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Gene Expression Profiling versus TNM Classification
Ophthalmology Volume 120, Number 7, July 2013 perfused and nonperfused retina is also not typical of Coats’ disease. In our opinion, the features of this fluorescein angiogram are more consistent with familial exudative vitreoretinopathy (FEVR). The retinal nonperfusion in patients’ with FEVR resembles that of retinopathy of prematurity, with large circumferentially oriented zones of avascular retina with scalloped edges.3 Dilated retinal vessels, which could be interpreted as telangiectasia, are also commonly seen in FEVR. The macular vessels on the cover photo also show mild temporal dragging, another classic finding in FEVR that would not be expected in Coats’ disease. Another possible diagnosis to consider is incontinentia pigmente, which also displays peripheral retinal ischemia, in which case dermatologic findings would also be expected. Interestingly, multiple developmental retinal vascular diseases including Coats’ disease, FEVR, Norrie disease, and retinopathy of prematurity are likely different phenotypes within a common disease spectrum. Each of these conditions has been found to be associated with mutations involving the wnt signaling pathway.4 Nevertheless, these conditions are usually differentiated based on typical clinical characteristics.
Although there is overlap between the features of Coats’ disease, FEVR, and other disorders within this disease spectrum, we feel the findings in this case are more consistent with FEVR.
PHILIP W. LAIRD, MD G. BAKER HUBBARD, MD Department of Ophthalmology, Atlanta, Georgia The authors of the August 2012 cover declined to reply.
References 1. Elshatory YM, Shah VA. Wide field fluorescein angiography in macular telangiectasis type 1 (Coats’ disease). Ophthalmology 2012;119:cover. 2. Shields JA, Sheilds CL. Review: coats disease. The 2001 LuEsther T. Mertz Lecture. Retina 2002;22:80 –91. 3. Canny CLB, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol 1976; 94:1114 –20. 4. Nikopoulos K, Venselaar H, Collin RWJ, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Human Mutat 2010;31:656 – 66.
Erratum With apologies from the editorial office, the Correspondence entitled, “Gene Expression Profiling vs. TNM Classification,” which printed in the May 2013 issue (Ophthalmology 2013;120:1109) erroneously included a statement that the authors of the original article declined to reply. A delayed response was received and both the original letter and its reply can be found at www.aaojournal.org.
Gene Expression Profiling versus TNM Classification Dear Editor: We appreciate the opportunity to respond to the letter from Kivelä and Kujala regarding our recent article that prospectively evaluated a gene expression profile (GEP) prognostic test for uveal melanoma.1 One of us (J.W.H.) was a primary member of the committee that developed the current 7th edition American Joint Committee on Cancer TNM system for uveal melanoma; thus, we are quite knowledgeable of this system and how it is applied. We agree that the clinical TNM system stratifies patients with a particular cancer into multiple categories based on tumor size, location, and extent, and then arranges those categories into stages that are relatively homogeneous with respect to prognosis. A critical fact that Kivelä and Kujala failed to mention, however, is that these stage groupings are determined by retrospective analysis of large numbers of patients with known outcome and, thus, are in constant evolution as more data are collected. In contrast, the purpose of our study was to analyze the prospective predictive accuracy of the GEP test without retrospective manipulation of prognostic categories, which is the everyday situation in which clinicians use the test.
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We agree that the word “categories” would have been preferred over the word “stages” in the title to Table 4. However, we believe that our colleagues misunderstand what we were attempting to accomplish with our data analysis. Real-life clinical decisions in patients with uveal melanoma are not usually made by academicians using complex staging systems, but by busy clinicians who must make practical decisions for individual patients: Is the patient at high enough risk to send to a medical oncology? To enroll in a clinical trial? To monitor with high-intensity surveillance? The GEP test was designed as a simple, reliable, straightforward, and highly accurate tool for making practical clinical decisions for individual patients. Consequently, in our comparison of the GEP with clinical and pathologic variables, we attempted to create optimized dichotomous classifications of these variables to more closely approximate a real-world decision-making environment. The result of this study was that the GEP test substantially outperformed all other variables, including the dichotomized TNM classification, in its ability to discriminate between patients who will and will not develop metastasis. Finally, we agree that there may be clinical situations where the TNM classification could enhance the prognostic information obtained by the GEP test, but this would require additional
Erratum retrospective data analysis, which was not the purpose of our prospective validation study.
