- Email: [email protected]
Nondiagnosed Uveal Melanomas: Author reply
Letters to the Editor Author reply Dear Editor: I appreciate the interest of Lall et al, who suggest that the poorer s for the parafoveal zones might be explained by the prevalence of clinically significant macular edema being less in these zones. The prevalences of clinically significant macular edema in the parafoveal zones were as follows: superior, 44/143 (31%); inferior, 42/143 (29%); nasal, 37/ 143 (26%); and temporal, 52/143 (36%), all of which are comparable to the foveal zone prevalence of 50/143 (35%). Therefore, their suggested explanation is not tenable, and the theoretical flaw in , which they cite, does not apply. The statistic is preferred to the statistic because it does not suffer from a dependence on the distribution of results as does. In my data, because the distribution of results is not extreme for any of the 5 zones (all zones with 26%–35% clinically significant macular edema), the results for and are similar; therefore, there is no additional interpretation to be made. I included in view of the trend to do so in the medical literature, given its theoretical advantages.1
undiagnosed melanomas reported in the study by Bove and Char. Indeed, a fast-growing choroidal melanoma was reported in an eye in which examination 16 months earlier disclosed no tumor. Its largest basal diameter was 19 mm and its thickness was 11 mm, from which the authors calculated an average doubling time for this melanoma of 64 days.6 Compared with this, the tumors belonging to the “1 year before undiagnosed” group of Bove and Char presented with smaller dimensions (mean diameter, 11.8 mm; mean thickness, 6 mm). Therefore, even if there is clearly a need to improve the efforts in continuing medical education of general ophthalmologists, it is possible that the number of tumors present but not detected by the eye care professionals in Bove and Char’s study could be markedly lower than reported. LAURENT KODJIKIAN, MD, PHD JUSTUS G. GARWEG, MD Bern, Switzerland FRANCK BACIN, MD Clermont-Ferrand, France
DAVID J. BROWNING, MD, PHD Charlotte, North Carolina Reference 1. McGinn T, Guyatt G, Cook R, Meade M. Diagnosis: measuring agreement beyond chance. In: Guyatt G, Rennie D, eds. User’s Guide to the Medical Literature: Essentials of Evidence-Based Clinical Practice. Chicago: AMA Press; 2002:461–70.
Nondiagnosed Uveal Melanomas Dear Editor: We enjoyed reading the article on the problems of detection of uveal melanoma by Bove and Char.1 The authors have concluded that “there are a notable number of patients seen by general ophthalmologists with symptomatic uveal melanomas in whom the diagnosis is not established.” Their main argument is that “it is highly likely that the tumor was present but not detected, given the natural history of uveal melanomas.” Unfortunately, the authors did not develop this last point in their “Discussion.” We felt, however, that this is important and may alter the interpretation of their results. Augsburger et al detailed that the mean tumor doubling time in uveal melanoma is 291.6 days for spindle-cell types and 128.2 days for mixed-cell types, which is consistent with the authors’ conclusion.2 But Gass found in his studies individual choroidal melanoma growth rates with doubling times as short as 2 months.3 These were rather constant within each tumor but widely variable between tumors and, moreover, correlated to the mitotic index. He further noted that most large as well as epithelioid and mixed cell–type tumors grow faster. Recently, 2 other studies have added further information about the spectrum of growth velocity in melanomas, with tumor-doubling times of 10.5 and 31.5 days, related to the pathology and the cell cycle protein immunohistochemical profile.4,5 Increased growth rates3–5 could explain some of the
JEAN-DANIEL GRANGE, MD Lyon, France References 1. Bove R, Char DH. Nondiagnosed uveal melanomas. Ophthalmology 2004;111:554 –7. 2. Augsburger JJ, Gonder JR, Amsel J, et al. Growth rates and doubling times of posterior uveal melanomas. Ophthalmology 1984;91:1709 –15. 3. Gass JD. Comparison of uveal melanoma growth rates with mitotic index and mortality. Arch Ophthalmol 1985;103: 924 –31. 4. Laquis SJ, Freeman JM, Fleming JC, et al. A rapidly growing choroidal melanoma. Am J Ophthalmol 2002;133:580 –1. 5. Honda S, Hirai T, Handa JT, et al. Expression of cell cycle related proteins in a rapidly growing uveal malignant melanoma. Retina 2004;24:646 –9. 6. Sahel JA, Pesavento R, Frederick AR Jr, Albert DM. Melanoma arising de novo over a 16-month period. Arch Ophthalmol 1988;106:381–5.
