Can Youi Use Cord Blood for Family Memeber
Haematologica. 2011 Nov; 96(11): 1700–1707.
Family-directed umbilical cord claret banking
Eliane Gluckman
aneEurocord, Hospital Saint Louis, University Paris 7, Paris, France
Annalisa Ruggeri
iEurocord, Hospital Saint Louis, University Paris Vii, Paris, French republic
Vanderson Rocha
aneEurocord, Hospital Saint Louis, University Paris Vii, Paris, French republic
2Agence de la Biomédecine, Saint Denis, Paris, France
Etienne Baudoux
3Liège Cord Claret Bank, Academy Hospital-Liège-Kingdom of belgium and The Netcord Foundation
Michael Boo
4National Marrow Donor Programme, Minneapolis, Minnesota, United states
Joanne Kurtzberg
5Pediatric Claret and Marrow Transplant Program, Carolinas Cord Blood Bank, Duke University Medical Eye, Durham, NC, The states
Kathy Welte
4National Marrow Donor Programme, Minneapolis, Minnesota, United states
Cristina Navarrete
6NHS Cord Blood Banking company, British Bone Marrow Registry, NHSBT, England
Suzanna Grand. van Walraven
7Europdonor, Leiden, Holland
Received 2011 May five; Revised 2011 Jun 16; Accustomed 2011 Jun xxx.
Abstruse
Umbilical cord claret transplantation from HLA-identical siblings provides practiced results in children. These results back up targeted efforts to bank family cord blood units that can be used for a sibling diagnosed with a disease which can be cured by allogeneic hematopoietic stem cell transplantation or for inquiry that investigates the utilise of allogeneic or autologous cord blood cells. Over 500 patients transplanted with related cord claret units have been reported to the Eurocord registry with a 4-yr overall survival of 91% for patients with not-malignant diseases and 56% for patients with malignant diseases. Principal hematologic indications in children are leukemia, hemoglobinopathies or inherited hematologic, immunological or metabolic disorders. Notwithstanding, family-directed cord blood banking is not widely promoted; many cord blood units used in sibling transplantation have been obtained from private banks that do not meet the necessary criteria required to store these units. Marketing past private banks who predominantly store autologous cord claret units has created public confusion. There are very few current validated indications for autologous storage but some new indications might announced in the future. Fiddling effort is devoted to provide unbiased information and to educate the public as to the distinction betwixt the different types of banking, economical models and standards involved in such programs. In order to provide a amend service for families in demand, directed-family unit string blood banking activities should be encouraged and closely monitored with common standards, and better information on current and future indications should be made available.
Keywords: string blood banking, family, cell source, allogeneic HSCT
Introduction
Since 1988, umbilical cord blood (CB) has been successfully used as a source of stem cells for hematopoietic reconstitution in allogeneic hematopoietic stem prison cell transplantation (HSCT). The offset transplant using CB was performed in a five-twelvemonth onetime male child with Fanconi anemia, an inherited bone marrow failure syndrome which can only be cured by allogeneic HSCT.1 The mother was pregnant with a daughter who was known, before nascence, to be HLA-identical to her blood brother and not a carrier of the aforementioned genetic defect. The sis'due south CB was collected and cryopreserved at birth and transplanted to the patient. More than 22 years afterwards, the patient is alive and well with a normal hematologic and immunological reconstitution provided by his donor cells. In 1991, the first public CB banking company (CBB) was established at the New York Blood Eye2 and, in 1993, the first unrelated CB transplant (CBT) was performed in a iv-yr onetime child with leukemia.3 Since then, more 100 public CBBs have nerveless over 500,000 CB units (CBUs) from donating, costless and anonymous donations that resulted in over 25,000 unrelated CBT worldwide. Virtually banks cooperate through international registries that list publicly banked CBUs in searchable databases, such as Os Marrow Donors Worldwide (BMDW), the Netcord Foundation, the National Marrow Donor Programme (NMDP) and other national registries, in order to provide admission to all patients in demand. International accrediting bodies and governmental regulatory requirements are in place to assure that publicly bachelor CBs meet strict rules for quality standards.iv , five Outcome information are routinely collected and are available for analysis through international data registries that allow good monitoring and analysis of CBT activity and outcomes. The activity of these international registries, such equally Eurocord (Figure 1) and the Center for International Blood and Marrow Transplant Research (CIBMTR) widens our knowledge of the use of unrelated CBT.
