[Hyperbaric oxygen and radiotherapy: From myth to reality]. / Oxygénothérapie hyperbare et radiothérapie : entre mythe et réalité.

Worldwide, more than a million people receive each year a curative radiotherapy. While local control and overall survival are steadily increasing, 5 to 15% of patients still develop above grade 2 late toxicities. Late toxicities treatments are complex. Hyperbaric oxygenation was shown to induce revascularization and healing of injured tissues, but indications are still debated. Through a literature review, we summarized the hyperbaric oxygenation indications in radiation-induced late toxicities. We also studied the knowledge and practice of French local radiation therapists. It seems that hyperbaric oxygen therapy can be a conservative treatment of haemorrhagic cystitis and radiation-induced pain, in case of drug therapies failure. Often associated with a significant morbidity and mortality, surgery could be avoided. The risk of complications in case of tooth extraction in irradiated tissues is also reduced. However, the role of hyperbaric oxygenation for mandibular osteoradionecrosis, radiation-induced proctitis, enteritis, lymphoedema, brachial plexopathy, skin and neurological sequelae seems more questionable since studies results are conflicting. Future outcomes of phase III studies are expected to clarify the role of hyperbaric oxygenation in the management of radio-induced toxicities, including for head and necks complications.

Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire.

This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

Collaboration between hematopoietic stem cell donor registry and cord blood banks.

Despite the huge number of volunteer donors registered worldwide, only a mean of 50% of patients not having a family donor are transplanted with an unrelated donor. Since 1990, a network has been implemented among some European registries. With the help of the European Community, a more sophisticated network has been developed, the European Marrow Donor Information System (EMDIS). A new project underwent development by registries and the Bone Marrow Donor Worldwide: the EMDIS Cord Blood Registry. It will in the future permit to obtain after a search request, one report containing all of the best donors worldwide and best umbilic cord blood for each patient, taking into account possible double cord blood transplantations and other factors, such as number of nucleated cells, number of CD34+ cells, and methods of reduction. Only a strong collaboration between all hematopoietic stem cell registries and cord blood banks would allow a Registry to propose the best donor/cord blood unit for each patient in each country. Progress in the field of hematopoietic stem cell transplantation may be obtained by the parallel development of cord blood banks worldwide and bone marrow donor registries among countries that include minorities.

Haematopoietic stem cell donor registries: World Marrow Donor Association recommendations for evaluation of donor health.

The ability to identify unrelated haematopoietic stem cell donors in one country for recipients in another country requires cooperation and standardization in many areas. The donor assessment and testing are very important issues affecting quality and safety of donation. This special report details the World Marrow Donor Association's recommended procedures regarding the medical evaluation of donors, with the intent to protect the volunteer from the risk to damage his health and to offer the recipient the appropriate quality of stem cells. This document describes criteria for permanent or temporary deferral, guidelines for risk evaluation of infectious disease, examples of conditions requiring assessment and questionnaires designed to elicit relevant information about a donor's medical history and general health.

[Economic evaluation of the organization of a registry of haematopoietic stem cell donors]. / Evaluation économique de l'organisation d'un registre de donneurs de cellules souches hématopoïétiques.

BACKGROUND: Availability of a healthy, human-leukocyte-antigen-matched hematopoietic stem cell source is a prerequisite for successful allogenic hematopoietic stem cell transplantation. In 70% of cases, the search of hematopoietic stem cells shifts from siblings to unrelated donor registries. Given that the Human Leucocytes Antigens (HLA) system is highly polymorphic and that the cost of HLA typing remains high, the adequacy between registry content and patient needs must be assessed. Registries should be optimally organized to increase the probability for any given patient to find a donor. METHODS: A welfare function associated with the existence of an HLA registry was defined as was a measure of the advantage for laboratories having performed HLA typing. We hypothesized a way to formalize registry efficiency and applied it to the French Hematopoietic Stem Cell donors Registry. RESULTS: The model determined an implicit value for the stem cell graft and showed that efficiency increased very slowly with increasing number of potential donors in registries. The optimal size of a registry was found to be sensitive to model parameters. CONCLUSION: Increased registry size, in terms of number of donors foreseeable in the French registry, would have a limited impact on registry efficiency and thus social effectiveness. Nevertheless, the calibration of the model justifies the goal of recruiting 100000 new volunteer donors over the next 10 years as proposed by the French government in the "Graft Plan". The policy of the regulatory agency should be oriented towards improving the probability a compatible potential donor identified during a preliminary search would become an actual fully compatible donor and towards reducing the cost of typing.

World Marrow Donor Association guidelines for use of HLA nomenclature and its validation in the data exchange among hematopoietic stem cell donor registries and cord blood banks.