Author reply Dear Editor: We appreciate the comments by Drs Kodjikian et al. The authors query whether unrecognized inclusion of very rapidly growing tumors in our data set would negate some of our conclusions on uveal melanoma nondiagnosis. Our group has had a long-standing interest in both in vivo and in vitro uveal melanoma growth rates, and has published a number of articles in that area since an initial 1982 clinical study of 30 patients with growing choroidal melanomas.1,2 We have reviewed a number of problems associated with studies to estimate uveal melanoma-doubling times, including the cited study by Gass.3 The largest clinical study of choroidal melanoma growth rates, in 145 patients, was reported by us.4 We have a reasonable data set on the growth rate of small pigmented tumors, although those cases were deliberately segregated from analysis of
735
Ophthalmology Volume 112, Number 4, April 2005 larger melanomas in our recent article. In smaller pigmented lesions, the mean doubling time was 1.4 years; however, Gompertzian models show that larger tumors, such as the cases in this study, have a slower doubling time.3 Our clinical and experimental data demonstrate that a very small number of uveal melanoma patients had tumors that grew rapidly. As we cited, the Armed Forces Institute of Pathology data showed that the mean age of patients with melanomas under 10 mm in diameter was 52 years, as compared with 59.3 years in tumors that were ⬎15 mm in diameter. This led to the conclusion that it took approximately 7 years to grow from a small uveal melanoma to a large one. The reason the 2 rapidly growing uveal melanoma cases cited in the letter by Kodjikian et al were reported is because that behavior is so unusual. In many of our cases there was a short interval (up to 3 weeks) between our initial evaluation and definitive surgery. In none of these cases did significant enlargement occur in that interval. Similarly, we see all patients 6 weeks after radiation, and none of these cases showed a marked change in tumor dimensions. We and others have previously shown that rapidly growing tumors regress more rapidly after radiation, and we did not note any rapid regression outliers in this patient cohort.5,6 Therefore, although the authors of this letter have an intriguing hypothesis, we believe it is not likely correct. We appreciate their sharing it with us. DEVRON H. CHAR, MD San Francisco, California References 1. Char DH, Heilbron DC, Juster RP, Stone RD. Choroidal melanoma growth patterns. Br J Ophthalmol 1983;67:575– 8. 2. Kroll S, Char DH, Kaleta-Michaels S. A stochastic model for dual label experiments: an analysis of the heterogeneity of S phase duration. Cell Prolif 1995;28:545– 67. 3. Juster RP, Char DH. Uveal melanoma: doubling time and mitotic index [letter]. Arch Ophthalmol 1986;104:174 –5. 4. Char DH, Kroll S, Phillips TL. Uveal melanoma. Growth rate and prognosis. Arch Ophthalmol 1997;115:1014 – 8. 5. Augsburger JJ, McNeary BT, von Below H, et al. Regression of posterior uveal malignant melanomas after cobalt plaque radiotherapy. Graefes Arch Clin Exp Ophthalmol 1986;224: 397– 400. 6. Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 1998;125:81–9.