Number of related and unrelated cord blood units provided per year, n= 6805 (Eastward. Gluckman for Eurocord, unpublished information, 2010).
In dissimilarity with the well developed public cyberbanking systems, few countries have a centralized program for family unit-directed CB collection and storage which requires different procedures in lodge to obtain high-quality products. This approach is clinically indicated and validated in families where the mother is significant and has an existing child or has a known risk of having a child affected by a disease which can be cured by allogeneic HSCT.1 , 6 – ix While in public banking about pregnant woman would be qualified to donate, family-directed banking requires a more focused arroyo to identify the few candidates that would do good from collection. As a issue, the practice of collecting CBUs from family unit members specifically stored for the potential benefit of another family member with a disease which can exist cured by HSCT is non widespread. This is in spite of the fact that family-directed CBT has several advantages over unrelated CBT, including greater likelihood of survival, decreased graft-versus-host disease (GVHD) and the opportunity to re-collect bone marrow cells from the aforementioned donor in case of relapse or rejection.8 , nine Today, CB cyberbanking for family use is by and large an indirect issue of autologous banking, marketed by the private sector, to families for private CB collection and storage without any electric current therapeutic purpose and for potential use by the donor later in life. A CB banked in this mode may occasionally benefit a sibling. Whereas family-directed banking for allogeneic purposes does not raise upstanding concerns, autologous CB banking in an a priori healthy family unit is controversial because its value is not entirely supported by clinical show. Despite this, autologous CB cyberbanking has developed into a private industry predominantly used by economically advantaged families.10 , 11 Give-and-take almost the development of hybrid CBB models that could combine efforts to support all cyberbanking activities is the subject of intense controversy considering of ethical, scientific, regulatory, economic and social concerns.12 , 13
The current situation of family unit-directed CB transplantation and banking
The Eurocord registry has identified 596 patients transplanted with related CB from 1988 to 2010 but, in contrast to unrelated CBT, the number of related CBTs has not increased year later year. Most recipients were children, and all but 29 were HLA-matched. The major characteristics of the patients and transplants are listed in Tables 1 and 2. Four twelvemonth overall survival was 91% for patients with non-malignant diseases and 56% for patients with malignant diseases (Table 3 and Figure two). The cumulative incidence (CI) of neutrophil engraftment was 91±iii% in a median of 22 days (range 12–80 days). The incidence of acute and chronic GVHD at day 100 and at 4 years was 12±3% and 13±2%, respectively (Eastward Gluckman for Eurocord, unpublished data, 2010). In another Eurocord study, on long-term outcomes of 147 HLA-identical sibling CBT recipients with hematologic malignancies, the 5-yr affliction-free survival was 44%.14 Compared with HLA-identical BMT, HLA-identical sibling CBTs displayed delayed granulocyte and platelet engraftment, and reduced incidence of acute and chronic GVHD, but survival was similar.xv Although the mechanism of such GVHD reduction is non fully understood, the immunological immaturity of the newborn and the enrichment of CB in T-reg cells may business relationship for at least part of it. Though generated from family-related CBTs, such clinical data, which indicated that GVHD was reduced when CB was used instead of bone marrow, were the basis for advocating HLA-mismatched CBTs, and for developing unrelated CBBs and programs for HLA-mismatched transplants.16 – 19
Table 1.
Illness and transplant characteristics of patients treated with family CB transplants (n=596) (E. Gluckman for Eurocord, unpublished data, 2010).
