Human amniotic membrane application in oral surgery-An ex vivo pilot study.

Objectives: The purpose of this pilot porcine study was to explore and illustrate the surgical application of human amniotic membrane (hAM) in an ex vivo model of medication-related osteonecrosis of the jaw (MRONJ). Material and methods: Five oral and maxillofacial surgeons participated to this study. MRONJ was simulated on porcine mandible specimens. hAM was applied using four different techniques: implantation with complete coverage, implantation with partial coverage, apposition and covering graft material. At the same time, the surgeons evaluated how well the hAM handled and its physical properties during the surgery. Results: Surgeons found that hAM had suitable mechanical properties, as it was easy to detach from the support, handle, bind to the defect and bury. hAM was also found to be strong and stable. The "implantation with complete coverage" and "implantation with partial coverage" techniques were the preferred choices for the MRONJ indication. Conclusion: This study shows that hAM is a graft material with suitable properties for oral surgery. It is preferable to use it buried under the gingiva with sutures above it, which increases its stability. This technical note aims to educate surgeons and provide them with details about the handling of hAM in oral surgery. Clinical relevance: Two surgical techniques for hAM application in MRONJ were identified and illustrated. hAM handling and physical properties during surgery were reported.

Tips and Tricks and Clinical Outcome of Cryopreserved Human Amniotic Membrane Application for the Management of Medication-Related Osteonecrosis of the Jaw (MRONJ): A Pilot Study.

Medication-related osteonecrosis of the jaw (MRONJ) is a complication of certain pharmacological treatments such as bisphosphonates, denosumab, and angiogenesis inhibitors. There are currently no guidelines on its management, particularly in advanced stages. The human amniotic membrane (hAM) has low immunogenicity and exerts anti-inflammatory, antifibrotic, antimicrobial, antiviral, and analgesic effects. It is a source of stem cells and growth factors promoting tissue regeneration. hAM acts as an anatomical barrier with suitable mechanical properties (permeability, stability, elasticity, flexibility, and resorbability) to prevent the proliferation of fibrous tissue and promote early neovascularization at the surgical site. In oral surgery, hAM stimulates healing and facilitates the proliferation and differentiation of epithelial cells in the oral mucosa and therefore its regeneration. We proposed using cryopreserved hAM to eight patients suffering from cancer (11 lesions) with stage 2-3 MRONJ on a compassionate use basis. A collagen sponge was added in some cases to facilitate hAM grafting. One or three hAMs were applied and one patient had a reapplication. Three patients had complete closure of the surgical site with proper epithelialization at 2 weeks, and two of them maintained it until the last follow-up. At 1 week after surgery, three patients had partial wound dehiscence with partial healing 3 months later and two patients had complete wound dehiscence. hAM reapplication led to complete healing. All patients remained asymptomatic with excellent immediate significant pain relief, no infections, and a truly positive impact on the patients' quality of life. No adverse events occurred. At 6 months of follow-up, 80% of lesions had complete or partial wound healing (30 and 50%, respectively), while 62.5% of patients were in stage 3. Radiological evaluations found that 85.7% of patients had stable bone lesions (n = 5) or new bone formation (n = 1). One patient had a worsening MRONJ but remained asymptomatic. One patient did not attend his follow-up radiological examination. For the first time, this prospective pilot study extensively illustrates both the handling and surgical application of hAM in MRONJ, its possible association with a collagen sponge scaffold, its outcome at the site, the application of multiple hAM patches at the same time, and its reapplication.

Umbilical Cord Blood as a Source of Less Differentiated T Cells to Produce CD123 CAR-T Cells.

