- Email: [email protected]
Endometrial cancer, is surgical staging warranted?
TUESDAY,
SEPTEMBER
5
following treatment of human endometrium to with steroids, antisteroids and growth factors. Secondly, we have used this approach to compare endometrium from fertile and infertile patients to identify genes which that might be responsible for altered endometrial function in these women. An important goal in identifying differences in gene expression in such samples is to develop novel therapeutic approaches for clinical problems such as infertility, menorrhagia and endometriosis. Gene therapy, in which expression of particular genes is temporarily altered in the endometrium, offers one such approach. Transfection of the uterine epithelium with plasmid expression constructs would allow increased expression of a selected gene. In contrast, transfection with antisense oligonucleotides has already been used successfully to reduce expression of target genes, and alter endometrial function. Examples of these studies, and the principles of uterine gene transfection will be discussed. In order to use these new approaches most effectively, it is essential to integrate gene profiling techniques such as cDNA arrays (to identify candidate genes of interest), with functional studies such as gene transfection. This will allow the identification of those genes whose role is truly important, compared with those that are not. This will allow the development of novel therapeutic approaches to treat endometrial gene function, based n targetting the actions of particular genes whose function is known to e critical.
SS2.07.03 ANGIOGENESIS IN REPRODUCTION S. K. Smith, D. S. Charnock-Jones, and C. G. Print, Department of Obstetrics and Gynaecology, Unversity of Cambridge, The Rosie Hospital, Cambridge, United Kindom Angiogenesis provides the basis for normal reproduction. The development of a receptive endometrium, the development, rupture and protein secretion from the ovary, implantation and the process of vasculogenesis and angiogenesis in the placenta aligned with the maternal adaptations of the mother confirm the critical importance of angiogenesis to reproduction. The female reproductive tract provides a rich source of angiogenic inhibitors and stimulators, the overall consequence of which is a coordinated regulation of blood vessel development. Interactions between cognate members of gene families result in the coordinated regulation of endothelial cell proliferation, migration and tube formation followed by subsequent association with pericytes and the establishment of mature vessels. Uniquely, the reproductive tract undergoes processes of restitution and involution that result in ovulation, menstruation and the birth of infants. Best characterised are the VEGF abd angiopoietin family of genes which have been shown in animal and human experiments to play a fundamental role in the most basic aspects of reproduction. There is now increasing evidence that disturbances of angiogenic gene expression or function may underlie many common disorders of women ranging from menorrhagia, endometriosis, to pre-eclampsia. The well recognised disorder of angiogenesis associated with maignancy is further enhanced in women where abnormal angiogenesis is a feature of pre-malignant cervical disease. Understanding the integrated gene pathways which regulate angiogenesis in the reproductive tract is likely to lead to a new understanding of wornens health and to the introduction of novel treatments in the future.
SS2.07.04 ETHICS IN RELATION TO GENE THERAPY J. Pennsylvania State University School of Medicine, Hershey, PA, United States Gene therapy presently spans exciting developments from changing somatic genes and thereby eliminating disease process for single gene defects to merely using the identified genes or products to alter targeted functions of cells to control the behaviors of cancers. Presently, gene therapy has avoided directly impacting the germ cell line of humankind but as this technology grows there is no doubt this will be a possibility, primarily or secondarily. Such fundamental changes in the basic structures of all humankind - our DNA - cannot occur without raising vexing ethical issues. Furthermore, as with all emerging research, the risks and the benefits remain murky at the present time. This presentation will review the present range of ethical issues surrounding these emerging therapies:
17
1. How should research be ethically constructed for this emerging area? a- Should research on germ cell lines be allowed? b- What should be done about balancing benefits and burdens of research so those whose genome provided the information have access to the fruits of that knowledge? c- Recent concerns have been raised about the conduct of such research, what are the guidelines that must be scrupulously adhered to to avoid endangering patients and this entire field of research? 2. Financial conflicts of interest abound in this area. Who “owns” the genome in relation to gene therapy and what are the arguments for and against patenting both the DNA and the products? 3. How does the ability to change the DNA we are born with change our concepts about humankind and what are the potential harms and benefits from these changes?
