herein, we illustrate the case of an 80‐year‐old man who presented with a slowly growing papule of the lower eyelid. Histopathologically, the adenomatous tumor was composed of large monomorphic cells with eosinophilic granular cytoplasm. Electron microscopy revealed abundant, enlarged and abnormally shaped mitochondria. These findings were consistent with an oncocytoma of the skin. The presented case is unique in that the thorough work‐up of the tumor tissue revealed not only hyperplastic mitochondria, representing the ultrastructural correlate of the observed granular cytoplasm, but additionally disclosed functional consequences with elevated levels of reactive oxygen specimen (ROS) within the tumor. Disrupted oxygen metabolism may result from cellular aging processes and may putatively represent the underlying pathogenesis of oncocytoma.
The biologic relevance of human connective tissue growth factor (hCTGF) for primary human tenon fibroblasts (HTFs) was investigated by RNA expression profiling using affymetrix(TM) oligonucleotide ...array technology to identify genes that are regulated by hCTGF.
Recombinant hCTGF was expressed in HEK293T cells and purified by affinity and gel chromatography. Specificity and biologic activity of hCTGF was confirmed by biosensor interaction analysis and proliferation assays. For RNA expression profiling HTFs were stimulated with hCTGF for 48h and analyzed using affymetrix(TM) oligonucleotide array technology. Results were validated by real time RT-PCR.
hCTGF induces various groups of genes responsible for a wound healing and inflammatory response in HTFs. A new subset of CTGF inducible inflammatory genes was discovered (e.g., chemokine C-X-C motif ligand 1 CXCL1, chemokine C-X-C motif ligand 6 CXCL6, interleukin 6 IL6, and interleukin 8 IL8). We also identified genes that can transmit the known biologic functions initiated by CTGF such as proliferation and extracellular matrix remodelling. Of special interest is a group of genes, e.g., osteoglycin (OGN) and osteomodulin (OMD), which are known to play a key role in osteoblast biology.
This study specifies the important role of hCTGF for primary tenon fibroblast function. The RNA expression profile yields new insights into the relevance of hCTGF in influencing biologic processes like wound healing, inflammation, proliferation, and extracellular matrix remodelling in vitro via transcriptional regulation of specific genes. The results suggest that CTGF potentially acts as a modulating factor in inflammatory and wound healing response in fibroblasts of the human eye.
Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to ...confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation.
Multicenter, double-masked, randomized, placebo-controlled phase III study.
Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180.
The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL.
Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related.
This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.
Helicobacter pylori is an etiological agent in the development of mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma. Patients infected with H. pylori carry a 3–6-fold increased ...risk of developing cancer compared with uninfected individuals. H. pylori strains expressing the cytotoxin-associated antigen A (CagA) are more frequently associated with the development of neoplasia than cagA-negative strains. However, the molecular mechanism by whichH. pylori causes neoplastic transformation remains unclear. Here we report that exposure of gastric epithelial cells to H. pylori induces activation of the transcription factor activator protein 1. Activation of the proto-oncogenes c-fos and c-jun is strongly induced. We show that H. pylori activates the ERK/MAP kinase cascade, resulting in Elk-1 phosphorylation and increased c-fos transcription. H. pylori strains that do not express CagA or that are mutated incag genes encoded by the CagI pathogenicity island do not induce activator protein 1, MAP kinase activity, or c-fosor c-jun activation. Proto-oncogene activation may represent a crucial step in the pathomechanism of H. pyloriinduced neoplasia.
Purpose
To evaluate the outcome of phacoemulsification in patients with chronic ocular Graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplantation (aHSCT).
Methods
...Retrospective, observational multicenter study from 1507 oGVHD patients. From the patient files, data were collected including best-corrected visual acuity (BCVA), intraocular pressure (IOP), Schirmer’s test
I
, tear film break-up time (TFBUT), corneal fluorescein staining score, postoperative complications, and pre- and post-operative topical therapy.
Results
Seventy-three patients underwent cataract surgery in 104 eyes. In
n
= 84 eyes, the oGVHD NIH grade was documented; 12% (
n
= 12) of analyzed eyes were staged oGVHD NIH grade 1, 31% (
n
= 32) NIH 2 and 39% (
n
= 41) NIH 3. The mean BCVA improved in 82% of the eyes (
n
= 86 eyes). BCVA significantly increased from 0.7 ± 0.5 to 0.4 ± 0.4 LogMAR after surgery independent from oGVHD severity. The mean IOP decreased from 14 ± 4 to 13 ± 4 mmHg after surgery. Visual acuity was moderately correlated to the pre-operative degree of corneal staining (Pearson
p
= 0.26,
p
= 0.002, Cohen’s effect size
f
= 0.29). The visual acuity decreased by 0.078 LogMar units (95% CI = 0.027–0.141) with each increase of corneal staining by one grade (
p
= 0.05). After surgery, corneal epitheliopathy increased significantly in 42% (
n
= 44) of the eyes. Postoperative complications included corneal perforation (
n
= 6, 6%), cystoid macular edema (
n
= 4, 4%), and endophthalmitis (
n
= 1, 1%).
Conclusion
Phacoemulsification in patients with chronic oGVHD significantly improves visual acuity, but is associated with an increased risk of complications in particular corneal epitheliopathy and corneal perforations.
Eye drops of aganirsen, an antisense oligonucleotide preventing insulin receptor substrate-1 expression, inhibited corneal neovascularization in a previous dose-finding phase II study. We aimed to ...confirm these results in a phase III study and investigated a potential clinical benefit on visual acuity (VA), quality of life (QoL), and need for transplantation.
Multicenter, double-masked, randomized, placebo-controlled phase III study.
Analysis of 69 patients with keratitis-related progressive corneal neovascularization randomized to aganirsen (34 patients) or placebo (35 patients). Patients applied aganirsen eye drops (86 μg/day/eye) or placebo twice daily for 90 days and were followed up to day 180.
The primary end point was VA. Secondary end points included area of pathologic corneal neovascularization, need for transplantation, risk of graft rejection, and QoL.
Although no significant differences in VA scores between groups were observed, aganirsen significantly reduced the relative corneal neovascularization area after 90 days by 26.20% (P = 0.014). This improvement persisted after 180 days (26.67%, P = 0.012). Aganirsen tended to lower the transplantation need in the intent-to-treat (ITT) population at day 180 (P = 0.087). In patients with viral keratitis and central neovascularization, a significant reduction in transplantation need was achieved (P = 0.048). No significant differences between groups were observed in the risk of graft rejection. However, aganirsen tended to decrease this risk in patients with traumatic/viral keratitis (P = 0.162) at day 90. The QoL analyses revealed a significant improvement with aganirsen in composite and near activity subscores (P = 0.039 and 0.026, respectively) at day 90 in the per protocol population. Ocular and treatment-related treatment-emergent adverse events (TEAEs) were reported in a lower percentage with aganirsen compared with placebo. Only 3 serious TEAEs (2 with aganirsen and 1 with placebo) were considered treatment-related.
This first phase III study on a topical inhibitor of corneal angiogenesis showed that aganirsen eye drops significantly inhibited corneal neovascularization in patients with keratitis. The need for transplantation was significantly reduced in patients with viral keratitis and central neovascularization. Topical application of aganirsen was safe and well tolerated.
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