Overall survival at 4-years after related CB transplants (n=519) co-ordinate to disease category (E. Gluckman for Eurocord, unpublished information, 2010).
Table 2.
Donor and transplant characteristics of patients treated with family CB transplants (Due east. Gluckman for Eurocord, unpublished data, 2010).
Table three.
Outcomes after family CB transplant (n=519) (Eastward. Gluckman for Eurocord, unpublished data, 2010).
A number of studies have reported on efforts to systematically identify, collect and shop CBs for family-directed use (Table 4). Reed et al. 20 were the first to document the value of a focused program to collect and bank family-directed CBs from donors in families with children who have disorders which tin can be cured past HSCT. String claret was collected in remote sites with a kit provided by the banking company. Participation was voluntary and unremunerated; 540 families from 42 different states were enrolled. Despite the lack of experience and the heterogeneity of collection centers, the median number of cells was satisfactory, with more than than 93% of the banked CBs containing enough cells for transplanting the sibling. Seventeen units (three.4%) had been transplanted. The aforementioned group published data on sibling donor cord blood transplantation in patients with thalassemia major. Thirty-two of 96 donor-recipient pairs were HLA identical and fourteen (44%) received a CBT. Eleven of the 14 survived free of thalassemia after transplantation.24
Table iv.
Number of family directed cord blood units stored and transplanted.
Smythe et al. 21 take reported the 10-year experience of family-directed CB cyberbanking in the National Blood Service in England. Informed consent, CB testing, processing and storage followed the same procedures as for unrelated public CB banking. A total of 268 CBs were nerveless from 244 mothers. Diagnoses were hematologic malignancies in 114 cases, non-malignant hematologic disorders in 68 cases, immunodeficiency in 44 cases, and enzyme deficiency in 9 cases. Of the matched units, 13 were transplanted. In a report limited to children with malignant diseases, in Greece, Goussetis et al. have reported a low usage rate of banked sibling CB (n=48).22 CBs were successfully collected, but just i out of 4 children who needed HSCT was successfully transplanted. The aforementioned authors reported their feel in 50 families with beta-thalassemia major.23 Eight out of 12 HLA matched collections were released for CBT. All patients survived, 7 out of viii thalassemia free. The authors conclude that the development of directed CBB programs requires a policy to limit long-term storage for banked CBs with a depression probability of usage. For example, CBs that are non HLA-matched to the patient or that are HLA-matched to a patient who has achieved long-term remission are unlikely to be used, while banking for hemoglobinopathies increases the probability of usage to 16%. In Italia, the family-directed cord blood cyberbanking is supported by a national program (Ministerial Decree of 18 November 2009). The Centro Nazionale Sangue (CNS) reported 2,176 CB units banked (242 were banked in the twelvemonth 2010) by the Italian public banking concern network up to 31 December 2010. Of these, 129 were used for transplantation. In France, two CBBs (Hospitals Saint-Louis in Paris and Henri Mondor in Creteil) have collected 548 family unit-directed CBUs (E. Gluckman for Eurocord, unpublished data, 2010). The first banked all CBUs as requested past the patients' physicians (number collected for 437 patients: 216 leukemia, 118 hemoglobinopathies, 23 aplastic anemia, 17 immune deficiencies, 10 Fanconi anemia, vi metabolic diseases, 5 solid tumors and 42 with unreported diagnoses), the second banked 111 CBUs more often than not from siblings of patients with sickle cell disease (89 collections, i.e. 80%). 20-4 CBTs were performed from HLA-identical sibling donors, thirteen from the beginning depository financial institution and 11 from the second bank. Outcome was excellent: the 5-year overall survival was 83%, and 100% when considering hemoglobinopathies only. These data indicate that hemoglobinopathies are extremely important indications of cases in which family-directed disease-oriented CB banking is worthwhile.