SS2.08
SOLVING THE DILEMMAS, PATIENTS WITH ABNORMAL PAP SMEARS I - INTERACTIVE SESSION
SS2.08.02 SHOULD CERVICAL
CANCER BE SURGICALLY
HYS Nean, Dept OB/GYN, University P.R., China
STAGED?
of Hong Kong, Hong Kong, SAR,
Staging is important in the management of malignant diseases. A good staging system should reflect on the extent of the disease and adverse prognostic factors. Modification of treatment and comparison of results could then be possible leading to improve outcome in cancer management. FIG0 staging of cervical cancer is a clinical staging. One important prognostic factor, namely lymph node metastasis, was not included in the staging. The main reason is because clinical methods such as ultrasound, computerized tomogram, magnetic resonance imaging and even with the latest positron emission scan offered only 38.75% sensitivity in the detection of metastatic nodes. Thus, it seems logical to introduce surgical staging with pelvic and para-aortic lymphadenectomy to ascertain the status of node involvement. Furthermore, surgical staging offers better assessment of the parametria and intra-peritoneal spread and hence more accurate staging. Indeed, 20.50% discrepancy between clinical and surgical staging in stage 2B and 3B diseases had been reported. Hence, the benefit of better assessment of prognosis using surgical staging is beyond doubt. What is worrying opponents of surgical staging is the survival benefit and morbidity in association with surgical staging. Extended field para-aortic radiotherapy after surgical staging especially in debulkable macroscopic nodes seems to offer some survival benefits. However, prophylactic extended field radiotherapy in advanced cervical cancer also seems to offer survival benefits. Radiation morbidity increased with proir surgery. Extraperitoneal approach and more recently laparoscopic staging had lowered the morbidity and risk of delay in treatment. With the decrease in morbidity, the remaining issue is whether surgical staging can help to improve survival. There is no randomized study to confirm the benefit of surgical staging yet. Furthermore, the latest findings of survival benefits of chemoradiation in advanced diseases opens an argument on whether paraaortic or pelvic nodes assessment is important when chemoradiation is recommended as a standard treatment. To conclude, it seem that there is no strong argument for surgical staging yet in cervical cancer.
SS2.08.03 ENDOMETRIAL CANCER, IS SURGICAL STAGING WARRANTED? H. Diisseldorf University, Medical Center, Diisseldorf, Germany Since 1988 FIG0 has recommended that endometrial cancer be surgically staged. This suggestion was based on the fact that nowadays 90 to 95 % of the patients are treated surgically so that there is only a limited extension of the procedure to achieve surgical verification of tumor extent. That surgical staging is much better in the prediction of prognosis and survival chances can be extracted from data from the Annual Report. This is a very important point which favours clinical staging. Another important factor would be a more solid basis for therapeutical decisions like radiation or chemotherapy. Figures are currently not sufficient to prove that and which steps of surgical staging are specifically leading to a better prognosis of the individual patient. Finally more extensive staging, particularly lymphadenectomy, may be contributing to better therapeutic results with some conflicts in the discussion what therapeutic role radical lymphadenectomy pelvic or/and
18
paraaortic may play. For these reasons surgical staging of endometrial cancer comprises some advantages which would give reason to recommend it.
SS2.09 SOLVING THE DILEMMAS, PATIENTS WITH ABNORMAL PAP SMEARS I INTERACTIVE SESSION H. Jones, Vanderbilt University Hospital, Nashville, TN, United States During this interactive session, a series of patient case histories of women with abnormal Pap tests will be presented. Cases will include women with: low grade Pap after LEEP moderate cervical dysplasia associated with vaginal and vulvar condyloma atypical glandular cells of undetermined significance and others These will include colpo photographs and the participants will be asked to make diagnostic and management decisions. These decision will be recorded and tallied electronically during the session, thus allowing the participants to “vote” for a diagnosis and management option. Course faculty will then discuss the options indicating the reason for their choice and answer questions or comments from the participants. ??
??