Chimeric Antigen Receptor (CAR) therapy has led to great successes in patients with leukemia and lymphoma. Umbilical Cord Blood (UCB), stored in UCB banks, is an attractive source of T cells for CAR-T production. We used a third generation CD123 CAR-T (CD28/4-1BB), which was previously developed using an adult's Peripheral Blood (PB), to test the ability of obtaining CD123 CAR-T from fresh or cryopreserved UCB. We obtained a cell product with a high and stable transduction efficacy, and a poorly differentiated phenotype of CAR-T cells, while retaining high cytotoxic functions in vitro and in vivo. Moreover, CAR-T produced from cryopreserved UCB are as functional as CAR-T produced from fresh UCB. Overall, these data pave the way for the clinical development of UCB-derived CAR-T. UCB CAR-T could be transferred in an autologous manner (after an UCB transplant) to reduce post-transplant relapses, or in an allogeneic setting, thanks to fewer HLA restrictions which ease the requirements for a match between the donor and recipient.

Surgical Application of Human Amniotic Membrane and Amnion-Chorion Membrane in the Oral Cavity and Efficacy Evaluation: Corollary With Ophthalmological and Wound Healing Experiences.

Due to its intrinsic properties, there has been growing interest in human amniotic membrane (hAM) in recent years particularly for the treatment of ocular surface disorders and for wound healing. Herein, we investigate the potential use of hAM and amnion-chorion membrane (ACM) in oral surgery. Based on our analysis of the literature, it appears that their applications are very poorly defined. There are two options: implantation or use as a cover material graft. The oral cavity is submitted to various mechanical and biological stimulations that impair membrane stability and maintenance. Thus, some devices have been combined with the graft to secure its positioning and protect it in this location. This current opinion paper addresses in detail suitable procedures for hAM and ACM utilization in soft and hard tissue reconstruction in the oral cavity. We address their implantation and/or use as a covering, storage format, application side, size and number, multilayer use or folding, suture or use of additional protective covers, re-application and resorption/fate. We gathered evidence on pre- and post-surgical care and evaluation tools. Finally, we integrated ophthalmological and wound healing practices into the collected information. This review aims to help practitioners and researchers better understand the application of hAM and ACM in the oral cavity, a place less easily accessible than ocular or cutaneous surfaces. Additionally, it could be a useful reference in the generation of new ideas for the development of innovative protective covering, suturing or handling devices in this specific indication. Finally, this overview could be considered as a position paper to guide investigators to fulfill all the identified criteria in the future.

Umbilical cord blood transplants facilitated by the French cord blood banks network. On behalf of the Agency of Biomedicine, Eurocord and the French society of bone marrow transplant and cell therapy (SFGM-TC).

The public French Cord Blood Banks Network was established in 1999 with the objective of standardizing the practices governing umbilical cord blood (UCB) banking in France. The Network adopted a strategy to optimize its inventory and improve the quality of its banked units based on a quality improvement process using outcome data regularly provided by Eurocord. This study aimed to describe the results, over 10 years, of UCBT facilitated by a national network that used the same criteria of UCB collection and banking and to assess how modifications of banking criteria and unit selection might influence transplant outcomes. Nine hundred and ninety-nine units (593 single-unit and 203 double-unit grafts) were released by the Network to transplant 796 patients with malignant (83%) and non-malignant (17%) diseases. Median cell dose exceeded 3.5 × 107 TNC/kg in 86%. There was a trend to select units more recently collected and with higher cell dose. Neutrophil engraftment was 88.2% (85.7-90.7) and 79.3% (72.6-86.5) respectively for malignant and non-malignant diseases with a trend to faster recovery with higher cell doses. The respective 3-year transplant-related mortality were 31.1% (27.5-35.1) and 34.3% (27.0-43.5). OS was 49% ± 4 in malignant and 62% ± 4 in non-malignant disorders. In multivariate analysis, cell dose was the only unit-related factor associated with outcomes. Our results reflect the benefit on clinical outcomes of the strategy adopted by the Network to bank units with higher cell counts.

Changes of Contamination Rate and Microorganism Evaluation in Organ-Cultured Human Corneas: A 14-Year Review From a French Regional Eye Bank.

