Vitamin E and Prostate Cancer

Ophthalmology Volume 119, Number 9, September 2012 Capillary Hemangioma Treatment Dear Editor: Capillary hemangiomas are the most common tumor of infancy affecting 10% of Caucasian infants. Up to 5% of these lesions may be present in the periocular region causing problems such as proptosis, obstruction of vision, or compression of the eye.1 Capillary hemangiomas are also characterized by rapid changes in cellular make-up during the respective phases.2 The proliferative phase is defined by high expression of vascular endothelial growth factor (VEGF), as well as proliferating cell nuclear antigen (PCNA), CD 31, and von Willebrand factor (vWF). Our study investigates the effect of anti-VEGF therapy on capillary hemangioma growth in Wistar R rats. A search of the literature revealed a novel animal model for developing capillary hemangiomas by inoculation of 3to 4-day-old rats with a high titer of murine polyomavirusstrain Marsaille (PyV).3 We were able to reproduce capillary hemangioma growth in Wistar R rat pups with 100% frequency after 3 weeks of biweekly injections. Rats were then separated into a control group (n ⫽ 12) and a treatment group (n ⫽ 15). Both groups received biweekly injections of the polyomavirus for 3 weeks. The control group was then observed, while the treatment group received biweekly bevacizumab (Avastin, Genentech, San Francisco, CA) 5 mg/kg intraperitoneally. Starting at week 4, a percentage of rats from each group were necropsied at weekly intervals to evaluate for hemangioma growth. When hemangiomas were found, they were stained for VEGF, PCNA, vWF, and CD-31. Table 1 (available at http://aaojournal.org) shows the results for each rat in the study. There was a statistically significant decrease in the number of rats that developed hemangiomas in the treatment group compared with the control group (P⬍0.05, Fisher exact test). In the control group, 100% of the rats developed capillary hemangiomas, whereas only 66% of the rats in the treatment group developed hemangiomas. The most common location for hemangioma growth was the brain (78%), followed by the feet (37%), heart (26%), and lungs (11%). Figures 1A-C (available at http://aaojournal.org) show representative examples of the capillary hemangiomas. The polyomavirus also caused other tumors including undifferentiated sarcoma of the kidneys (92%), bone (48%), and skeletal muscles (11%). Only 44% of the hemangiomas from the control group tested positive for VEGF, while 80% were positive from the treatment group. For the control group, 75% of the rats that tested positive for VEGF were necropsied at week 4. In the treatment group, only 37% of the rats that tested positive for VEGF were necropsied at week 4. There was no significant difference between the groups with respect to the PCNA, CD 31, and vWF stains. We found it interesting that the majority of rats in the treatment group that tested positive for VEGF did so after receiving a higher number of bevacizumab injections. A potential explanation for this finding is upregulation of VEGF. In the setting of VEGF inhibition, these tumors may have upregulated more VEGF to allow tumor growth. It is conceivable that the route of administration of bevacizumab

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(intraperitoneal) allowed the tumor to be exposed to subtherapeutic doses of the medication. Partial blockage of the VEGF receptors may have resulted in the upregulation of more VEGF. In a retrospective review of bevacizumabevasive glioblastomas, Rose and Aghi4 found that VEGFtargeted treatments like bevacizumab could cause hyperinvasive or hyperangiogenic phenotypes associated with glioblastoma recurrence. They hypothesized that upregulation of VEGF allowed the tumor to exceed the capacity of VEGF blockade at the dose given to the patient, thus permitting a revascularization of the tumor. In a recent study, Greenberger et al5 found that dexamethasone silenced VEGF-A expression and inhibited hemangioma-like blood vessel growth in nude mice injected with hemangioma-derived stem cells. This study helped elucidate the previously unknown mechanism by which corticosteroids treat capillary hemangiomas, and gives further credibility to targeting VEGF as a treatment mechanism. In conclusion, anti-VEGF therapy shows promise as a future treatment modality for infantile capillary hemangiomas. BRETT W. DAVIES, MD, MS KRISTINE K. PIERCE, MD DAVID E. HOLCK, MD San Antonio, Texas References 1. Haik BG, Karcioglu ZA, Gordon RA, Pechous BP. Capillary hemangioma (infantile periocular hemangioma). Surv Ophthalmol 1994;38:399 – 426. 2. Takahashi K, Mulliken JB, Kozakewich HPW, et al. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994;93:2357– 64. 3. Liekens S, Verbeken E, Vandeputte M, et al. A novel animal model for hemangiomas: Inhibition of hemangioma development by the angiogenesis inhibitor TNP-470. Cancer Res 1999;59:2376 – 83. 4. Rose SD, Aghi MK. Mechanisms of evasion to antiangiogenic therapy in glioblastoma. Clin Neurosurg 2010;57:123– 8. 5. Greenberger S, Boscolo E, Adini I, et al. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med 2010;362:1005–13.

Vitamin E and Prostate Cancer Dear Editor: We would like to address the issue regarding the association of vitamin E with prostate cancer. The long-term follow-up from The Selenium and Vitamin E Cancer Prevention Trial (SELECT) found that dietary supplementation with vitamin E (400 international units [IU] per day) significantly increased the risk of prostate cancer among healthy men.1 The researchers found that the risk of prostate cancer at 7 years of median follow-up was increased by 17% in the men randomized to supplementation with vitamin E alone compared with placebo. This is the relative risk. What is the absolute risk and what does this mean clinically? There will be between 1 to 2 more prostate cancers per 1000 patients who would be given vitamin E for 1 full year. Interestingly, in men who received both vitamin E and selenium, there was no increased rate of prostate cancer.