??
TUESDAY, SEPTEMBER 5
SEPTEMBER
5
following treatment of human endometrium to with steroids, antisteroids and growth factors. Secondly, we have used this approach to compare endometrium from fertile and infertile patients to identify genes which that might be responsible for altered endometrial function in these women. An important goal in identifying differences in gene expression in such samples is to develop novel therapeutic approaches for clinical problems such as infertility, menorrhagia and endometriosis. Gene therapy, in which expression of particular genes is temporarily altered in the endometrium, offers one such approach. Transfection of the uterine epithelium with plasmid expression constructs would allow increased expression of a selected gene. In contrast, transfection with antisense oligonucleotides has already been used successfully to reduce expression of target genes, and alter endometrial function. Examples of these studies, and the principles of uterine gene transfection will be discussed. In order to use these new approaches most effectively, it is essential to integrate gene profiling techniques such as cDNA arrays (to identify candidate genes of interest), with functional studies such as gene transfection. This will allow the identification of those genes whose role is truly important, compared with those that are not. This will allow the development of novel therapeutic approaches to treat endometrial gene function, based n targetting the actions of particular genes whose function is known to e critical.
SS2.07.03 ANGIOGENESIS IN REPRODUCTION S. K. Smith, D. S. Charnock-Jones, and C. G. Print, Department of Obstetrics and Gynaecology, Unversity of Cambridge, The Rosie Hospital, Cambridge, United Kindom Angiogenesis provides the basis for normal reproduction. The development of a receptive endometrium, the development, rupture and protein secretion from the ovary, implantation and the process of vasculogenesis and angiogenesis in the placenta aligned with the maternal adaptations of the mother confirm the critical importance of angiogenesis to reproduction. The female reproductive tract provides a rich source of angiogenic inhibitors and stimulators, the overall consequence of which is a coordinated regulation of blood vessel development. Interactions between cognate members of gene families result in the coordinated regulation of endothelial cell proliferation, migration and tube formation followed by subsequent association with pericytes and the establishment of mature vessels. Uniquely, the reproductive tract undergoes processes of restitution and involution that result in ovulation, menstruation and the birth of infants. Best characterised are the VEGF abd angiopoietin family of genes which have been shown in animal and human experiments to play a fundamental role in the most basic aspects of reproduction. There is now increasing evidence that disturbances of angiogenic gene expression or function may underlie many common disorders of women ranging from menorrhagia, endometriosis, to pre-eclampsia. The well recognised disorder of angiogenesis associated with maignancy is further enhanced in women where abnormal angiogenesis is a feature of pre-malignant cervical disease. Understanding the integrated gene pathways which regulate angiogenesis in the reproductive tract is likely to lead to a new understanding of wornens health and to the introduction of novel treatments in the future.
SS2.07.04 ETHICS IN RELATION TO GENE THERAPY J. Pennsylvania State University School of Medicine, Hershey, PA, United States Gene therapy presently spans exciting developments from changing somatic genes and thereby eliminating disease process for single gene defects to merely using the identified genes or products to alter targeted functions of cells to control the behaviors of cancers. Presently, gene therapy has avoided directly impacting the germ cell line of humankind but as this technology grows there is no doubt this will be a possibility, primarily or secondarily. Such fundamental changes in the basic structures of all humankind - our DNA - cannot occur without raising vexing ethical issues. Furthermore, as with all emerging research, the risks and the benefits remain murky at the present time. This presentation will review the present range of ethical issues surrounding these emerging therapies:
17
1. How should research be ethically constructed for this emerging area? a- Should research on germ cell lines be allowed? b- What should be done about balancing benefits and burdens of research so those whose genome provided the information have access to the fruits of that knowledge? c- Recent concerns have been raised about the conduct of such research, what are the guidelines that must be scrupulously adhered to to avoid endangering patients and this entire field of research? 2. Financial conflicts of interest abound in this area. Who “owns” the genome in relation to gene therapy and what are the arguments for and against patenting both the DNA and the products? 3. How does the ability to change the DNA we are born with change our concepts about humankind and what are the potential harms and benefits from these changes?