PURPOSE: This study aimed to assess how the contamination rate of organ-cultured corneas has evolved and to analyze the evolution of microorganisms involved. METHODS: Data from the Besançon eye bank were reviewed over 14 years (2005-2018). The changes in the contamination rate and the contaminant species found during the organ culture storage were analyzed. Microbiological tests were performed twice on the storage media-at day 5 and before the deswelling phase. RESULTS: Among the 17,979 donor corneas collected, 1240 corneas were microbiological-test positive. The average annual contamination rate was 6.8% (range: 5.2%-8.9%). Seventy-five percent of contaminations were bacterial. The most frequently found bacterium was Staphylococcus spp. (31.3%), followed by non-Enterobacteriaceae Gram-negative Bacilli (GNB) (27.3%), with most Sphingomonas spp. and Pseudomonas spp. Fungal contamination (21.9%) was dominated by Candida (82.7%). Seventy-seven types of microorganisms were identified. The Staphylococcus rate tended to decrease, whereas non-Enterobacteriaceae GNB rate has increased in the past few years to reach 46% of bacteria. Most of the contaminations were detected in the early phase of organ culture at day 5 (89.2%). The second microbiological test found 44.8% of fungal contaminations (predominantly Candida spp.). CONCLUSIONS: The annual contamination rate was stable and remains low, but the types of contaminating microorganisms varied from year to year. Staphylococcus spp. and non-Enterobacteriaceae GNB accounted for a significant proportion of the contaminations. We found a significant proportion of contamination, especially fungal, at the late phase of storage. Reassessing the antibiotics and antifungals in the storage medium may be useful to limit corneal disposal.

Therapeutic leukapheresis and thrombapheresis in medical emergencies.

The management of hyperleukocytosis or thrombocytosis by therapeutic cytapheresis in the early 21 st century is far from codified (universal). Therapeutic cytapheresis have been proposed to achieve more rapid cytoreduction in peripheral blood than old universal support in order to quickly prevent potential complications. But, there are no randomized studies demonstrating the superiority of cytapheresis over other treatments alone. In this short review, based on our own experience (since 1980), we will give the indications and the role of cytapheresis procedures and we will try to answer the questions: when is therapeutic cytapheresis appropriate and do they still have a place in 2020, especially as a medical emergency?

Altered thymic CD4+ T-cell recovery after allogeneic hematopoietic stem cell transplantation is critical for nocardiosis.

PURPOSE OF THE STUDY: Nocardia affects immunocompromised human host exhibiting an altered cell-mediated immunity. Infectious risk after allogeneic hematopoietic cell transplantation (AHCT) is significantly correlated to the recovery status of donor-derived immune system, especially CD4+ T-cells reconstitution and thymopoiesis. The purpose of this paper is to highlight a lack of cell-mediated immunity recovery for patients presenting a nocardiosis compared to a control cohort. PATIENTS AND METHODS: This is a case control retrospective monocentric study. We retrospectively analyzed a monocentric cohort of 15 cases of nocardiosis after AHCT and we explored the degree of patients' immunosuppression by phenotyping circulating lymphoid subpopulations, including NK cells, CD8+ T-cells, CD4+ T-cells and CD19+ B-cells. We focused on CD4+ T-cell subsets to appreciate thymic output, especially on naive CD4+ T-cells (NTE, CD45RA+/RO- CD4+ T-cells) and recent thymic emigrants (RTE, CD4+CD45RA+/RO-/CD31+). Infected patients were paired with a control cohort of patients with identical transplantation characteristics screened on hematological disease, AHCT conditioning, primary graft-versus-host disease (GHVD) prophylaxis, graft type, sex, age, and season at the AHCT and data concerning immunological reconstitution were compared. RESULTS: At onset of nocardiosis, circulating lymphocytes and CD4+ T-cells means count were respectively 730/µL and 162/µL. CD8+ T-cells, CD56+ NK cells and CD19+ B-cells means count were respectively 362/µL, 160/µL, 112/µL. CD4+ T-cells subpopulations, naïve CD4+ T-cells production was impaired with NTE and RTE means count at 26/µL and 11/µL respectively. Comparison between nocardiosis cohort and control cohort over time highlight significant lower cellular count for lymphocytes, CD4+ T-cells, NTE and RTE with p = 0.001, p < 0.001, p < 0.001, p < 0.001 respectively. CONCLUSION: Immune recovery monitoring follow-up after AHCT is of particular importance to identify patients susceptible to develop Nocardiosis. Efficient microbiological investigations toward Nocardia such PCR should be used in case of compatible clinical presentation.

