Most of the diseases treated by stem cell transplantation involve abnormalities of the blood, metabolic, or immune systems. These diseases include several forms of cancer as well as certain nonmalignant diseases. They strike all races, although one racial group or another may have a higher incidence rate for a particular disease. Not all patients with diseases that may be cured by stem cell transplants necessarily pursue them. Depending on a number of donor and patient characteristics, from about 10 to 50 percent of patients are alive 5 years after transplants. The patients who do not survive may succumb either to their diseases or to the consequences of transplantation. Because of these low survival rates, some patients and physicians may be reluctant to select this stressful treatment under most or all circumstances. For most of the diseases involved, other therapies are available that may be less invasive, carry lower risk, or be the medically preferred initial treatment. Nevertheless, some of these diseases are best treated by stem cell transplantation, either initially or after other treatments have failed. Prior to stem cell transplantation, the patient’s bone marrow and, consequently, immune system are destroyed with radiation or chemotherapy. The patient’s bloodstream is then infused with healthy stem cells from a donor. Healthy stem cells can be therapeutic because they can develop into all the components of blood, including those needed to replace the patient’s immune system. In an “autologous” transplant, these cells come from the patient’s own marrow. In a “syngeneic” transplant, the cells come from an identical twin. For many diseases, the most common type of transplant is an “allogeneic” transplant, which consists of stem cells from a genetically compatible donor. Although bone marrow was initially the only source of stem cells for transplantation, in recent years two other sources of stem cells, umbilical cord blood and peripheral blood stem cells (PBSC), have also been used. In 2001, 1,215 of the transplants facilitated by NMDP (70 percent) involved marrow, 42 (2 percent) involved cord blood, and 491 (28 percent) involved PBSC. Umbilical cord blood is collected from the placenta and umbilical cord of a newborn and then preserved in a cord blood bank until needed by a matched patient. The number of stem cells typically obtained from cord blood is relatively small but is often adequate for pediatric patients. For transplantation from cord blood, the blood is volunteered when the blood is banked, not when it is used. The Registry began an umbilical cord blood stem cell program in 1998. Stem cells from peripheral blood may be obtained in numbers sufficient for transplantation when the donor is treated with a drug that causes the cells to leave the marrow and enter the bloodstream where they can be extracted using a process where the stems cells are removed and the remaining components of the blood are returned to the donor. A donor, matched to a patient, may be asked to donate either bone marrow or PBSC, depending on the preference of the patient’s physician. The Registry has offered PBSC to patients since 1999. In addition to its dependence on such common determinants of treatment success as patient age and disease severity, the outcome of a transplant depends on the degree of match between donor and patient with respect to particular blood cell proteins—the human leukocyte antigens (HLA)— that are part of a person’s genetic makeup. Each person has three primary pairs (one set of three from each parent) of these antigens that play a major role in the compatibility of a transplant. A matched donor is defined as one for whom each of these six antigens has the same kind of HLA. If a matched donor cannot be found, then a donor with certain types of mismatch may be used, depending on the transplant center’s preferences, although usually with poorer results. In general, the more closely related two people are, the more likely it is that their HLA will match. At one extreme, identical twins always match, and, in fact, match on all antigens, not just the six ordinarily focused upon. At the other extreme, members of separate racial groups are relatively unlikely to match one another. Full siblings can provide a six out of six match, resulting in what is called an “HLA-identical sibling transplant,” but only about 30 to 40 percent of patients can be expected to have a matched sibling donor. As a result, unrelated donors with matched HLA are sought from the registries in which their HLA type has been recorded. The definition of a match has been refined over time as scientific understanding of HLA increases. HLA are being typed more precisely, so more types of HLA can now be distinguished. Thus, some of today’s matches may be judged as mismatches in the future because better matches are possible. This increasing refinement does not mean, however, that finding a suitable match for transplantation is inevitably becoming more difficult. Some kinds of mismatch may be less dangerous than others. As a result, as research continues, there may be fewer matches by today’s standards, but relatively