Since the advent of the European Marrow Donor Information System in the first half of the last decade, fully automated data exchange between registry computer systems has been playing an ever-increasing role in the international search for unrelated donors of blood progenitor cells. This exchange, however, was hampered by different local conventions used to present HLA data and complicated by the need to extend the official WHO nomenclature to accommodate the registries' information systems and to cross-validate HLA data obtained with different methods and/or at different loci. The guidelines presented here have been developed by the World Marrow Donor Association to standardize the nomenclature to be used and the validation checks to be applied in the international electronic exchange of HLA-typing data among unrelated volunteer hematopoietic stem cell donor registries and umbilical cord blood banks. Two reference web sites have been designated to maintain and update the approved HLA nomenclature and all the ancillary information needed by the conventions described here.

Strategies for new donor typing based on donor HLA type or donor characteristics.

Registries of volunteer unrelated haematopoietic stem cell donors must make decisions on the procedures used to human leukocyte antigen type new donors based on various factors including available finances and donor diversity. This manuscript describes a comparison of new donor typing strategies for three European registries which was presented for discussion at the 14th International Histocompatibility Workshop.

Relevance of KIR gene matching in unrelated hematopoietic stem cell transplantations.

The aim of this collaborative study was to evaluate the impact of killer cell immunoglobulin-like receptor (KIR) gene disparities on unrelated hematopoietic stem cell transplantations (HSCT) outcome. To address this question, we have determined the presence or absence of 14 functional KIR genes in HLA-matched (n= 164) or HLA-mismatched (n= 100) donor/recipient pairs and investigated whether KIR gene disparities had an impact on both the occurrence of acute graft-vs-host-disease incidence and overall survival. In a univariate analysis, our preliminary results suggest a detrimental effect of a few KIR gene disparities on patient survival that should be avoided in unrelated HSCT.

World Marrow Donor Association: international standards for unrelated hematopoietic stem cell donor registries.

World Marrow Donor Association standards are aimed at enhancing the quality of unrelated volunteer donor hematopoietic stem cell registries assisting transplant physicians in the international search for unrelated donors for their patients. The standards cover: (1) general organization of registries; (2) donor recruitment; (3) donor characterization; (4) information technology; (5) facilitation of search requests; (6) second/subsequent donations; (7) collection/processing/transport of stem cells; (8) follow-up of patient/donor; and (9) financial/legal responsibilities.

A special report: suggested procedures for international unrelated donor search from the donor registries and quality assurance working groups of the World Marrow Donor Association (WMDA).

This special report details the World Marrow Donor Association's recommended procedures regarding the international search for an unrelated donor for hematopoietic stem cell transplantation. The responsibilities of the national hubs, transplant center and donor registry staff are outlined for all actions associated with the preliminary search, formal search, donor confirmatory typing and final donor selection.

Hematopoietic stem cell donor registry strategies for assigning search determinants and matching relationships.

Registries and cord blood banks around the world collect and store the HLA types of volunteers in order to identify matched unrelated donors for patients requiring hematopoietic stem cell transplantation. This task is complicated by the many formats in which HLA types are provided by the testing laboratories (types obtained by serology vs by DNA-based methods; high vs intermediate vs low resolution) and by the need to identify which of these diverse types are most likely to match the HLA assignments of a searching patient as closely as possible. Conversion of the assignments to 'search determinants' may be included within the algorithm used to select and prioritize a list of potentially suitable donors, either as an aid to matching or as a tool to optimize the performance of comparisons within large data files. The strategies used by registries to create search determinants are described. A set of search determinants, utilized by the National Marrow Donor Program, is provided as an example and is intended to initiate further discussion aimed at understanding the process used by each registry with the possibility of developing a standard process among registries worldwide.

Cost-effectiveness analysis of two strategies for typing unrelated donors for bone marrow transplantation in France.

Large Registries of HLA-typed potential volunteer donors have been set up in numerous countries to find HLA-matched unrelated bone marrow donors. This study compared two strategies medicoeconomically for HLA typing in the context of a bone marrow volunteer donor Registry. It investigated the cost-effectiveness of strategies before and after the French Registry was modified in January 1999: HLA- A, B typing only at registration and secondary HLA-DR typing on part of the Registry (AB strategy) vs. typing at once for HLA- A, B, and DR (ABDR strategy). The point of view considered was that of payers, French typing tariffs with a 5% discount rate were used, effectiveness was defined as identification of at least one donor with no HLA-A, B, DR incompatibilities for a given recipient (compatible potential donor), the observation period was 9 months, and the judgement criterion was the differential cost-effectiveness ratio. The ABDR strategy identified 94.7% (142/150) of compatible potential donors. The differential cost-effectiveness ratio between the two strategies was 387,005 francs (Euro 58,995) for one supplementary compatible potential donor. Compared with a "do nothing" policy, the ratio was 3,744,087 francs (Euro 570,745) for the AB strategy vs. 576,136 francs (Euro 87,826) for the ABDR strategy. The ABDR strategy is thus more effective but also more costly than the AB strategy. Nevertheless, because of its lower effectiveness and the size of available ABDR Registries, the AB strategy will become obsolete.