In vitro osteodifferentiation of intact human amniotic membrane is not beneficial in the context of bone repair.

The human amniotic membrane (hAM) is an attractive biomaterial for regenerative medicine, as it contains amniotic mesenchymal stromal cells (hAMSC), epithelial cells (hAEC) and growth factors. We examined the potential use of hAM in orthopaedic and maxillofacial bone surgery, integrating the requirements of current regulations regarding advanced therapy medicinal products (ATMP) in the European Union. Previous studies have described the potential osteodifferentiation of intact hAM during whole-tissue culture in osteogenic conditions. The present study aims to determine whether in vitro osteodifferentiation of hAM is needed in the context bone repair, and the influence of this process on tissue structure, cell phenotype and cell function. Different conditions (fresh or cultured hAM; intact or hAM-derived cells) were tested. Phenotypic and functional analyses were performed with standard approaches (cell culture and staining, histological and immunolabelling) as well as original approaches (tissue staining, energy dispersive X-ray and X-ray diffraction). In our study, non-osteodifferentiated hAM (i.e., fresh or native hAM) exhibited innate pre-osteoblastic potential. Osteodifferentiation of fresh hAM induced a change in tissue structure, cell phenotype and function. Therefore, we hypothesize that pre-osteodifferentiation may not be necessary, especially if it induces unwanted changes. To our surprise, in these osteogenic conditions, hAEC had a mesenchymal phenotype with osteocyte function, and even native synthesis of hydroxyapatite, focusing osteogenic potential mainly in this epithelial layer. In conclusion, in vitro osteodifferentiation by tissue culture does not appear to be necessary for hAM to be used as an innovative ATMP for bone repair.

Da Vinci Xi Robot-Assisted Penetrating Keratoplasty.

PURPOSE: This study aims (1) to investigate the feasibility of robot-assisted penetrating keratoplasty (PK) using the new Da Vinci Xi Surgical System and (2) to report what we believe to be the first use of this system in experimental eye surgery. METHODS: Robot-assisted PK procedures were performed on human corneal transplants using the Da Vinci Xi Surgical System. After an 8-mm corneal trephination, four interrupted sutures and one 10.0 monofilament running suture were made. For each procedure, duration and successful completion of the surgery as well as any unexpected events were assessed. The depth of the corneal sutures was checked postoperatively using spectral-domain optical coherence tomography (SD-OCT). RESULTS: Robot-assisted PK was successfully performed on 12 corneas. The Da Vinci Xi Surgical System provided the necessary dexterity to perform the different steps of surgery. The mean duration of the procedures was 43.4 ± 8.9 minutes (range: 28.5-61.1 minutes). There were no unexpected intraoperative events. SD-OCT confirmed that the sutures were placed at the appropriate depth. CONCLUSIONS: We confirm the feasibility of robot-assisted PK with the new Da Vinci Surgical System and report the first use of the Xi model in experimental eye surgery. Operative time of robot-assisted PK surgery is now close to that of conventional manual surgery due to both improvement of the optical system and the presence of microsurgical instruments. TRANSLATIONAL RELEVANCE: Experimentations will allow the advantages of robot-assisted microsurgery to be identified while underlining the improvements and innovations necessary for clinical use.

Corneal transplantation: study of the data of a regional eye bank for the year 2013 and analysis of the evolution of the adverse events reported in France since 2010.