harmless mismatches will be recognized as such and used. Further, there is evidence that cord blood may not require as exact an HLA match as is usually sought. In support of the Registry, NMDP manages a worldwide network consisting of more than 400 donor centers, recruitment groups, contract laboratories where tissue is typed, apheresis centers, cord blood banks, collection centers where marrow is harvested, blood sample repositories, and transplant centers. More than half of these organizations are donor (91) or transplant centers (149). The relationship of these network components to NMDP varies. Some, such as the recruitment groups, were designed to be parts of the network and work with NMDP, whereas others, such as the transplant centers, exist separately from the network and function independently of NMDP except where specified by contract. The NMDP network includes donor centers and other organizations in foreign countries. The foreign donor centers merge their files with the Registry, contributing more than one million donors. These centers are required to comply with NMDP policies, program standards, and other criteria, although fees for recruiting donors and other financial incentives and payments that go to U.S. centers are not paid to foreign centers. NMDP has also signed cooperative agreements with national registries in 13 foreign countries. Although certain data on donors recruited into these registries are not entered into the Registry’s computer system, these foreign registries will search their donor files on behalf of a U.S. patient searching the Registry. In addition, 6 foreign apheresis centers, 18 foreign bone marrow collection centers, and 36 foreign transplant centers are affiliated with the Registry. NMDP’s affiliations with foreign donor and transplant centers result in its facilitation of both foreign-to-U.S. and U.S.- to-foreign donations. The existence of these international affiliations with the Registry does not prevent U.S. transplant centers from obtaining stem cells through foreign registries directly, that is, without going through Registry channels. Even domestically, the Registry is not a monopoly; other U.S. registries also maintain lists of donors, conduct searches for stem cells, or perform both of these functions. These other registries, however, are relatively small; often specialize in donors from particular racial or ethnic groups; and are private, with no national requirements. The Registry serves two groups of people, donors and patients. The Registry’s donor centers and recruitment groups recruit donors, who are then managed by the donor centers. The Registry pays these centers and groups for signing up donors. In view of the past underrepresentation of minorities in the Registry, NMDP has initiated several recruitment efforts to increase its racial and ethnic diversity. For example, it provides free or low-cost minority-specific educational materials to donor centers and recruitment groups. Probably the most important aspects of managing donors are to maintain their commitment to donation so that they are locatable and willing to donate when their stem cells are requested, to keep records of how to contact them, and to drop from the list any individuals who are too old or no longer able or willing to donate. A patient’s first contact with the Registry occurs when his or her physician or a transplant center conducts a free, preliminary search of the Registry for stem cell donors and cord blood units. The preliminary search, which takes about 24 hours, produces a list of donors and cord blood units that are potentially suitable for that patient. However, many patients for whom such searches are conducted are not necessarily good candidates for stem cell transplants. For example, some searches may be conducted for patients who are too sick for transplantation or who are good candidates for less invasive therapies. If the physician and patient decide to continue a search for an unrelated donor (or unrelated cord blood) on the Registry, then more information about the matching stem cells is required and a formal search is begun. Only a physician affiliated with a transplant center in the NMDP network may conduct a formal search of the Registry. The Registry bills the transplant center a one-time activation fee of $600. It also bills the center for the cost of the four or five testing components of the search process, each of which costs more than $100. Since several donors may have to be tested before one is selected for the patient, these component charges may be made repeatedly, resulting in a search costing thousands of dollars to the transplant center, and more to the patient when the center adds its markups. Relatively few insurance plans pay for searches; however, plans often pay for the actual transplantation including the procurement of stem cells. The details of the formal search and the subsequent steps in the process possibly leading to transplantation depend on the additional information needed; the results of laboratory tests; and the kind of stem cells sought, whether stored blood from an umbilical cord or blood or marrow from a living donor.