J. WILLIAM HARBOUR, MD1 JAMES J. AUGSBURGER, MD2 DEVRON H. CHAR, MD3 1
Ocular Oncology Service, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida; 2Department
of Ophthalmology, University of Cincinnati School of Medicine, Cincinnati, Ohio; 3Tumori Foundation, San Francisco, California
Reference 1. Onken MD, Worley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012;119:1596 – 603.
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Although there is overlap between the features of Coats’ disease, FEVR, and other disorders within this disease spectrum, we feel the findings in this case are more consistent with FEVR.
PHILIP W. LAIRD, MD G. BAKER HUBBARD, MD Department of Ophthalmology, Atlanta, Georgia The authors of the August 2012 cover declined to reply.
References 1. Elshatory YM, Shah VA. Wide field fluorescein angiography in macular telangiectasis type 1 (Coats’ disease). Ophthalmology 2012;119:cover. 2. Shields JA, Sheilds CL. Review: coats disease. The 2001 LuEsther T. Mertz Lecture. Retina 2002;22:80 –91. 3. Canny CLB, Oliver GL. Fluorescein angiographic findings in familial exudative vitreoretinopathy. Arch Ophthalmol 1976; 94:1114 –20. 4. Nikopoulos K, Venselaar H, Collin RWJ, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Human Mutat 2010;31:656 – 66.
Erratum With apologies from the editorial office, the Correspondence entitled, “Gene Expression Profiling vs. TNM Classification,” which printed in the May 2013 issue (Ophthalmology 2013;120:1109) erroneously included a statement that the authors of the original article declined to reply. A delayed response was received and both the original letter and its reply can be found at www.aaojournal.org.
Gene Expression Profiling versus TNM Classification Dear Editor: We appreciate the opportunity to respond to the letter from Kivelä and Kujala regarding our recent article that prospectively evaluated a gene expression profile (GEP) prognostic test for uveal melanoma.1 One of us (J.W.H.) was a primary member of the committee that developed the current 7th edition American Joint Committee on Cancer TNM system for uveal melanoma; thus, we are quite knowledgeable of this system and how it is applied. We agree that the clinical TNM system stratifies patients with a particular cancer into multiple categories based on tumor size, location, and extent, and then arranges those categories into stages that are relatively homogeneous with respect to prognosis. A critical fact that Kivelä and Kujala failed to mention, however, is that these stage groupings are determined by retrospective analysis of large numbers of patients with known outcome and, thus, are in constant evolution as more data are collected. In contrast, the purpose of our study was to analyze the prospective predictive accuracy of the GEP test without retrospective manipulation of prognostic categories, which is the everyday situation in which clinicians use the test.
e52
We agree that the word “categories” would have been preferred over the word “stages” in the title to Table 4. However, we believe that our colleagues misunderstand what we were attempting to accomplish with our data analysis. Real-life clinical decisions in patients with uveal melanoma are not usually made by academicians using complex staging systems, but by busy clinicians who must make practical decisions for individual patients: Is the patient at high enough risk to send to a medical oncology? To enroll in a clinical trial? To monitor with high-intensity surveillance? The GEP test was designed as a simple, reliable, straightforward, and highly accurate tool for making practical clinical decisions for individual patients. Consequently, in our comparison of the GEP with clinical and pathologic variables, we attempted to create optimized dichotomous classifications of these variables to more closely approximate a real-world decision-making environment. The result of this study was that the GEP test substantially outperformed all other variables, including the dichotomized TNM classification, in its ability to discriminate between patients who will and will not develop metastasis. Finally, we agree that there may be clinical situations where the TNM classification could enhance the prognostic information obtained by the GEP test, but this would require additional
Erratum retrospective data analysis, which was not the purpose of our prospective validation study.
J. WILLIAM HARBOUR, MD1 JAMES J. AUGSBURGER, MD2 DEVRON H. CHAR, MD3 1
Ocular Oncology Service, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida; 2Department
of Ophthalmology, University of Cincinnati School of Medicine, Cincinnati, Ohio; 3Tumori Foundation, San Francisco, California
Reference 1. Onken MD, Worley LA, Char DH, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology 2012;119:1596 – 603.
e53