An International Virtual Bank of Sarcoma Tissues:
A resource that could be of immense value to the entire sarcoma community
If tissue banks are central to cancer research, one might question if there is a national or an international bank of sarcoma tissues. Given there are no national tissue banks for any disease, you probably already know the answer to this question.
I recently sent a letter similar to the following one to a number of sarcoma oncologists — surgeons, clinicians, and researchers — in various sarcoma centers in the US and abroad, modified accordingly with some country specific details:
"Some of my questions that follow may be particularly naive. It is my layman's belief that access by sarcoma researchers to tissue banks is increasingly important in the study of sarcoma and may lead to significant insights into the diagnosis and treatment of sarcoma. Some institutions (e.g., MSKCC) are known to have created "large" sarcoma tissue banks over a period of time. However, since sarcomas are rare I think that it would be virtually impossible for individual institutions to collect sufficient numbers of comparable samples in any reasonable amount of time to be of use to the sarcoma community at large. It seems to me that there is a significant need for either a national sarcoma tissue bank or a well defined process for institutions to share tissues for research purposes. One can easily conjecture the need for an international sarcoma tissue bank or process for accessing specimens for research purposes.
Could you please tell me something about sarcoma tissue banks in the US? To the best of my knowledge, there is no national sarcoma tissue bank (e.g., at NIH). Rather, various cancer research institutes and sarcoma centers maintain their own tissue banks. Do they employ similar techniques in dealing with (i.e., acquiring, storing, and distributing) specimens? Are these tissue banks certified in any way on an annual basis? Is there a medical oversight board involved? How do researchers at one institution apply for the use of specimens from another institution for research studies? Are such cross-institution studies common? Are they encouraged? Etc.
Is there a national governmental organization (e.g., NIH) or advocacy group (e.g., ACS) involved in organizing and/or promoting sarcoma tissue banks? Is the American Association of Tissue Banks a relevant organization? Is CTOS involved in organizing and/or promoting sarcoma tissue banks internationally in any way?"
I received quite a number of replies a number of which reinforced the need for sarcoma tissue banks. It is clear, however, from the replies that collaboration among the many institutions that have tissue banks face a number of problems. I believe (perhaps naively so) that these problems can be resolved. Agreed upon procedures must be in place for the collection, storage, access, use, and distribution of specimens. Quality control mechanisms need to be in place at every step along the way. It seems to me that the incentive for individual institutions to make their tissue specimens available to other researchers in the sarcoma community is obvious: the entire research community could benefit from having access to the complete number and quality of specimens to conduct research and to ensure the long-term collaboration of researchers.
If tissue sharing is to occur across national borders, national laws need to be taken into account. Lastly, there are the ethical questions that arise in dealing with specimens taken from human subjects. Many countries already have legislation dealing with this issue and researchers must take these laws into account in their research, protecting the privacy of the individuals involved and giving them the right to withdraw their consent for the use of their tissue at any time. Again, I believe these ethical issues can indeed be resolved in an acceptable way to allow the research to proceed.
Suppose every patient worldwide who has been diagnosed with a sarcoma requested that tissue taken during a biopsy or the surgical removal of a tumor be sent to a national or international tissue bank, and that every one of these patients signed a consent form indicating that their tissue can be used for research purposes. Each year the number of tissues available might grow by 10,000 or 20,000 tissues each year. What an incredible resource this would be for sarcoma researchers worldwide to study the molecular biology of the various sub-types of sarcoma, to explore their genetics, new drugs and new treatment options, exploring "molecular targets" for new sarcoma therapies; studying chromosomal translocations, the oncogenes they generate and their role in sarcoma development; translational studies; studying vaccines, monoclonal antibodies, and mTOR inhibitors; studying the use of nanotechnology in the diagnosis and treatment of sarcomas; understanding the basis of radiation-induced sarcoma; modeling of the process of metastases; studying the onset of resistance to targeted therapy; exploring the differences in the development of sarcomas in children, adolescents, young adults and adults; research directed at the early detection and diagnosis of sarcoma. Such tissue banks could potentially provide sarcoma tissue blocks in paraffin wax, flash frozen sarcoma tissue, sarcoma cell lines or microarray analysis of sarcoma tissue to qualified research teams. By genetically profiling sarcoma tissue, the many variations of mutations that each sub-type of sarcoma has could be identified and shared in a universally accessible database containing, among other things, the response of a tumor and genetic mutations of a specific sub-type of sarcoma to treatment with specific drugs.
It is also important to note that the accuracy and completeness of the medical data accompanying the tissue is as important as the tissue itself. The "medical history" of the tissue — the patient’s age, sex, ethnicity, prior medical treatment, nature and location of the tumor, surgery related issues, the patient’s response to therapy and long-term outcome, etc. — is critical and must be easily accessible without compromising the patient’s privacy. Sophisticated database inquiry and analysis techniques, e.g., data mining and biostatistical analysis, should be available to optimize the use of this data.