These studies should be contrasted with the as notwithstanding limited reports of the feel of using private banking as the source of CB for either autologous or sibling utilise. Thornley et al. have presented information from a 2004 cross-sectional survey of 152 pediatric HSCT physicians from 57 centers in the United states and Canada.25 The respondents reported 9 autologous and 41 allogeneic transplants using privately banked CB. In 36 of 40 allogeneic cases, the CB had been collected because of a known indication in the recipient. The indications for allogeneic CBTs were acute leukemia (20 cases), hemoglobinopathies (vii cases), Fanconi anemia (seven cases) and others (7 cases). The 9 autologous CBTs were performed in severe aplastic anemia (4 cases), neuroblastoma (one case), retinoblastoma (ane case), Schwachman-Diamond syndrome (one case), brain tumor (i case) and i with unreported diagnosis. Few respondents stated they would choose autologous CB over culling stalk prison cell sources for treating astute leukemia in second remission, whereas 55% said they would cull autologous CB to care for high-run a risk neuroblastoma or aplastic anemia in the absence of an available donor. No respondent would recommend banking autologous CB for a newborn when both parents are of northern European descent; xi% would recommend such banking when parents are of different minority ethnicities. Indeed, the probability of using family-directed CB for allogeneic HSCT is very low when patients have frequent, highly represented haplotypes in the large unrelated bone marrow or CB inventories, whereas the situation is quite different in families with parents of different ethnic minorities and for whom the chance of finding a suitable unrelated donor is express. However, current results of HLA matched sibling CBT are meliorate than when an unrelated os marrow or CB donor is used. More recently, Rosenthal et al. accept reported the successful apply of banked autologous CB to care for severe aplastic anemia in 3 patients.26 However, they note that the probability of being able to use an autologous CB is very low (4 in a one thousand thousand).
Cost-do good analysis
The potential cost of family unit-directed cyberbanking can exist estimated by looking at matched rates found in the published studies and estimating the average cost of CBUs banked using the data published by the Institute of Medicine (IOM) in 2004, where the costs of collecting, processing and banking for public cyberbanking are estimated. At that place, these costs were estimated to be approximately $1,500 per unit plus $50 annually for storage. The IOM estimates reverberate costs of collecting just not of processing units adamant to exist unsuitable for collection prior to any processing or the costs of HLA typing for all banked units. Family unit-directed banking would likely incur lower per-unit cyberbanking costs every bit units of smaller size would exist adequate for banking and HLA testing would merely be carried out at the time of potential need. The estimated costs per unit used are consistent with graft acquisition costs for unrelated donors when costs of donor screening, testing and selection are taken into account.
According to the 2011 study by Rosenthal et al.,26 the toll for the first year of private storage, including collection, shipping and storage fees, varies in the U.s. from $1,993 to $two,195 plus an annual storage fee of $125. Of more than 355,000 CBUs stored in ii large private banks, 77 were used for allogeneic HSCT and 32 for autologous HSCT. The average cost of the CBU used would so exist over 100 times that of an unrelated bone marrow or CB production.
Kaimal et al. 27 have investigated the toll-effectiveness of individual CB banking relative to no cyberbanking. They conclude that private banking is not cost-constructive because information technology costs an boosted $1,374,246 per life-yr gained. In sensitivity assay, if the toll of CB cyberbanking is less than $262 or the likelihood of a kid needing a HSCT is greater than ane in 110, individual cyberbanking becomes price-constructive. They conclude, therefore, that individual CB banking is cost-effective but in families with children with a very loftier likelihood of needing a HSCT.
