© 1998 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 23, 0VII-0VIII,
1998
© 1998 Oxford University Press
First National AIDS Malignancy Conference Monograph: Introduction
* Affiliation of author: Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
Correspondence to: Ellen Feigal, M.D., National Institutes of Health, Bldg. 31, Rm. 3A44, Bethesda, MD 20892.
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Introduction |
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 Top Introduction Overview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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Scientists, physicians, health care workers, and community and patient advocates from around the world gathered at the first national forum focused on acquired immunodeficiency syndrome (AIDS)-associated cancers in April 1997 on the grounds of the National Institutes of Health campus in Bethesda, MD. The first National AIDS Malignancy Conference, sponsored by the National Cancer Institute, featured multidisciplinary presentations on the epidemiology, biology, virology, immunology, and treatment of cancers in the setting of human immunodeficiency virus (HIV) infection. Cancers have been associated with HIV since the beginning of the epidemic in the late 1970s. With almost 1 million individuals infected with HIV across the United States and 10 million infected worldwide, AIDS-associated cancers offer a unique perspective on the interplay of viruses, immune dysregulation, and cancer pathogenesis. This monograph is a comprehensive compilation of papers from 18 plenary speakers.
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Overview of Cancers, Viruses, and Immunodeficiency |
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TopIntroductionOverview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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Dr. Valerie Beral opened the conference with a presentation of the epidemiologic evidence on the effect of immunosuppression on cancer risk. Immunodeficiency, whether congenital, therapeutic, or infectious in origin, increases the risk of certain, but not all, types of cancer. A common feature of these cancers is that specific infectious agents appear to be important in their etiology. The study of cancer in immunodeficient populations offers a unique opportunity to investigate the role of the immune system in controlling the development, growth, and dissemination of tumors. Such studies have already contributed substantially to knowledge about the role of infectious agents in human cancer.
Given the strategic role that infectious agents may have in the etiology of these cancers, Dr. Elliott Kieff discussed the molecular mechanisms by which human papillomavirus (HPV), Epstein-Barr virus (EBV), human herpesvirus type 8 (HHV-8), and HIV persist and effect changes in cell growth that result in malignancy. Pharmacologic strategies to inhibit the mechanisms by which these viruses cause persistent infection and cell growth transformation may be useful in preventing and treating these cancers. Those approaches may also be useful in considering prevention and treatment of the underlying HIV and other opportunistic infections.
The focus of the overview talks next centered on a discussion of the epidemiologic role of HPV in the development of anogenital neoplasia in both men and women, the higher incidence of HPV in the HIV-infected population, and clinical features of the disease in the HIV-infected as contrasted to the immunocompetent individual. Dr. Joel M. Palefsky postulated that the higher incidence of HPV may reflect loss of systemic immune response to HPV antigens or local HPV-HIV interactions at the tissue or cellular level.
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Activist Community |
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TopIntroductionOverview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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The AIDS activist community is a source of expertise on how science and clinical medicine interact with politics and policy. Activists have had an enormous impact on how the research community shapes its directions, and they have opened the doors for other community and patient advocates to be involved in the decision-making process that ultimately has an impact on patients and individuals at risk for the disease. In his plenary talk, Mr. Michael Marco challenged the National Cancer Institute, the Food and Drug Administration, and the biotechnology and pharmaceutical industries to become more engaged in the basic and clinical scientific communities. A primary emphasis of his presentation was asking how the National Cancer Institute can assure that patients with AIDS and cancer will receive the best medical care for their cancer as well as for their underlying HIV infection.
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Non-AIDS-Defining, HPV-Associated, and Pediatric Cancers |
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TopIntroductionOverview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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A frequently asked question is whether new cancers are emerging in the HIV-infected population. Dr. Charles S. Rabkin examined evidence on whether there are age-related as well as geographic variations in their prevalence. Varying levels of evidence link several additional neoplasms to HIV infection, including Hodgkin's disease and anogenital intraepithelial neoplasia, although invasive disease is still uncertain for both cervical and anal cancers. Leiomyosarcoma and benign leiomyomas are increased in HIV-infected children, but they are unusual in HIV-infected adults. Conjunctival cancer is seen in HIV-infected individuals from sub-Saharan Africa, but it is uncommon in Western countries.
The strong epidemiologic data linking particular subsets of HPV to anogenital disease, combined with knowledge gained from molecular biology and immunology, have spurred recent efforts that have focused on the development of vaccines against HPV. Dr. Douglas R. Lowy raised the possibility that virus-like particles, resembling native HPV capsids, might be effective immunogens for a prophylactic HPV vaccine. Dr. Mitchell Maiman provided his insight on the diagnosis and management of cervical intraepithelial neoplasia and cervical cancer in HIV-infected women.
Children with HIV infection have a lower incidence of cancer than adults with HIV infection, but they appear to have unusual and extremely rare tumors, such as leiomyosarcomas and leiomyomas, and a high prevalence of lymphoproliferative disorders. Dr. Brigitta U. Mueller noted that there are approximately 130 cases of cancer per million non-HIV-infected children (0.013%) per year. A conservative estimate is that children with HIV infection appear to have at least a 100-fold higher incidence of cancers. The need for oncologic and infectious disease expertise in treating these types of uncommon tumors was stressed.
