Matthew H. Ip

Significance of Fuchs Flecks in Patients With Pterygium/Pinguecula: Earliest Indicator of Ultraviolet Light Damage.

Purpose: Fuchs flecks (FFs) have been previously identified at the leading edge of pterygia and may represent collections of epithelial stem-like cells that give rise to this condition. This study aims to evaluate the clinical significance of FFs in patients with ocular surface disorders, such as pterygium and pinguecula, by in vivo confocal microscopy (IVCM). Methods: This study is a Single-center, retrospective, observational case series of 40 eyes from 20 patients with clinical diagnoses of pinguecula or pterygium, or both. IVCM (Rostock Cornea Module; Heidelberg Engineering, Heidelberg, Germany) was performed on patients with pinguecula or pterygium, or both. The presence of FFs on the ocular surface of patients with pterygium and pinguecula was assessed by IVCM and subsequently documented. Results: FFs were present in 24 of 30 eyes (80.0%) in paired macroscopically normal nasal or limbal regions, 19 of 20 (95.0%) in pinguecula, 13 of 15 (86.7%) in primary pterygia, and 7 of 7 (100%) in recurrent pterygia. Conclusions: High rates of FFs were identified at the head of pinguecula, primary pterygium, recurrent pterygium, and macroscopically normal nasal and temporal limbus. We postulate that FFs may represent precursor lesions to UV-associated ocular surface pathology. Identification of Fuchs fleck by IVCM may permit clinicians to predict the patients who may progress to develop more advanced pathology.