SS2.08
SOLVING THE DILEMMAS, PATIENTS WITH ABNORMAL PAP SMEARS I - INTERACTIVE SESSION
SS2.08.02 SHOULD CERVICAL
CANCER BE SURGICALLY
HYS Nean, Dept OB/GYN, University P.R., China
STAGED?
of Hong Kong, Hong Kong, SAR,
Staging is important in the management of malignant diseases. A good staging system should reflect on the extent of the disease and adverse prognostic factors. Modification of treatment and comparison of results could then be possible leading to improve outcome in cancer management. FIG0 staging of cervical cancer is a clinical staging. One important prognostic factor, namely lymph node metastasis, was not included in the staging. The main reason is because clinical methods such as ultrasound, computerized tomogram, magnetic resonance imaging and even with the latest positron emission scan offered only 38.75% sensitivity in the detection of metastatic nodes. Thus, it seems logical to introduce surgical staging with pelvic and para-aortic lymphadenectomy to ascertain the status of node involvement. Furthermore, surgical staging offers better assessment of the parametria and intra-peritoneal spread and hence more accurate staging. Indeed, 20.50% discrepancy between clinical and surgical staging in stage 2B and 3B diseases had been reported. Hence, the benefit of better assessment of prognosis using surgical staging is beyond doubt. What is worrying opponents of surgical staging is the survival benefit and morbidity in association with surgical staging. Extended field para-aortic radiotherapy after surgical staging especially in debulkable macroscopic nodes seems to offer some survival benefits. However, prophylactic extended field radiotherapy in advanced cervical cancer also seems to offer survival benefits. Radiation morbidity increased with proir surgery. Extraperitoneal approach and more recently laparoscopic staging had lowered the morbidity and risk of delay in treatment. With the decrease in morbidity, the remaining issue is whether surgical staging can help to improve survival. There is no randomized study to confirm the benefit of surgical staging yet. Furthermore, the latest findings of survival benefits of chemoradiation in advanced diseases opens an argument on whether paraaortic or pelvic nodes assessment is important when chemoradiation is recommended as a standard treatment. To conclude, it seem that there is no strong argument for surgical staging yet in cervical cancer.
SS2.08.03 ENDOMETRIAL CANCER, IS SURGICAL STAGING WARRANTED? H. Diisseldorf University, Medical Center, Diisseldorf, Germany Since 1988 FIG0 has recommended that endometrial cancer be surgically staged. This suggestion was based on the fact that nowadays 90 to 95 % of the patients are treated surgically so that there is only a limited extension of the procedure to achieve surgical verification of tumor extent. That surgical staging is much better in the prediction of prognosis and survival chances can be extracted from data from the Annual Report. This is a very important point which favours clinical staging. Another important factor would be a more solid basis for therapeutical decisions like radiation or chemotherapy. Figures are currently not sufficient to prove that and which steps of surgical staging are specifically leading to a better prognosis of the individual patient. Finally more extensive staging, particularly lymphadenectomy, may be contributing to better therapeutic results with some conflicts in the discussion what therapeutic role radical lymphadenectomy pelvic or/and
18
paraaortic may play. For these reasons surgical staging of endometrial cancer comprises some advantages which would give reason to recommend it.
SS2.09 SOLVING THE DILEMMAS, PATIENTS WITH ABNORMAL PAP SMEARS I INTERACTIVE SESSION H. Jones, Vanderbilt University Hospital, Nashville, TN, United States During this interactive session, a series of patient case histories of women with abnormal Pap tests will be presented. Cases will include women with: low grade Pap after LEEP moderate cervical dysplasia associated with vaginal and vulvar condyloma atypical glandular cells of undetermined significance and others These will include colpo photographs and the participants will be asked to make diagnostic and management decisions. These decision will be recorded and tallied electronically during the session, thus allowing the participants to “vote” for a diagnosis and management option. Course faculty will then discuss the options indicating the reason for their choice and answer questions or comments from the participants. ??
??
??
TUESDAY, SEPTEMBER 5