Letters to the Editor These findings from SELECT should be reviewed in the context of prior trials. These SELECT results differ from the 34% reduction (log rank test, P⬍0.01) in the risk of prostate cancer in male participants taking 50 mg/d of vitamin E enrolled in the Alpha-Tocopherol, Beta Carotene (ATBC) trial and followed for a median of 6.1 years.2 The Physicians Health Study II (PHS II) tested 400 IU/d of vitamin E every other day for a median of 8 years and found no effect on incident prostate cancer (hazard ratio [HR], 0.97; 95% CI of 0.85–1.09; P ⫽ 0.58).3 We have conducted an analysis of the Age-Related Eye Disease Study (AREDS) data.4 The daily dose of antioxidant vitamins and minerals used in AREDS included 400 IU of vitamin E, which was similar to the supplementation tested in SELECT. Of the 975 men randomized to no antioxidants 73 developed prostate cancer over a median 6.3 years of following up as part of the AREDS clinical trial. This is compared to 68 out of 967 males randomized to antioxidants (including 400 IU/d of vitamin E). The hazard ratio was not statistically significant (HR, 0.93; P ⫽ 0.65). If we conduct a similar analysis including both the clinical trial period and the clinical course follow-up (median, 10 years) a total of 108 men randomized to no antioxidants developed prostate cancer while 91 men randomized to antioxidants developed prostate cancer (HR, 0.84; P ⫽ 0.23). For both cases the antioxidants were protective, yet not reaching statistical significance, for the development of prostate cancer. Vitamin E, which is given with other antioxidants, in the AREDS formulation appeared to have no increased adverse effect on prostate cancer in this period of follow-up in less than 2000 male participants. As the power of the AREDS analysis to definitively evaluate the role of vitamin E in prostate cancer is limited, given the analysis, a large detrimental effect of vitamin E on prostate cancer may be ruled out. In summary, the results of AREDS study, the ATBC and PHS studies have not demonstrated a harmful effect of supplementation of vitamin E on prostate cancer. There was also a lack of a harmful effect on prostate cancer when the combination of vitamin E and selenium were given in the SELECT study. These issues should be clarified for physicians who are prescribing the AREDS formulation for their patients with intermediate age-related macular degeneration (AMD) or advanced AMD in one eye. As with all therapies, there is always a balance between the risks and benefits of the treatment. We hope this information will aid physicians and their patients in their decision-making regarding treatment with the AREDS supplements. EMILY Y. CHEW, MD Bethesda, Maryland TRACI CLEMONS, PHD Rockville, Maryland References 1. Klein EA, Thompson IM, Tangen CM, et al. Vitamin E and the risk of prostate cancer. The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2011;306:1549 –56. 2. Albanes D, Heinonen OP, Huttunen JK, et al. Effects of alpha-tocopherol and beta-carotene supplements on cancer

incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 1995;62(6 Suppl):1427S– 30S. 3. Gaziano JM, Glynn RJ, Christen WG, et al. Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA 2009;301:52– 62. 4. The Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol 2001;119:1417–36.

Acronyms in Ophthalmology Dear Editor: In recent years, we have observed a trend toward the usage of acronym titles1 for many clinical trials and studies in ophthalmology (Table 1, available at http://aaojournal.org). These may range from decidedly eye-related titles (“VISION,” “FOCUS,” “SEE”) to maritime-inspired names (“ANCHOR,” “MARINA,” “PIER,” “SAILOR”) and seemingly arbitrary ones (“VIP,” “TAP,” “SCORE”). While this convention may bring some benefits to studies, we are of the opinion that researchers should be prudent with its application and exercise caution against potential misuse. An acronym is a pronounceable word formed from the initial letters of a group of words. A fundamental virtue of acronym titles lies in the ease of memory and communication through the use of mnemonics and heuristics.2 Appropriately devised acronyms can provide a certain degree of prestige to the trial,3 and may even result in positive cognitive associations, a phenomenon called “automatic attitude activation.”1 Moreover, acronym-titled studies were 4 times more likely to be funded by the pharmaceutical industry and were cited at twice the rate of trials that were not named with an acronym.1 Trials in ophthalmology titled “VISION,” “PROTECT,” and “FOCUS,” for instance, would most likely benefit from such affirmative linguistic “branding,” on top of their individual scientific merits. However, there may be problems associated with the use of acronym titles in research trials. Obscure acronyms can be puzzling, particularly specialty-specific ones, and this is further compounded when citations are made without a proper context.4 Some acronyms have been formed in an apparently random manner without any rules to govern their creation.5 Titles such as “COMET,” “SCORE,” and “MUST,” seem not to have any linkage to the studies they represent. Furthermore, trials in different specialties with identical titles may be a source of confusion. For example, the acronym title “PROTECT” is shared by disparate trials in age-related macular degeneration, diabetes, prostate cancer, gastroenterology, intensive care, traumatic brain injury, and cardiac failure research (Table 2, available at http:// aaojournal.org). As such, acronyms should always be explained fully and defined at first mention.3,4 In all, an acronym title may be a useful aid in medical research, if sensibly formulated and judiciously applied. A good acronym title should be simplistic, meaningful, and of direct relevance to the research subject. Researchers should

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