To analyze the data of the adverse events collected in a single major eye bank (EFS Bourgogne Franche Comté, Besançon, France) for the year 2013 and to report the French data of biovigilance provided by the French National Agency for Medicines and Health Products Safety (ANSM) between 2010 and 2013. we have set up a study of adverse events in 2013, in collaboration with a single eye bank (EFS Bourgogne Franche Comté, Besançon, France). A survey was sent to the surgeon for each delivered corneal button by the eye bank in 2013. They were asked for each grafted patient performed in their center, the type of graft (penetrating keratoplasty, anterior keratoplasty or endothelial keratoplasty), the occurrence of adverse events (primary failure, infectious keratis, endophthalmitis, immune rejection, and other events) and the time interval between surgery and events (Less than 1 postoperative month, between 1 month and 1 year postoperatively, >1 year postoperatively). In 2013, 407 corneal buttons were delivered by the eye bank of Besançon in 21 medical centers which performed corneal grafts and we sent 407 surveys. We received 243 completed questionnaires (59.75%) from 11 centers (52.38%). The global reported rate of adverse events was 27.54% of the graft (n = 65/236 corneal grafts performed in 11 centers in 2013; 20% of Primary graft failure, 11% of infectious keratitis, 1% of endophthalmitis, 34% of rejection, 34% of other incidents). 30.16% of complications were noticed before the first month after surgery versus 52.38% of complications noticed between the first month and the first year after surgery and 17.46% of complications noticed after the post-operative first year The most common causes of adverse events after PK were Immune rejection (13.17%), surgical causes (5.98%) and infection (4.79%) and after EK were Primary graft failure (8.2%) and surgical causes (19.67%). In 2013, in France 0.83% of adverse events were notified in ANSM. For the 236 performed graft issued from a major eye bank (EFS Besançon) in 2013 the global reported rate of post-graft adverse events was 27.54% of the grafts (20% of Primary graft failure, 11% of infectious keratitis, 1% of endophthalmitis, 34% of rejection and 34% of other incidents). Compared to the ANSM data (0.83% of adverse events reported in 2013) this rate is high. This difference can be explained by the low rate of annual notification to the ANSM and shows that biovigilance in France must be more developed. Since biovigilance needs constant improvement for the safety of the graft system, training, information for practitioners, simplifications of procedures and international standardization of the definition are the main points that could be improved.

Impact of CTLA4 genotype and other immune response gene polymorphisms on outcomes after single umbilical cord blood transplantation.

We evaluated the impact of recipient and cord blood unit (CBU) genetic polymorphisms related to immune response on outcomes after unrelated cord blood transplantations (CBTs). Pretransplant DNA samples from 696 CBUs with malignant diseases were genotyped for NLRP1, NLRP2, NLRP3, TIRAP/Mal, IL10, REL, TNFRSF1B, and CTLA4. HLA compatibility was 6 of 6 in 10%, 5 of 6 in 39%, and ≥4 of 6 in 51% of transplants. Myeloablative conditioning was used in 80%, and in vivo T-cell depletion in 81%, of cases. The median number of total nucleated cells infused was 3.4 × 107/kg. In multivariable analysis, patients receiving CBUs with GG-CTLA4 genotype had poorer neutrophil recovery (hazard ratio [HR], 1.33; P = .02), increased nonrelapse mortality (NRM) (HR, 1.50; P < .01), and inferior disease-free survival (HR, 1.41; P = .02). We performed the same analysis in a more homogeneous subset of cohort 1 (cohort 2, n = 305) of patients who received transplants for acute leukemia, all given a myeloablative conditioning regimen, and with available allele HLA typing (HLA-A, -B, -C, and -DRB1). In this more homogeneous but smaller cohort, we were able to demonstrate that GG-CTLA4-CBU was associated with increased NRM (HR, 1.85; P = .01). Use of GG-CTLA4-CBU was associated with higher mortality after CBT, which may be a useful criterion for CBU selection, when multiple CBUs are available.