Patching Regimens for Amblyopia Dear Editor: The Pediatric Eye Disease Investigator Group (PEDIG) attempted to compare full-time patching to 6 hours of patching per day for treating severe amblyopia.1 They concluded that the treatments were equally effective. This study has created a serious dilemma for clinicians. When faced with an amblyopic child who is not improving on part-time patching, common sense and common knowledge say that increasing the number of hours of patching may bring success. That has been my experience, as well as the experience of others.2,3 How can the scientifically up-to-date clinician now make such a recommendation, in light of the
736
findings of the PEDIG study? The answer is simple. The PEDIG study does not address that issue. As pointed out in 2 letters to the editor regarding the study, as well as the reply from the PEDIG authors, the amount of patching in the 2 groups may in fact not have differed due to poor compliance.2,4 Fully two thirds of the full-time patching group may have only patched half-time. The PEDIG authors addressed this concern by claiming they were comparing the effectiveness of the act of simply prescribing 2 different treatment programs, rather than the actual effectiveness of the 2 treatments, had the prescriptions actually been followed. In other words, if poor compliance resulted in both groups actually receiving the same treatment, the groups were still analyzed as though they had been treated differently, simply because different treatments had been prescribed. This is known as an intention-to-treat analysis—an analysis that compares the outcome in 2 groups in which different treatments were attempted, even if not carried out. To their credit, the PEDIG was careful to state in the abstract that its conclusions were based on prescribed patching programs. Also, in the article they did suggest the possibility that the equal results found in the 2 groups may have been a result of their receiving equal amounts of patching. However, readers still need to understand that the authors are making a distinction between comparing 2 patching programs and comparing 2 prescribed patching programs. I am concerned that the subtlety of this differentiation was lost to most readers due to the syntax. This nuanced use of language initially confused not only me, but also the authors of the letters to the editor.2,4 In addition, it apparently confused the authors of “This Issue at a Glance”: the headline over the précis of the PEDIG article read “Six-Hour Patching and Full-Time Patching Produce Similar Visual Acuity Improvements in Patients with Severe Amblyopia.” Notably absent were the words “prescribed full-time patching.” If the editors of Ophthalmology were led astray by the confusing use of prescribed in the PEDIG study, it is no wonder there is a widespread misconception about what this article actually has proven. Put in reductionist terms, the PEDIG study claims only that if you prescribe full-time patching, or prescribe halftime patching, there will be no difference if the patients do not follow the prescribed regimen. The study does not address what would happen if the prescribed treatments are carried out. I feel that readers will now be reassured to know clearly and plainly the conclusions of the PEDIG article. Readers would have been better informed if the article’s “Discussion” stated this conclusion in a more transparent manner. BURTON J. KUSHNER, MD Madison, Wisconsin References 1. Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching regimens for treatment of severe amblyopia in children. Ophthalmology 2003;110:2075– 87. 2. von Noorden GK, Campos EC. Patching regimens [letter]. Ophthalmology 2004;111:1063, author reply 1064 – 6.
undiagnosed melanomas reported in the study by Bove and Char. Indeed, a fast-growing choroidal melanoma was reported in an eye in which examination 16 months earlier disclosed no tumor. Its largest basal diameter was 19 mm and its thickness was 11 mm, from which the authors calculated an average doubling time for this melanoma of 64 days.6 Compared with this, the tumors belonging to the “1 year before undiagnosed” group of Bove and Char presented with smaller dimensions (mean diameter, 11.8 mm; mean thickness, 6 mm). Therefore, even if there is clearly a need to improve the efforts in continuing medical education of general ophthalmologists, it is possible that the number of tumors present but not detected by the eye care professionals in Bove and Char’s study could be markedly lower than reported. LAURENT KODJIKIAN, MD, PHD JUSTUS G. GARWEG, MD Bern, Switzerland FRANCK BACIN, MD Clermont-Ferrand, France
DAVID J. BROWNING, MD, PHD Charlotte, North Carolina Reference 1. McGinn T, Guyatt G, Cook R, Meade M. Diagnosis: measuring agreement beyond chance. In: Guyatt G, Rennie D, eds. User’s Guide to the Medical Literature: Essentials of Evidence-Based Clinical Practice. Chicago: AMA Press; 2002:461–70.