Indications of family unit-directed CB banking is now limited to children with hematologic malignancies, genetic disorders or caused aplastic anemia. If a genetic disease is the indication for HSCT, the chances of a sibling being a non-carrier and HLA lucifer range from 1:8 to 1:xvi, depending on the inheritance of the genetic condition. In some diseases (e.k. hemoglobinopathies) matched carrier siblings are advisable donors, but in others (east.k. inherited metabolic disorders) they cannot be utilized. In the United States, the annual incidence of ALL in children aged 0–nineteen years is estimated at thirty.6 in a 1000000 for Caucasians and fifteen.ix in a million for Afro-Americans. The annual incidence of astringent aplastic anemia is estimated at 3 in a million and that of high-take chances neuroblastoma which tin can be treated past autologous transplant at 3–5 in a million.25 Moreover, parents considering family banking in the absence of a patent indication should be informed of the remote likelihood that a CB will be used for the donor child or another family member. Information technology should, however, be noted that these considerations are based on current hematologic indications without taking into account the potential apply of CB in non-hematologic diseases. Indeed, several studies are exploring the possibility of treating infants with cerebral palsy or blazon 1 diabetes using autologous CBTs28 (www.clinicaltrials.gov). If current clinical trials are successful, directed CB banking may become more and more than price efficient as new indications appear.
Discussion
Efforts to expand family-directed banking as well have to take into account alternatives to sibling CBT, especially in non-malignant settings when HSCT could be delayed, such every bit the use of a sibling os marrow. This approach is less expensive than a CBT and has shown skillful clinical results; however, the process of graft acquisition, although safe, is non harmless in a very immature donor. Moreover, the delay of the transplant and the potential for other complications, or the possibility that the sibling donor may not otherwise exist fit to donate when needed, should as well be considered. CB collection is harmless for the baby and the mother and does not enhance any ethical business concern,11 while one should consider the possible side effects of bone marrow or peripheral blood collection for mobilized hematopoietic stem cells in young children, which to our noesis have not nonetheless been evaluated. Moreover, in some cases, the patient cannot wait long enough for the donor'due south bone marrow to be safely nerveless, e.thou. when HSCT is indicated for leukemia, aplastic anemia or a hereditary disorder, such equally severe combined immunodeficiency, osteopetrosis or mucopolysaccharidosis. In all these cases, the current alternative options, in the absence of a matched related or unrelated donor, are to propose a haploidentical family hematopoietic stem cell bone marrow or peripheral blood transplant or a mismatched unrelated cord claret transplant whose results are conspicuously less favorable than an HLA matched sibling cord blood transplant.
Family-directed CB banking may have other advantages. For instance, CB usage may be the only practical pick available in developing countries where infant mortality is high and the risks associated with bone marrow drove and/or insertion of central venous access for obtaining mobilized hematopoietic stem cells in the peripheral blood are a concern. Where the gamble of acquired infectious diseases such as hepatitis or HIV infection is present, drove of the CB may also be the best manner to limit or forbid the risk of transmission of infectious diseases, since testing of the CB units for these diseases can then be carried out to assure no transmission. However, information technology is of import to be aware that in this context, a transplant program would only be feasible if the necessary bones healthcare infrastructure (e.m. vaccination, air, h2o quality, diet, etc.) and teaching policies are well established to ensure quality and safety. Hemoglobinopathies are, indeed, the master indications of CBT in many developing countries and, even though information on the cost of CB banking and transplantation in these countries is unknown and could vary from country to country, 1 can speculate that the cost of CB HSCT might exist adequate compared with life-long complications, iron chelation or the cost of obtaining bone marrow. If a price-constructive mode tin be found to identify a matched CB, this could permit an extended use of this therapy in these countries. Costs might even be decreased by the evolution of defended centers for handling of hemoglobinopathies in developing countries where the price of labor is lower than in developed countries. The utilize of reduced intensity conditioning regimens and protocols of supportive care adjusted to the local situation might decrease the cost even further.