There are two examples of tissue banks that provide us with some useful insight. The first is Children's Oncology Group (COG) tumor bank which is a model of what can be accomplished on a national/partial-international level with a large set of tumor categories including pediatric bone and soft tissue sarcomas, such as Ewing’s sarcoma, osteosarcoma and rhabdomyosarcoma. COG is a cooperative clinical trials study group supported, in part, by the National Cancer Institute.
The COG repository is housed at the National Cancer Institute’s Cooperative Human Tissue Network (CHTN). CHTN was formed in 1987 to provide increased access to human cancer tissue for basic and applied scientists from academia and industry to accelerate the advancement of discoveries in cancer diagnosis and treatment. It provides access to malignant, benign, diseased and uninvolved (normal adjacent) tissues. Investigators can select from several methods to fix the specimen such as fresh, frozen, or chemically fixed. CHTN also produces tissue microarrays representing multiple tissue types to disease-specific blocks. Tissues are annotated with patient demographics including gender, age, and race and additional patient information can be requested where applicable. There is a coordinating committee, regional contacts, policies for collecting, storing and distributing specimens, and a well defined peer-review process for applying for access and use of the specimens. Quality control assessments of tissues are provided by CHTN principal investigators (PIs) who are actively involved in the practice of anatomic pathology. CHTN PIs are responsible for proper histopathological characterization, participate in research, and understand the importance of quality control in the tissues provided. Specimens are shipped to investigators using specific guidelines. A tissue processing fee and the cost of shipping are paid by the investigator.
Because the COG tissues are gathered in association with the therapeutic trial mechanism that COG provides, there are excellent clinical annotations available for these materials. I have been told that the biggest shortcoming for these specimens, currently, is the small size of most samples in the banks and, because many surgeons prefer to obtain needle biopsies rather than open biopsies, the amount of tissue available for storage is often quite small. Nonetheless, the organized methods for collecting, storing, and distributing these materials might serve as a paradigm for other sarcoma banking efforts in the US and abroad.
The second example is an effort to form a pan-European "virtual" sarcoma tissue bank. Although not yet functioning, it provides another useful model through the extensive planning that has taken place so far. It is called the TuBaFrost project. In this model, collected tissue samples remain stored at the collecting institute and under the custodianship of the collecting institute. As seen on the TuBaFrost website, its mission statement states, in part, the intent to:
"Create an innovating virtual European human frozen tumor tissue bank for the whole scientific community composed of high quality frozen tumor tissue sample collections with a corresponding accurate diagnosis stored in major European cancer centers and universities. This bank will be searchable through an uncomplicated query system on the Internet and provided with rules for access and use of the tissues complete with a European code of conduct to comply with the various legal and ethical regulations in the different European countries.
The resulting platform not only improves tissue sample visibility and accessibility for cancer research, but in addition, allows the rapid accrual of tissue samples of defined subtypes, including uncommon types. Research using large numbers of samples has the potential to enable clinical and translational studies with sufficient statistical power. A further aim of the network is to enhance collaborations between European institutes, for example between the active tissue collecting groups and groups with access to cutting edge technology. This basic infrastructure has the potential to enormously speed up the advances in cancer research, from which future cancer patients can benefit and therefore, should be considered as a main interest of the entire tissue donor community."
Since there are a number of sarcoma centers and programs in the United States, each of which has one or more sarcoma tissue banks, the benefits of having a similar project to COG’s tissue bank and the TuBaFrost virtual tissue bank in the US are obvious. Having researchers from different countries collaborate using such tumor bank projects could indeed hasten the creation and use of an international virtual tissue bank — a resource that could be of immense value to the entire sarcoma community. However, it must be stressed that tumor banks are costly, not only to initially set up, but to maintain, grow, and run. The annual costs associated with a tumor bank may well exceed $1,000,000/year.
It should be quite clear that given all of the hurdles to overcome, I am nonetheless a proponent of forming an "international virtual sarcoma tissue bank." The reader is cautioned, however, to understand that not all sarcoma research relies on the availability of tissue. A few days ago I posed the following questions to a sarcoma researcher, "What are some of the areas that do not necessarily benefit from the availability of tissue banks? What are the most important areas that should benefit from them?" Here is the interesting reply:
"Good questions. There is a lot of work that can be done using patient-derived cell lines (which initially required patient tumor specimens), and other non-patient-derived cell lines. For example, a good deal of our work on the molecular biology of Ewing’s sarcoma uses cell lines. These are cheap, easy to grow, and replenishable. Thus, they’re good for exploratory work. Once we’ve made a finding that we want to follow up on, though, it becomes important to see whether the effect we’re studying also occurs in the real tumor. I would call this validation work, and can only be done from tumor specimens. Another type of study that really needs tumor specimens is analysis of prognostic markers. In this case, samples with clinical information are needed, and one tests whether some marker of interest is expressed more (or less) in patients who did well with their treatment, versus those in whom the treatment didn’t work well."
Before embarking on an effort to form an international virtual sarcoma tissue bank, it is definitely important to ask and get answers to such questions as:
- Are tissue banks essential to understanding the molecular biology and genetics of the many sub-types of sarcoma or to finding new drugs, potential treatments, and cures for them?
- What useful information will come from research conducted using virtual tissue banks?
- Are tissue banks worth the time, money, and human resources involved?