Nondiagnosed Uveal Melanomas Dear Editor: We enjoyed reading the article on the problems of detection of uveal melanoma by Bove and Char.1 The authors have concluded that “there are a notable number of patients seen by general ophthalmologists with symptomatic uveal melanomas in whom the diagnosis is not established.” Their main argument is that “it is highly likely that the tumor was present but not detected, given the natural history of uveal melanomas.” Unfortunately, the authors did not develop this last point in their “Discussion.” We felt, however, that this is important and may alter the interpretation of their results. Augsburger et al detailed that the mean tumor doubling time in uveal melanoma is 291.6 days for spindle-cell types and 128.2 days for mixed-cell types, which is consistent with the authors’ conclusion.2 But Gass found in his studies individual choroidal melanoma growth rates with doubling times as short as 2 months.3 These were rather constant within each tumor but widely variable between tumors and, moreover, correlated to the mitotic index. He further noted that most large as well as epithelioid and mixed cell–type tumors grow faster. Recently, 2 other studies have added further information about the spectrum of growth velocity in melanomas, with tumor-doubling times of 10.5 and 31.5 days, related to the pathology and the cell cycle protein immunohistochemical profile.4,5 Increased growth rates3–5 could explain some of the
JEAN-DANIEL GRANGE, MD Lyon, France References 1. Bove R, Char DH. Nondiagnosed uveal melanomas. Ophthalmology 2004;111:554 –7. 2. Augsburger JJ, Gonder JR, Amsel J, et al. Growth rates and doubling times of posterior uveal melanomas. Ophthalmology 1984;91:1709 –15. 3. Gass JD. Comparison of uveal melanoma growth rates with mitotic index and mortality. Arch Ophthalmol 1985;103: 924 –31. 4. Laquis SJ, Freeman JM, Fleming JC, et al. A rapidly growing choroidal melanoma. Am J Ophthalmol 2002;133:580 –1. 5. Honda S, Hirai T, Handa JT, et al. Expression of cell cycle related proteins in a rapidly growing uveal malignant melanoma. Retina 2004;24:646 –9. 6. Sahel JA, Pesavento R, Frederick AR Jr, Albert DM. Melanoma arising de novo over a 16-month period. Arch Ophthalmol 1988;106:381–5.
Author reply Dear Editor: We appreciate the comments by Drs Kodjikian et al. The authors query whether unrecognized inclusion of very rapidly growing tumors in our data set would negate some of our conclusions on uveal melanoma nondiagnosis. Our group has had a long-standing interest in both in vivo and in vitro uveal melanoma growth rates, and has published a number of articles in that area since an initial 1982 clinical study of 30 patients with growing choroidal melanomas.1,2 We have reviewed a number of problems associated with studies to estimate uveal melanoma-doubling times, including the cited study by Gass.3 The largest clinical study of choroidal melanoma growth rates, in 145 patients, was reported by us.4 We have a reasonable data set on the growth rate of small pigmented tumors, although those cases were deliberately segregated from analysis of
735
Ophthalmology Volume 112, Number 4, April 2005 larger melanomas in our recent article. In smaller pigmented lesions, the mean doubling time was 1.4 years; however, Gompertzian models show that larger tumors, such as the cases in this study, have a slower doubling time.3 Our clinical and experimental data demonstrate that a very small number of uveal melanoma patients had tumors that grew rapidly. As we cited, the Armed Forces Institute of Pathology data showed that the mean age of patients with melanomas under 10 mm in diameter was 52 years, as compared with 59.3 years in tumors that were ⬎15 mm in diameter. This led to the conclusion that it took approximately 7 years to grow from a small uveal melanoma to a large one. The reason the 2 rapidly growing uveal melanoma cases cited in the letter by Kodjikian et al were reported is because that behavior is so unusual. In many of our cases there was a short interval (up to 3 weeks) between our initial evaluation and definitive surgery. In none of these cases did significant enlargement occur in that interval. Similarly, we see all patients 6 weeks after radiation, and none of these cases showed a marked change in tumor dimensions. We and others have previously shown that rapidly growing tumors regress more rapidly after radiation, and we did not note any rapid regression outliers in this patient cohort.5,6 Therefore, although the authors of this letter have an intriguing hypothesis, we believe it is not likely correct. We appreciate their sharing it with us. DEVRON H. CHAR, MD San Francisco, California References 1. Char DH, Heilbron DC, Juster RP, Stone RD. Choroidal melanoma growth patterns. Br J Ophthalmol 1983;67:575– 8. 2. Kroll S, Char DH, Kaleta-Michaels S. A stochastic model for dual label experiments: an analysis of the heterogeneity of S phase duration. Cell Prolif 1995;28:545– 67. 3. Juster RP, Char DH. Uveal melanoma: doubling time and mitotic index [letter]. Arch Ophthalmol 1986;104:174 –5. 4. Char DH, Kroll S, Phillips TL. Uveal melanoma. Growth rate and prognosis. Arch Ophthalmol 1997;115:1014 – 8. 5. Augsburger JJ, McNeary BT, von Below H, et al. Regression of posterior uveal malignant melanomas after cobalt plaque radiotherapy. Graefes Arch Clin Exp Ophthalmol 1986;224: 397– 400. 6. Char DH, Kroll SM, Castro J. Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 1998;125:81–9.