Further efforts should be fabricated to determine whether a national loftier-quality program of sibling CB cyberbanking tin be maintained at relatively low price despite the logistic difficulties of organizing collections from many hospitals and issuing CBs for transplantation to diversely located transplant centers. Growing recognition of the benefits of family-directed banking has resulted in programs to more than systematically exam the toll and benefit of this approach. These include a pilot program currently underway in the United states of america, sponsored by the Section of Health and Human Services and administered through NMDP, which involves the development of promotional materials and campaigns to create awareness of the value of directed donation banking. 5 public banks and one family unit depository financial institution participate under agreements to collect, store and bank units that meet the program criteria. The processes applied to these CBs are almost identical to those applied to public units. Many private banks also offer this service costless of charge for families in need. These should exist encouraged merely only if they are pursued along with the goal of banking high quality units.29 Most private banking is not subject area to the same regulatory review that public banks are required to satisfy. For example, in the United States, autologous banks exercise not demand to exist licensed. Voluntary accreditation may address the lack of regulatory overview simply many autologous banks do not seek accreditation through Fact-Netcord, the standard for public banks that has been adopted in many European countries, too as in Australia and Canada. Specific criteria for family-directed banking have been established by Fact-Netcord only few existing individual banks are Fact-accredited. Accreditation is also available through the American Association of Blood Banks (AABB) or other national accreditation bodies.
In order to detect a compromise, public-private hybrid bank models are currently the subject field of intense discussion.10 – 13 Ane driver for these models is to better the fiscal viability of the CBBs. A number of models for combined banking take been developed, including joint marketing of split up cyberbanking operations, opportunities to split units for private and public apply, and the offering to initially bank units every bit either public or private, just with the potential of converting their status at a later appointment or issue. To exist useful to families, these new approaches will need to exist more than rigorously adopted, accreditation standards need to be practical, the accuracy of their informed consent improved, benefits to help research on CB cells need to exist shared, and sibling banking when there is a articulate indication for allogeneic HSCT demand to exist offered. In order to transfer some private units to the public inventory, a WMDA policy statement on the combined private and public banking of CB and other related products has been established (world wide web.worldmarrow.org). Many families with children affected by hematologic cancerous affliction or a hereditary disorder later accept other children. However, births are scattered amongst hospitals that may lack the infrastructure required to collect or banking company locally and CB may often be collected in hospitals that are non accredited for drove, unlike CB collected by accredited maternity units.26 Efforts to improve the quality of collections will, therefore, be an important part of whatever programme to collect family-directed units. Optimal policies, procedures and indications have not been clearly established for use in these routine birthing centers. Information should state clearly that banking CB does not guarantee that the cells will provide a cure or be applicable in every situation.29 Medical treatments using family banked cord tissue are still in an early phase of enquiry and are not currently bachelor, and in that location is no guarantee that therapies volition be developed in the future. Factor and cellular therapies for various disorders, including thalassemia or severe combined immunodeficiency syndrome, prove promising results.30 , 31 In the future, prenatal diagnosis may identify patients who may benefit from factor therapy using their own CB. In this case, factor-modified CB cells could exist infused early on in life fugitive the treatments and complications related to these diseases. Pre-implantation genetic testing has been canonical in many countries to ensure that a pregnancy volition result in a child gratuitous from a serious inherited disorder and, HLA-identical to his sibling, a candidate for an allogeneic HSCT. This practice will increase the probability of finding an HLA-identical sibling donor and so the number of sibling CB collections is probable to increase.32 The potential telescopic of medically indicated family-directed CB banking is considerable (Table v). Some other important factor using family-directed CBU is that the unit could be combined with unlike sources of stalk cell, such equally BM from the same donor, in case it is needed. So far there accept been over 100 transplants reported to Eurocord, using related CB in combination with BM for cancerous and non-cancerous diseases. In the future, some non-hematologic diseases might exist treated with allogeneic or autologous cells.33 Standing academic inquiry and help from the manufacture for the development of new products and for the implementation of worldwide regulation will control and guarantee the quality, prophylactic and dominance of the CB market place on the ground of new scientific and clinical protocols and rigorous clinical trials.
Table 5.
Indication of family-directed cord blood employ in developed countries
Conclusion
The use of CB units for allogeneic HSCT has saved many lives all over the world and holds groovy promise to benefit many more. The current do and arroyo to CBB, both public and individual, are overlooking an important opportunity to provide an optimal cell source for families in whom there is the possibility of collecting CB for a sibling with a known condition that would benefit from a related CBT. For this purpose private banks should meet the same standards, quality control and accreditation requirements as those required for public cord blood cyberbanking. Outcomes can be improved and more lives saved through a more than organized arroyo to the identification and collection of CB for family-directed uses.
