It is a daunting challenge to write another textbook of ophthalmic oncology at the millennium. Several issues combine to make this undertaking difficult. First, paradoxically obtaining inclusive literature searches has become harder over the last 10 years. A generation ago, I was confident that I could survey the entire world’s literature in an area. Several factors have coalesced to make this an almost impossible challenge. One, there has been a virtual revolution in the number of publications in ophthalmology and cancer. Almost 20,000 biomedical journals exist. Two, library budgets have been severely restricted. In some cases, it has taken up to 2 months to get an interlibrary loan of an article I wish to review. Three, although we have come to rely on computer searching, the relative explosion in the number of publications has resulted in many of those journals not being indexed. Some studies estimate that “inclusivity” of a thorough computerized library search is approximately 75%.1 Even occasionally in a journal that is indexed, differences in spelling between “countries separated by a common language” have occasionally provided an interesting challenge in obtaining articles.

Second, we are in the midst of a molecular biology revolution regarding medicine. Unfortunately for a book author with a significant interval between writing and publication, this presents several potential quagmires. Our understanding of the molecular biology of oncogenesis and tumor progression is becoming more clear cut, and there are some shared central pathways in most malignancies (Figure 1). In several tumors, the abnormalities in the p53 pathway are important in tumor development and in response to radiation. p53 has been termed the guardian of the genome. Its role is to determine if there is significant DNA damage. When DNA damage occurs, p53 either shuts down the cell cycle until repair can be accomplished or shunts the cell to an apoptotic pro-

grammed cell death pathway. The retinoblastoma gene abnormality (Rb1), although first described in the intraocular tumor, is also present in many systemic neoplasms. Loss of the RB protein with subsequent increased activation of the transcription factor E2F occurs in a number of human malignancies and may be a central component of malignant transformation (see Figure 1). In melanomas and other neoplasms, alterations in the cdk-4 inhibitor p161NK4A occurs and impacts the central cell cycle control pathway. This area is discussed in the first chapter on retinoblastoma.

In any new research area, progress is uneven. For some tumors, such as retinoblastoma, our understanding of many of the important molecular events is well understood. In other areas, there have been many false starts. As an example, in neuroblastoma,

S phase entrance

inhibition by tumor

Figure 1. Normal cell cycle components. Note both positive (→ ) and suppressor (•) influences that have been demonstrated in many tumors.

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it was thought that the expression of N-mye was one of the early examples in which molecular biologic tests would have great clinical import. Patients whose tumors expressed this oncogene had an adverse outcome. A recent article has demonstrated that a more primitive analysis, gain in a portion of the 17th chromosome, actually has a better correlation with prognosis in multivariate analysis.2 As with any rapidly evolving field, I suspect that some of the chapters on oncogenesis and pathophysiology will be out of date shortly after they have been finished. A good example is molecular therapy. Although these approaches have been used for various hematologic abnormalities for a number of years, there is a paucity of phase III clinical trial data. I suspect that it will be another 3 to 4 years before important data on the use of gene therapy for ophthalmic malignancy become available. At the time of writing this book, a proposed gene therapy trial for retinoblastoma was rejected by one of the governing agencies.3

As always in writing a large book, I want to thank my collaborators, the editorial staff, and the support staff who have allowed this to happen, and my teachers and mentors who have helped me attain the knowledge I have.

REFERENCES

1.Kleijen J, Knipschild P. The comprehensiveness of MEDLINE and Embase computer searches. Searches for controlled trials of homeopathy, ascorbic acid for common cold and gingko biloba for cerebral insufficiency and intermittent claudication. Pharm Weekbl Sci 1992;14:316–20.

2.Brown N, Cotterill S, Lastowska M, O’Neill S, Pearson AD, Plantaz D, Meddeb M, Danglot G, Brinkschmidt C, Christiansen H, Laureys G, Speleman F. Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 1999; 340:1954–61.

3.Graber K. RAC nixes plan to treat retinoblastoma. Science 1999;284:2006.