Topical Cidofovir for Treatment-Refractory Ocular Surface Squamous Neoplasia

Ocular surface squamous neoplasia (OSSN) is defined as a group of dysplastic, preinvasive, and malignant squamous lesions involving the cornea and conjunctiva. Management of OSSN varies, and typically is governed by lesion size, distribution, and pathologic severity. Treatment incorporates surgical excision with adjuvant cryotherapy to margins, topical chemotherapy, or both, the latter commonly with mitomycin C and 5-fluorouracil. More recently, the application of topical interferon alfa-2b has been used successfully for treating OSSN. Yet despite the prevailing contemporary standard of care, recurrence remains high at up to 53% of cases. Human papilloma virus (HPV) has been implicated as an etiologic agent in the pathogenesis of OSSN. We demonstrated that approximately 6.5% of OSSN specimens showed positive results for a high-risk HPV serotype (HPV-16), detection of which corresponded with more severe pathologic OSSN types, namely squamous cell carcinoma. Cidofovir is an antiviral with activity against different double-stranded DNA viruses, including HPV, and has been used previously to treat HPV-associated lesions. This single-center, retrospective, interventional case series recruited 6 patients with treatment-refractory OSSN. Patients satisfied inclusion criteria if they possessed biopsy-proven diagnoses of OSSN before cidofovir administration and were treatment refractory to surgery, adjuvant cryotherapy, and an additional topical agent. Patients were excluded if additional or alternate diagnoses on biopsy were identified. Formalin-fixed paraffin-embedded tissues and ThinPrep (Cytyc Corp; Marlborough, MA) specimens were analyzed for HPV presence using a hybrid-capture assay. Details of our HPV detection methodology can be found in Appendix 1 (available at www.aaojournal.org). A chart review of all patients treated with topical cidofovir (2.5 mg/ml thrice daily) between 2014 and 2016 was conducted. Topical cidofovir vials were compounded at an external pharmacy, and patients were treated for at least 4 weeks. Tumor regression was diagnosed with slit-lamp biomicroscopy and photography and, if required, repeat histopathologic analysis. Recurrence was monitored after first documented instance of tumor resolution. Institutional ethics review board approval was obtained for this study. This study was approved by the South-Eastern Sydney Area Health Service Human Research Ethics Committee (Eastern Section) 15/200 and was performed in accordance with the tenets of the Declaration of Helsinki. Five men and 1 woman (mean age, approximately 82.1 years) with treatment-refractory OSSN were treated with 2.5 mg/ml topical cidofovir (1 drop thrice daily) for 4 to 9 weeks (Table 1; Fig S1, available at www.aaojournal.org). Patients responded to topical cidofovir at varying times, with first observation for tumor clearance ranging between 24 and 60 days. Patients thus continued topical cidofovir until the end of the week after tumor clearance was first observed. Our patients had been previously managed for 1337 days (mean) of excisional biopsy, adjuvant cryotherapy, topical interferon alfa-2b and retinoic acid, intralesional interferon, oral cimetidine, topical mitomycin C cycles, or a combination thereof before commencing topical cidofovir. A mean tumor-free follow-up of approximately 454 days (range, 222e876 days) was achieved from our case series of 6 patients, with tumor clearance identified in 5 of 6 eyes affected and no observable recurrence even at present. One eye demonstrated conjunctivitis and punctal stenosis during treatment with cidofovir that settled on treatment cessation. Two lacrimal punctum plugs were placed as prophylaxis (patient 4). All 5 treatment specimens obtained before cidofovir administration were analyzed for high-risk HPV presence, and HPV-16 was identified in 1 patient (patient 4) only. No HPV detection after treatment was performed. Conundrums that prevent optimal OSSN control include invisible disease with lacrimal system metastases and multifocal limbal disease. Topical therapy represents a solution for mitigating these, being able to treat the entirety of the ocular surface and inconspicuous spread within the lacrimal drainage system. Unfortunately, contemporary topical chemotherapeutic agent application (mitomycin C or 5-fluorouracil drops) is associated with transient ocular adverse effects, and occasionally destructive sight-limiting complications. Topical interferon alfa-2b monotherapy represents an alternative with a decreased side-effect profile and improved tumor-free follow-up. We previously demonstrated in an 89-patient study excellent tumor clearance of approximately 97.8% and tumor-free follow-up of approximately 51.5 months when using topical interferon alfa-2b and all-trans retinoic acid combination therapy. Despite the excellent results, approximately 2% of patients demonstrated recurrent disease, and we hypothesized that a viral coinfection with HPV may be contributing toward therapy-resistant diseases. We observed only 1 case each of transient conjunctivitis and punctal stenosis, both of which resolved after treatment cessation and lacrimal punctum plugging. Because of the known toxicity of cidofovir, other antiviral agents may be warranted that have less impact on the lacrimal drainage apparatus, or lacrimal plugs may be used as an adjunct. We observed that most of our patients (n 1⁄4 5) showed complete resolution after topical cidofovir application with an average tumor-free follow-up of approximately 454 days. More severe grades of OSSN (cornealeconjunctival intraepithelial neoplasia II/III; patients 2e5) were more likely to respond to topical cidofovir compared with lower-grade tumors (cornealeconjunctival intraepithelial neoplasia I; patient 1), which may be the result of a correlation between more severe tumor types and viral coinfection. However, 1 patient (patient 6) demonstrated observable tumor clearance despite histopathologic identification as a benign papilloma. Only 1 specimen obtained before cidofovir treatment showed positive results for HPV-16, although there exist factors that may have influenced viral detection. First, our assay, although comprehensive, did not analyze presence of all HPV subtypes, and therefore pathogenic subtypes may be missed. Furthermore, we conducted our assays using formalin-fixed paraffin-embedded

Conjunctival Squamous Cell Carcinoma with Corneal Stromal Invasion in Presumed Pterygia: A Case Series

Aim: To describe 4 cases of conjunctival squamous cell carcinoma (SCC) with corneal stromal invasion. Methods: Retrospective, clinicopathologic case series. Results: All patients had prior resections of presumed pterygia. The degree of corneal involvement dictated the extent of surgical management. One eye with localized invasion was treated with lamellar keratoplasty and plaque brachytherapy. Another case with widespread invasion warranted penetrating keratoplasty and eventual enucleation. Two cases were treated medically prior to surgical intervention: one with localized invasion was treated with topical interferon and retinoic acid; another with significant inflammation was treated with doxycycline and fluorometholone. The patient who underwent keratoplasty and brachytherapy had no recurrence after 7 years of follow-up. Those initially treated medically had resections of recurrence but ultimately required enucleation. Histologically, specimens demonstrated SCC invading the deep corneal stroma, with 2 tumors of the mucoepidermoid type. Conclusions: This series demonstrates the importance of maintaining clinical suspicion of conjunctival squamous neoplasia in pterygia. We recommend that all excised pterygia be submitted for histopathologic evaluation and be carefully evaluated for dysplasia and variants of SCC associated with increased risk of intraocular invasion. Undetected ocular surface squamous neoplasia may give rise to potentially vision- and eye-threatening invasive corneal SCC.