DPB1 disparities contribute to severe GVHD and reduced patient survival after unrelated donor bone marrow transplantation.

In order to evaluate the impact of HLA-DBP1 incompatibilities on the occurrence of acute graft-versus-host disease (GVHD) in unrelated hematopoietic cell transplantation, we studied 57 donor/recipient pairs characterized by their allelic identity for HLA-A, B, C, DRB1 and DQB1 and also for DRB3, 4, 5 loci and aimed to correlate DPB1 mismatches to already described risk factors for GVHD using multivariate Cox regression analysis. DPB1 identity between donor and recipient was observed in 24% and DPB1 compatibility (GVHD vector) in 42%. Two factors were independently associated with severe acute GVHD: two DP incompatibilities (RR = 8.25, 95% confidence interval (CI): 1.67-40.10, P = 0.010) and disease risk (RR = 10.23, 95% CI: 1.12-93.13, P = 0.012). Two DPB1 incompatibilities appeared also to be a factor in poorer survival independent of its effect on acute GVHD (RR = 4.97, 95% Cl: 1.80-13.71, P = 0.002). A correlation between acute GVHD and matching for each individual DPB1 polymorphic region and for residue 69 of the DP beta molecule, which seems to be a key residue in the alloimmune response, was not observed. Our data indicate that the outcome of unrelated hematopoietic cell transplantation in terms of GVHD but also survival, could be improved through HLA-DPB1 matching or at least by avoiding two DPB1 mismatches.

HLA class I and class II are both associated with the genetic predisposition to primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is an autoimmune disease characterized by progressive destruction of the exocrine glands leading to mucosal and conjunctival dryness. It is marked by lymphocytic infiltration of the glands and the accumulation of several types of autoantibodies such as rheumatoid factor (RF), antinuclear, anti-SS-A (anti-Ro) and anti-SS-B (anti-LA) autoantibodies. The susceptibility to pSS and/or the presence of SS-A/SS-B autoantibodies in pSS patients is associated with DRB1*03-DQB1*02 and DRB1*02-DQB1*06 haplotypes, whereas no associations have been described with any HLA class I allele. To define the impact of HLA class I alleles in predisposition to pSS, 46 patients responding to the European criteria and 222 healthy unrelated Caucasians were analyzed for their HLA class I and class II haplotypes. Our results confirm the association of the DRB1*03-DQB1*02 haplotype with SS-A/SS-B autoantibodies positive pSS and demonstrate a significant association of the HLA-A24 with the disease. Moreover, HLA-A24 is more often associated with DRB1*11-DQB1*0301 and/or DRB1*0301-DQB1*02 in pSS patients than in the controls. The novel association of HLA class I alleles with susceptibility to pSS provides new insights to the genetic predisposition to this disease and subsequently to its physiopathology.

A novel HLA-B null allele (B*4022N) generated by a nonsense codon in the alpha1 domain.

We describe in this work a novel HLA-B null allele designated B*4022N. This new variant was found in a Caucasian individual who was serologically typed for one HLA-B allele as a B-blank, Bw-blank. Retrospective DNA typing by polymerase chain reaction using sequence-specific primers (PCR-SSP) has established the correspondence of this blank allele with the classical HLA-B*4001 allele. Nucleotide sequence analysis of exon 2 and 3 has revealed the presence of two adjacent point mutations at position 170 and 171 of exon 2 (GG to TT). While the first difference is silent, the second leads to the creation of a nonsense codon at position 58 of the alpha1 domain, providing the most likely mechanism underlying the observed null phenotype.

A novel HLA-B*51 allele (B*5116) identified by nucleotide sequencing.

We report here an additional HLA-B*51 variant designated HLA-B*5116. Detected by an abnormal serological reactivity pattern, this variant was identified as a B*51 allele by polymerase chain reaction using sequence-specific primers (PCR-SSP) and characterized by nucleotide sequencing. The new variant sequence match closely with the classical HLA-B*5101 excepted two adjacent nucleotide substitutions at positions 216 and 217 of the third exon and the subsequent Leucine to Glutamic acid change at codon 163 of the alpha2 domain (CTG-->GAG). This new variant was not detected in three different ethnic groups (French, Algerian and Lebanese) suggesting a very rare frequency.