[Modalities for preparation, cryopreservation, thawing of hematopoietic stem cells and precautions for infusion to patient: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Modalités de préparation, cryopréservation, décongélation des cellules souches hématopoïétiques et précautions pour infusion au patient : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

To date, despite an existing regulatory framework and standards, there are no true technical recommendations. A survey of 23 cell processing facilities (France, Belgium and Switzerland) has allowed to overview current practices according to cellular products specifications upon arrival at the facility, with modalities for their preparation prior to cryopreservation, storage, thawing and finally for infusion to patient. Data analysis shows great variability of collected volumes and cell concentrations in cellular products. Despite homogeneous practices for handling cells at the facility, methods vary between centers, especially for the choice of cryoprotective solutions and thawing methods. During the workshop, practices have been discussed and summarized to write of recommendations about the following topics: processing and cryopreservation, thawing, bedside precautions (for infusion). This work identifies some improvements in terms of collection, choice of wash solution of thawed cells and validation of the conditions of carriage.

Evaluation of microbial contamination of corneal transplants: one-year report from a French regional eye bank.

PURPOSE: The aim of this study was to report the rate of corneal transplant microbial contamination in a single major eye bank and to identify the contributive factors. METHODS: The contamination rate of 1156 organ-cultured corneas harvested in 2010 in a single eye bank (EFS Bourgogne Franche-Comté, Besançon, France) was studied together with the following factors: age, sex, tissue-recovery method (single or multiorgan donors), death-to-excision time, excision-to-reception time, cause of death, positive serology, and endothelial cell count. Student t test for quantitative data was used for statistical comparisons between groups. Qualitative data were assessed using the χ test. RESULTS: The contamination rate was 5.5%. Most contaminations were of bacterial origin (77.9%), with Staphylococcus species (62.3%) being predominant. Fungal contaminations (19.1%) were dominated by Candida species (76.9%). Death resulting from cancer was related to a higher risk of corneal contamination (P < 0.001). The other factors were not related to an increased risk of contamination. CONCLUSIONS: The rate of microbiological contamination of corneal transplants remains low. However, special caution should be exercised with grafts collected from patients dying from cancer. To minimize this risk, further studies on the antibacterial effect of the conservation media should be conducted in the context of increased bacterial resistance.

Engraftment kinetics and graft failure after single umbilical cord blood transplantation using a myeloablative conditioning regimen.

Umbilical cord blood transplant recipients are exposed to an increased risk of graft failure, a complication leading to a higher rate of transplant-related mortality. The decision and timing to offer a second transplant after graft failure is challenging. With the aim of addressing this issue, we analyzed engraftment kinetics and outcomes of 1268 patients (73% children) with acute leukemia (64% acute lymphoblastic leukemia, 36% acute myeloid leukemia) in remission who underwent single-unit umbilical cord blood transplantation after a myeloablative conditioning regimen. The median follow-up was 31 months. The overall survival rate at 3 years was 47%; the 100-day cumulative incidence of transplant-related mortality was 16%. Longer time to engraftment was associated with increased transplant-related mortality and shorter overall survival. The cumulative incidence of neutrophil engraftment at day 60 was 86%, while the median time to achieve engraftment was 24 days. Probability density analysis showed that the likelihood of engraftment after umbilical cord blood transplantation increased after day 10, peaked on day 21 and slowly decreased to 21% by day 31. Beyond day 31, the probability of engraftment dropped rapidly, and the residual probability of engrafting after day 42 was 5%. Graft failure was reported in 166 patients, and 66 of them received a second graft (allogeneic, n=45). Rescue actions, such as the search for another graft, should be considered starting after day 21. A diagnosis of graft failure can be established in patients who have not achieved neutrophil recovery by day 42. Moreover, subsequent transplants should not be postponed after day 42.