Expert-led didactic versus self-directed audiovisual training of confocal laser endomicroscopy in evaluation of mucosal barrier defects

Background and study aims  Confocal laser endomicroscopy (CLE) allows mucosal barrier defects along the intestinal epithelium to be visualized in vivo during endoscopy. Training in CLE interpretation can be achieved didactically or through self-directed learning. This study aimed to compare the effectiveness of expert-led didactic with self-directed audiovisual teaching for training inexperienced analysts on how to recognize mucosal barrier defects on endoscope-based CLE (eCLE). Materials and methods  This randomized controlled study involved trainee analysts who were taught how to recognize mucosal barrier defects on eCLE either didactically or through an audiovisual clip. After being trained, they evaluated 6 sets of 30 images. Image evaluation required the trainees to determine whether specific features of barrier dysfunction were present or not. Trainees in the didactic group engaged in peer discussion and received feedback after each set while this did not happen in the self-directed group. Accuracy, sensitivity, and specificity of both groups were compared. Results  Trainees in the didactic group achieved a higher overall accuracy (87.5 % vs 85.0 %, P  = 0.002) and sensitivity (84.5 % vs 80.4 %, P  = 0.002) compared to trainees in the self-directed group. Interobserver agreement was higher in the didactic group (k = 0.686, 95 % CI 0.680 – 0.691, P  < 0.001) than in the self-directed group (k = 0.566, 95 % CI 0.559 – 0.573, P  < 0.001). Confidence (OR 6.48, 95 % CI 5.35 – 7.84, P  < 0.001) and good image quality (OR 2.58, 95 % CI 2.17 – 2.82, P  < 0.001) were positive predictors of accuracy. Conclusion  Expert-led didactic training is more effective than self-directed audiovisual training for teaching inexperienced analysts how to recognize mucosal barrier defects on eCLE.

306 Impaired Mucosal Permeability Underlies Ongoing Irritable Bowel Syndrome-Like Symptoms, in Patients With Inflammatory Bowel Disease Who Have Achieved Mucosal Healing

Rationale: Idiopathic pulmonary fibrosis (IPF) identifies patients with pulmonary fibrosis in a usual interstitial pattern, with no identifiable associations. Esophageal motility disorders and gastroesophageal reflux (GER) are common in patients with end-stage lung disease including IPF. GER-induced aspiration has been proposed as a risk factor for development of IPF and may contribute to further lung injury. Recognition of subtle manifestations of GER in this population is therefore imperative. We intend to characterize esophageal motility disturbances and GER in IPF and explore their relationship to clinical symptoms and lung function. Methods: We performed a retrospective data review of patients with idiopathic pulmonary fibrosis (IPF) referred for combined 24-hour pH-impedance off PPI and high resolution esophageal manometry studies between January 2009 and October 2013 from an interstitial lung disease clinic and a pre-lung transplant clinic. Results: Twenty-eight patients qualified for our study, 71% male, mean age 64±1.4 years, with a mean total lung capacity (TLC) of 62.8±2.9% predicted. Sixty-eight percent of patients had abnormal high resolution manometry: 22% of all patients had ineffective esophageal motility (IEM), 18% had weak upper esophageal sphincters, 14% had weak lower esophageal sphincters (LES), 11% had elevated LES resting pressures, and 28% had a hiatus hernia. Fifteen patients had symptomatic heartburn at the time of investigations, of whom three had a DeMeester score >14.7. Four of the 28 patients (14.3%) reported esophageal symptoms (dysphagia or regurgitation) at the time of the investigations, which was associated with a sensitivity of 16%, and a specificity of 89% for a manometric abnormality. There was no association between abnormal esophageal motility, increased esophageal acid exposure and forced vital capacity (FVC), diffusion capacity of carbon monoxide adjusted for alveolar volume, or 6MWT. Conclusions: Esophageal motility is frequently abnormal in patients with IPF. Despite symptoms of heartburn, GERD is infrequent in patients with IPF. The presence or absence of GERD and/or esophageal dysmotility is not associated with the severity of lung function in IPF patients.