Three years after the last meeting of the International Bladder Cancer Network (IBCN) group in Barcelona, Spain, an international bladder cancer meeting at Ancona, Italy was used for an interim analysis of the output of what was intended to be a major step forward in linking international research activities. Although some initiatives were never activated, however, several projects that were launched in the spirit of the Barcelona meetings were executed.
Therefore, the ultimate aim of this meeting was to revive the ideas of the “Barcelona” group and to define and discuss some of the issues for the future direction of this initiative. Thanks to the generosity of the hosts of the “International Consultation on the Diagnosis of Non Invasive Urothelial Neoplasms” we had the opportunity to present the past and future projects.

Agenda
After a warm welcome from our generous hosts, represented through Pierfrancesco Bassi, Yves Fradet presented the needs and opportunities of network research and summarized the history and development of the IBCN: From the early initiative of the members of the Bladder Tumor Marker Network (an NCI funded cooperative) as a predecessor for the formation of the International Bladder Cancer Network (IBCN). This initiative has gathered scientists with a highly diverse background sharing a common interest in improving the care of patients with bladder cancer through the use of biomarkers. There were two meetings in Barcelona, Spain (1997 and 1998) which helped to define the state of the art of markers in bladder cancer. These two meetings also resulted in a series of publications in an issue of Urologic Oncology [Urol Oncol, 5 (2000)] summarizing the discussions at these meetings. Yves Fradet also pointed out, that although, there were multiple promising proposals of this Network including needed clinical trials and studies for marker development, a follow-up initiative from leaders of this consortium was lacking.
A very successful collaboration of Network members resulted in a large multi-institutional combined analysis of p53 as a prognostic marker in bladder cancer (ISBC trial). A summarized overview on the status, results and lessons from this international study initiative were presented by Bernd J. Schmitz-Dräger. Although comprising a number of different recognized problems, this multi-institutional study was clearly able to identify the needs in such combined analyses and was able to provide solutions and approaches to the variability between the executed trials. This initiative demonstrated the strong will of the members of the Network to contribute to combined efforts in order to elucidate the mechanisms for standardization of marker development and use.
There was general agreement among the participants of the session, that only networks are able to provide the basis for these needed standards. Another approach was introduced by Yves Fradet, who reported on an important contribution from the National Cancer Institute sponsored Bladder Tumor Marker Network towards the aim to standardize p53 immunohistochemistry in bladder tumors: a finished study, that evaluated the reproducibility of p53 immunohistochemistry in bladder tumors and examined the possible role of interlaboratory differences of performing p53 assays [McShane et al. (2000)]. Within this study, a unique evaluation of intra- and interlaboratory differences with regards to staining protocols and scoring criteria was performed, using adjacent slides from fifty tumor blocks. The identification of some discordance, only among the p53 assays on specimens with an intermediate percentage of positive stained tumor cells, due to staining and scoring differences, was discussed and the authors of this work recommended that assessment of assay reproducibility should be regarded as an essential prerequisite in the development of any prognostic marker. The authors also concluded that the reproducibility of marker assays between laboratories may improve with the use of standardized staining protocols and the selection of a uniform threshold for defining the results of an assay as being positive or negative.  However, the use of a uniform threshold remains controversial and this issue has not yet been resolved.
The discussion of this issue also gave raise to the questions of mechanisms to ensure the needed high quality standards for this kind of reproducibility testing in a multi-institutional setting and demonstrated the lack of “Net”-working among less “established” institutions. It became clear, that only within a Network with defined standards of tissue procurement, test-performance and interpretation (including data analysis), it would be possible to perform the needed studies in marker development. To address the needs and provide the basis to meet the criteria for such studies, Network proposals with a new design are highly needed.
An example of such a proposal was introduced by Peter J. Goebell, who presented a pilot project of the International Bladder Cancer Bank (IBCB). The IBCB is a proposed multi-institutional bladder cancer database and virtual tumor bank as a resource to evaluate the biological and prognostic significance of potential markers for bladder cancer. The consortium of the collaborating centers will provide prospectively collected, consistent data sets with long-term follow-up that are available and linked to specimens, at the time that the specimens are selected for analysis of new markers. As a result, studies can be completed much sooner than would possible with a conventional prospective study, in which follow-up begins at the time of specimen acquisition.  Furthermore, the quality of prospectively collected data and samples will be superior to that of retrospectively collected data and samples.
As a start for this undertaking, a bladder cancer tissue micro arrayer will be produced at two different sites and a number of 20 institutions will provide the tissue (up to a maximum of 20 blocks) and adjacent data for each arrayer. This would enable the collaborating group to perform a marker studies on a total of 800 different tumor samples. This project is intended to serve as a feasibility study and should proof the principle that the consortium is “functioning” and to obtain funding for the larger-scale establishing of the IBCB. Based on the gained experience the tissue and the established infrastructure will be used for further projects.

Summary
The final discussion among the participants was moderated by Pierfrancesco Bassi and brought up some substantial issues for the future of the IBCN:

Restructuring is required

This would certainly support the needed reliability of the organization for possible contributors and sponsors, since this would attempt to guarantee the continuation of this initiative independent from persons. Although there is consensus, that only Network structures are likely to answer some of the major issues in bladder cancer, it became clear that it is needed to increase the “attractiveness” of the existing Network. In detail this would mean a more structured and formalized organization with defined positions and responsibilities. Furthermore, a clear concept is required how participating groups will benefit from the network activities. Pierfrancesco Bassi suggested that an adequate solution of this Problem will be of key importance to further attract participation within multi-institutional projects.
 

The ISBC project has demonstrated that there is a great interest in international research networks, but it also became apparent that “clear and focused” proposals are needed to attract researchers and institutions. There was consensus that the presented “Tissue array project” could function as a starting point for such initiatives and others should follow (e.g. a proposed multi-institutional diagnostic trial for urine markers)

• Funding, as a key issue of every discussion lead to different ideas on possible sources:

1. Funding opportunities on the European side are indicated through the EU/EORTC
2. To maintain the ability to meet on a regular basis and to use the infrastructure of existing formalized organizations, there was the idea to have the IBCN under the auspices of one or more existing Societies. The ESUR could function as one of these, giving patronage to the International Bladder Cancer Network. WHO could be another option underlining the interest of the IBCN in world-wide activities. Mechanisms on how to formalize this are pending.


Again, we welcome input from everyone to this combined international and multi-institutional effort to create this unique oportunity of an international resource in bladder cancer research.

Yours sincerely,

H. Barton Grossman Department of Surgery  University of Texas MD Anderson Cancer Center  1515 Holcombe Blvd, Box 110  Houston, TX 77030, USA hbgrossman@notes.mdacc.tmc.edu

Bernd J. Schmitz-Dräger Department of Urology EuromedClinic Europa-Allee 1 D-90763 Fürth, Germany  bsd@euromed.de