Appendix.
EBMT centers who kindly provided data on related cord blood transplant (in alphabetical society):
Algeria - Alger: Middle Pierre et Marie Curie/Australia -Sydney: The Children's Hospital at Westmead & Randwick/Austria – Graz: Medical University Graz/Innsbruck: University Infirmary Innsbruck/Vienna: St. Anna Kinderspital/Belarus - Minsk: Belarusian Centre for Paediatric, Oncology and Hematology/Belgium - Brussels: Cliniques Universitaires St. Luc, Institut Jules Bordet, Children's University Hospital, BMT Unit of measurement/Gent: University Hospital Gent/Haine-St-Paul: Hôpital de Jolimont/Leuven: University Hospital Leuven (Dept. of Paediatrics), University Hospital Gasthuisberg (Dept. of Hematology)/Yvoir: UCL Mont-Godinne/Brazil - Campinas: Univ. Est. de Campinas/Bulgaria - Sofia: Children's Onco-Hematology Hospital/Croatia - Zagreb: University Infirmary Center Rebro/Czechia - Prague: University Hospital Motol/Denmark - Copenhagen: Rigshospitalet/Finland - Helsinki: Academy of Helsinki, Hospital for Children & Adolescents/France – Angers: Eye Hospitalier Régional d'Angers/Besançon: Hôpital Saint Jacques/Bordeaux: Hôpital Haut-Lévêque, CHU Bordeaux Groupe Hospitalier Pellegrin-Enfants/Clermont-Ferrand: Hôtel Dieu CHU/Jean Perrin/Créteil: Hôpital Henri Mondor/Grenoble: Tronche CHU-Albert Michallon/Lille: Claude Huriez/Lyon – Hôpital Debrousse (pédiatrie)/Marseille: Hôpital d'Enfants de La Timone/Nancy: Hôpital de Brabois/Nantes: Hôtel Dieu/Nice: Hôpital de l'Archet/Paris: Hôpital Necker (adulte), Hôpital Necker Enfants Malades, Hôpital Saint-Louis, Hôpital Robert Debré/Poitiers: Hôpital Jean Bernard/Rennes: Hôpital de Pontchaillou/Rouen: Hôpital Charles Nicolle (pédiatrie)/Saint-Etienne: Hôpital Nord Institut de Cancérologie de la Loire/Strasbourg: Hôpital de Hautepierre (pédiatrie)/Germany - Berlin: Charité-CVK, University Medicine Berlin/Dresden: Universitaetsklinikum Dresden/Düsseldorf: Universitaetsklinikum/Essen: University Hospital, Dept. of Pediatric Hematol./Oncol/Hannover: Hannover Medical School/Heidelberg: University of Heidelberg/Jena: University of Jena/Munich: Klinikum Grosshadern/Tübingen: Universität Tübingen, Medizinische Klinik/Ulm: Universitaet Ulm/Greece -Athens: St. Sophia' Children'due south Hospital/Patras: Patras University Medical School/Hungary - Budapest: St. László Hospital, St. István/Miskolc: Postgraduate Medical School/India - Chennai: Apollo Speciality Infirmary/Islamic republic of iran - Teheran: Shariati Hospital/Ireland - Dublin: Our Lady's Infirmary for Sick Children/Israel - Haifa: Rambam Medical Center/Jerusalem: Hadassah University Hospital/Petach-Tikva: Schneider Children's Medical Middle of Israel/Tel-Hashomer: Edmond & Lily Safra Children's Hospital, Chaim Sheba Medical Middle/Italian republic - Bologna: Azienda Ospedaliero-Universitaria di Bologna/Brescia: Universitá degli Studi di Brescia/Genova: Ospedale San Martino, Department of Haematology Two, Constitute One thousand. Gaslini,/Milano: San Raffaele Scientific Plant/Monza: Ospedale San Gerardo, Clinica Pediatrica dell'Universita di Milano Bicocca/Padova: Clinica di Oncoematologia Pediatrica/Pavia: Fondazione IRCCS Policlinico San Matteo/Pescara: Ospedale Civile Section of Hematology/Pisa: Azienda Ospedaliera Universitaria Pisa/Reggio_Calabria: Azienda Ospedaliera/Roma: Univ. 