Hodgkin's disease represents another cancer that is not AIDS-defining, although its clinical and pathologic characteristics differ from those in the immunocompetent setting. Dr. Alexandra M. Levine compared and contrasted the characteristics of Hodgkin's disease in the immunocompetent and immunodeficient settings.
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Kaposi's Sarcoma (KS): KSHV/HHV-8, Inflammatory Cytokines, and Treatment |
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TopIntroductionOverview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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In the next series of overviews, Dr. Robin A. Weiss set the scene with a presentation on the epidemiology, current serologic tests, and various KS-associated herpesvirus (KSHV)/HHV-8-encoded proteins that may play a role in the promotion of cellular growth. Later in the conference, molecular biologists analyzed the viral genome and described how it replicates and functions.
Challenging prevailing views on KSHV/HHV-8 and its etiologic relationship to disease, Dr. Robert C. Gallo suggested that the role of HIV-1 is more active in the KS disease process than simply promoting immunodeficiency. He suggested that HIV-1 acts directly by promoting an increase in inflammatory cytokines, which, through sustained release, influences early stage KS by inciting local micro-inflammatory responses and affects growth of the inflammatory cells through the Tat protein.
The clinical aspects of KS were presented by Dr. Susan E. Krown. Four questions critical to the development of improved therapeutic and prophylactic strategies included the following: 1) Can we identify risk factors and predict who will develop KS? 2) Can we translate hypotheses about pathogenesis into improved therapeutic or prophylactic strategies, e.g., target new blood vessel development or inhibit inflammatory cytokines? 3) How does improved anti-HIV therapy have an impact on KS treatment? 4) How can we best evaluate the benefit of therapy beyond conventional measures of tumor response?
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KSHV/HHV-8 Symposium |
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TopIntroductionOverview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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The KSHV/HHV-8 symposium was led by Dr. Patrick S. Moore, co-discoverer with Dr. Yuan Chang and colleagues of KSHV/HHV-8. Molecular biologic studies of KSHV have identified a number of potential oncogenes that may contribute to neoplasia. With the publication of the full-length genomic sequence, new opportunities to investigate its molecular biology and virology are becoming available. This presentation provided a road map for subsequent papers in this symposium on the major features of the KSHV genome and its potential oncogenes. The virus is already providing unique insights into tumorigenesis and may serve as an important model for virus-induced oncogenesis.
The first known human member of the genus Rhadinovirus is HHV-8/KSHV. Dr. Bernhard Fleckenstein noted that acquisition of genes from the host cell genome is a common feature of most herpesviruses and of rhadinoviruses in particular. Although different rhadinoviruses acquire different host-cell genes, their putative functions apparently converge to achieve three common goals: 1) enhance DNA replication independent from the cell cycle, 2) expand the pool of infectable cells, and 3) counteract the host's responses to infection.
Dr. Gary S. Hayward delved into the HHV-8 genome structure and strain differences. These differences would provide the opportunity to address the origins, geographical preferences, transmissibility, and disease association.
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Lymphomas: EBV, Molecular Pathogenesis, and Treatment |
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TopIntroductionOverview of Cancers, Viruses,...Activist CommunityNon-AIDS-Defining, HPV...Kaposi's Sarcoma (KS): KSHV/HHV...KSHV/HHV-8 SymposiumLymphomas: EBV, Molecular... |
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EBV-associated lymphoproliferative disease is a frequently fatal complication of organ transplantation and HIV infection. Dr. Cliona M. Rooney presented her study on the safety and efficacy of adoptively transferred, gene-marked, virus-specific cytotoxic T lymphocytes as prophylaxis and treatment of EBV-associated lymphoproliferative disease and its implications for HIV-related cancers.
Molecular pathogenesis of AIDS-associated non-Hodgkin's lymphoma is a complex process involving both host factors and the accumulation of genetic lesions within the tumor clone. Dr. Riccardo Dalla-Favera reviewed the pattern of molecular lesions in these tumors and several distinct pathogenic pathways in AIDS-related lymphomagenesis. These pathways selectively associate with the different clinicopathologic variants of AIDS-associated non-Hodgkin's lymphoma. On the basis of the differences in molecular characteristics and presumed mechanisms of pathogenesis among the AIDS-associated non-Hodgkin's lymphomas and given the relatively modest survival of patients treated with conventional cytotoxic chemotherapy, Dr. Lawrence D. Kaplan suggested that development of future therapeutic approaches should take advantage of some of these unique molecular characteristics.
This monograph is just a taste of the energizing atmosphere of the first National AIDS Malignancy Conference. Multidisciplinary, interactive discussions took place during the abstract presentations and poster sessions. The Second National AIDS Malignancy Conference occurred on April 6-8, 1998. Next-day summaries for those who were unable to attend the conference are available on http://www.healthcg.com.
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Acknowledgments |
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I would like to acknowledge and thank Dr. Richard D. Klausner and Dr. Robert Wittes for their guidance and support and Dr. James Goedert and the other members of the 16-person program steering committee for their time and effort in the organization of this conference.
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