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      Bilateral Severe Corneal Ulcer in a Patient with Lung Adenocarcinoma Treated with Gefitinib

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          Abstract

          We describe the case of Gefitinib-related bilateral corneal perforation. An 86-year-old female patient had bilateral painless and progressive vision loss due to neurotrophic corneal ulcer, following a 2-month treatment with Gefitinib, a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for metastatic adenocarcinoma of the lung with confirmed EGFR gene mutation. She had no signs of ocular infection, inflammation, or lid problems to account for the development of corneal damage. Neurotrophic ulcer evolved into a frank perforation in one eye and an impending perforation on the other eye. EGFR inhibitors have been associated with dry eye, epithelial erosions, ulcerative keratitis, and corneal edema. However, to the best of our knowledge, this is the first case of bilateral severe corneal ulcer due to Gefitinib. The patient went on to have bilateral corneal graft surgery. This case aims to raise awareness among ophthalmologists and oncologists of the association between EGFR inhibitors, corneal neurotrophic ulcers, and possible evolution in corneal perforation.

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          Most cited references 11

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          Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

          Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.) 2009 Massachusetts Medical Society
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            Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.

            Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. Copyright 2004 Massachusetts Medical Society
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              The epidermal growth factor receptor (EGFR): role in corneal wound healing and homeostasis.

              To evaluate the role of the epidermal growth factor receptor (EGFR) in corneal epithelial wound healing, the effect of an EGFR inhibitor on epithelial cell proliferation and cell stratification during wound healing was investigated. From 3 days prior to wounding until wound healing was complete, rats were systemically treated with either an EGFR tyrosine kinase inhibitor (ZD1839) at 40 mg kg(-1) day(-1)or 80 mg kg(-1) day(-1), or with vehicle only (control). A single corneal wound was made in the center of 66 rat corneas, using a 6.0 mm glass tube wrapped in tissue paper soaked in n-heptanol. Subsequently, each wound was photographed and measured by a computer-assisted digitizer every 12 hr. To determine the number of cells in S phase, entire corneas were labelled with (3)H-thymidine and subjected to autoradiography at 0, 12, 24 and 48 hr after wounding. Epithelial thickness was also measured at these time points by microscopy. Epithelial wound healing was significantly and dose-dependently delayed following administration of ZD1839. At 24 hr after wounding, the number of S-phase cells in the limbal corneal epithelium was significantly lower in both the treated groups compared with the control group (P < 0.05). In the cornea before wounding (0 hr) and at 48 hr post-wounding, epithelial thickness was also significantly less in treated rats compared with controls (P < 0.05). These results indicate that EGFR inhibition affects epithelial cell proliferation and stratification during corneal epithelial wound healing and may play a role in maintaining normal corneal epithelial thickness. Copyright 2001 Academic Press.
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                Author and article information

                Journal
                Case Rep Ophthalmol
                Case Rep Ophthalmol
                COP
                Case Reports in Ophthalmology
                S. Karger AG (Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com )
                1663-2699
                Jan-Apr 2021
                30 April 2021
                30 April 2021
                : 12
                : 1
                : 288-292
                Affiliations
                aOcular Immunology Unit, Azienda USL − IRCCS Reggio Emilia, Reggio Emilia, Italy
                bMedical Oncology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
                cPredictive Biomarkers and Novel Therapeutic Strategies in Oncology, Inserm U981, Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France
                dOphthalmology Unit, Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy
                Article
                cop-0012-0288
                10.1159/000514696
                8138211
                34054472
                Copyright © 2021 by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.

                Page count
                Figures: 1, References: 12, Pages: 5
                Categories
                Case Report

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