'La Sapienza', Ospedale S. Camillo, Rome Transplant Network/Torino: Ospedale Infantile Regina Margherita, Onco-Ematologia Pediatrica, Istituto per la Ricerca eastward la Cura del Cancro, Ospedale San Luigi Orbassano, Academy of Turin/Trieste: Istituto per l'Infanzia Burlo Garofolo/Jordan - Amman: King Hussein Cancer Centre/Poland – Bydgoszcz: Academy Hospital, Collegium Medicum/Poznan: Poznan University of Medical Sciences/Wroclaw: Wroclaw DCTK, Wroclaw Medical University/Portugal – Lisboa: Inst. Portugues Oncologia/Porto: Inst. Portugues de Oncologia do Porto/Russia - Moscow: Russian'due south Children's Hospital/St. Petersburg: Saint Petersburg Land Medical Pavlov University/Saudi Arabia - Riyadh: Male monarch Faisal Specialist Hospital & Research Centre/Spain – Barcelona: Hospital Vall d'Hebron, Hospital Santa Creu i Sant Pau/Córdoba: Hosp. Reina Sofia/Madrid: Infirmary Gregorio Marañón, Infirmary Universitario La Paz, Niño Jesus Children'due south Hospital, Hospital Universitario Puerta de Hierro/Málaga: Hospital Carlos Haya/Palma_De_Mallorca: Hospital Universitari Son Dureta/Sevilla: Hospital Universitario Virgen del Rocío/Valencia: Infirmary Infantil La Iron/Slovakia - Bratislava: Pediatric University Teaching Hospital/South Africa -Cape_Town: University of Cape Town Faculty of Health Sciences/Sweden - Goeteborg: Sahlgrenska University Infirmary, The Queen Silvia Children's Hospital/Lund, Academy Hospital/Stockholm: Huddinge University Infirmary, Karolinska University Hospital Children's Hospital/Umeå: Umea University Hospital/Uppsala: University Hospital/Switzerland, Zürich, University Children's Hospital/Kingdom of the netherlands - Leiden: Academy Hospital/Nijmegen: Radboud University - Nijmegen Medical Eye/Utrecht: University Medical Middle, University Hospital for Children/Turkey - Ankara: Hacettepe University Children's Hospital, Ankara University Kinesthesia of Medicine/Ankara (Cebeci): University of Ankara/Ankara Sihhiye: Hacettepe University/Antalya: Akdeniz Academy Medical School/Izmir, Ege University/United Kingdom – Birmingham: Birmingham Children's Hospital/Bristol: Avon Haematology Unit Bristol Oncology Centre, Bristol Royal Hospital for Children/Glasgow: Imperial Hospital for Sick Children/Leeds: Mid Yorkshire Hospitals NHS Trust - Yorkshire Blood & Marrow Transplant Programme/London: St. Mary's Infirmary Division of Paediatrics, Swell Ormond Street Hospital, Majestic Marsden Hospital, Imperial College Hammersmith Infirmary/Manchester: Department of Paediatric Haematology/Newcastle-Upon-Tyne: Newcastle General Hospital (Dept. of Paediatric Immunology), Purple Victoria Infirmary (Hematology, Paediatric Oncology Unit of measurement)/Sheffield: Purple Hallamshire Hospital.
Footnotes
Funding: this work was supported by INSERM grant TGIR 0805.
Authorship and Disclosures
The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the total text of this paper at world wide web.haematologica.org.
Fiscal and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208689/
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