Patching Regimens for Amblyopia Dear Editor: The Pediatric Eye Disease Investigator Group (PEDIG) attempted to compare full-time patching to 6 hours of patching per day for treating severe amblyopia.1 They concluded that the treatments were equally effective. This study has created a serious dilemma for clinicians. When faced with an amblyopic child who is not improving on part-time patching, common sense and common knowledge say that increasing the number of hours of patching may bring success. That has been my experience, as well as the experience of others.2,3 How can the scientifically up-to-date clinician now make such a recommendation, in light of the
736
findings of the PEDIG study? The answer is simple. The PEDIG study does not address that issue. As pointed out in 2 letters to the editor regarding the study, as well as the reply from the PEDIG authors, the amount of patching in the 2 groups may in fact not have differed due to poor compliance.2,4 Fully two thirds of the full-time patching group may have only patched half-time. The PEDIG authors addressed this concern by claiming they were comparing the effectiveness of the act of simply prescribing 2 different treatment programs, rather than the actual effectiveness of the 2 treatments, had the prescriptions actually been followed. In other words, if poor compliance resulted in both groups actually receiving the same treatment, the groups were still analyzed as though they had been treated differently, simply because different treatments had been prescribed. This is known as an intention-to-treat analysis—an analysis that compares the outcome in 2 groups in which different treatments were attempted, even if not carried out. To their credit, the PEDIG was careful to state in the abstract that its conclusions were based on prescribed patching programs. Also, in the article they did suggest the possibility that the equal results found in the 2 groups may have been a result of their receiving equal amounts of patching. However, readers still need to understand that the authors are making a distinction between comparing 2 patching programs and comparing 2 prescribed patching programs. I am concerned that the subtlety of this differentiation was lost to most readers due to the syntax. This nuanced use of language initially confused not only me, but also the authors of the letters to the editor.2,4 In addition, it apparently confused the authors of “This Issue at a Glance”: the headline over the précis of the PEDIG article read “Six-Hour Patching and Full-Time Patching Produce Similar Visual Acuity Improvements in Patients with Severe Amblyopia.” Notably absent were the words “prescribed full-time patching.” If the editors of Ophthalmology were led astray by the confusing use of prescribed in the PEDIG study, it is no wonder there is a widespread misconception about what this article actually has proven. Put in reductionist terms, the PEDIG study claims only that if you prescribe full-time patching, or prescribe halftime patching, there will be no difference if the patients do not follow the prescribed regimen. The study does not address what would happen if the prescribed treatments are carried out. I feel that readers will now be reassured to know clearly and plainly the conclusions of the PEDIG article. Readers would have been better informed if the article’s “Discussion” stated this conclusion in a more transparent manner. BURTON J. KUSHNER, MD Madison, Wisconsin References 1. Pediatric Eye Disease Investigator Group. A randomized trial of prescribed patching regimens for treatment of severe amblyopia in children. Ophthalmology 2003;110:2075– 87. 2. von Noorden GK, Campos EC. Patching regimens [letter]. Ophthalmology 2004;111:1063, author reply 1064 – 6.