Validation of an automated blood culture system for sterility testing of cell therapy products.

BACKGROUND AIMS: Automated blood culture systems are widely used for the detection of microorganisms in cell therapy products. However, they are not validated by the manufacturers for this purpose. The aim of this study was to assess the ability of the Bactec system (Becton-Dickinson, Le Pont-De-Claix, France) to detect the microorganisms that could contaminate cell therapy products. METHODS: Three types of vials and conditions were tested: Plus Aerobic/F and Anaerobic/F media incubated at 35°C and Mycosis IC/F medium incubated at 30°C. All vials were incubated 10 days. We tested 18 microorganisms, including slow growers and some with fastidious nutritional requirements (10 bacteria, four yeasts, four filamentous fungi), each with four inocula (10-10(4) colony-forming units) performed in quintuplicate. RESULTS: The combination of Plus Aerobic/F and Plus Anaerobic/F vials detected all the tested pathogenic bacteria, all the tested Gram-positive skin commensal or environmental bacteria, all the tested yeasts, and three of four tested filamentous fungi. The addition of the Mycosis IC/F vial extended the range of detected microorganisms to one fungal environmental contaminant. Two bacterial environmental contaminants were not detected by our method. Low inocula of the skin contaminant Propionibacterium acnes were detected only after 7 days of incubation. CONCLUSIONS: These data suggest that (i) the prolongation of the incubation time of Plus Aerobic/F and Plus Anaerobic/F vials from 7 to 10 days and (ii) the use of Mycosis IC/F medium make minor contributions in the sterility testing of cell therapy products. We have validated the Bactec method using aerobic and anaerobic vials incubated 7 days at 35°C.

Incidence and risk factors of anti-HLA immunization after pregnancy.

Pregnancy is the only natural source of anti-HLA immunization. The exact frequency of this immunization remains undetermined as prior studies either used methods with a low sensitivity or were performed late after delivery. We present here the first study on women at delivery evaluating anti-HLA immunization by Luminex. We also attempted to isolate factors influencing immunization, such as soluble HLA-G (sHLA-G) levels and genetic polymorphisms. With Luminex, anti-HLA immunization was observed in 54.4% of the women. As expected, immunization frequency increased with the number of children, reaching 74% in women with >2 deliveries. Among immunized women, strong cytotoxic Ab (as detected by Complement Dependent Cytotoxicity) were associated with a lower level of sHLA-G. None of the studied polymorphisms influenced immunization rate in the whole cohort. Among 94 first pregnant women with no history of miscarriage, the -174 IL-6 gene promoter mutation (G/C) appeared more frequently in non immunized women (69% vs. 45% in immunized ones, p=0.02). Lastly, the occurrence of a miscarriage before the first live delivery significantly decreased immunization. These results may help to understand mechanisms of pregnancy induced immunization. They also have an impact in the management of previous pregnant women requiring organ or hematopoietic stem cell transplantation.

Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy.

Transplantation-related mortality (TRM) is high after HLA-mismatched umbilical cord blood (UCB) transplantation (UCBT). In utero, exposure to noninherited maternal antigen (NIMA) is recognized by the fetus, which induces T regulator cells to that haplotype. It is plausible that UCBTs in which recipients are matched to donor NIMAs may alleviate some of the excess mortality associated with this treatment. To explore this concept, we used marginal matched-pair Cox regression analysis to compare outcomes in 48 NIMA-matched UCBTs (ie, the NIMA of the donor UCB unit matched to the patient) and in 116 non-NIMA-matched UCBTs. All patients had a hematologic malignancy and received a single UCB unit. Cases and controls were matched on age, disease, disease status, transplantation-conditioning regimen, HLA match, and infused cell dose. TRM was lower after NIMA-matched UCBTs compared with NIMA-mismatched UCBTs (relative risk, 0.48; P = .05; 18% versus 32% at 5 years posttransplantation). Consequently, overall survival was higher after NIMA-matched UCBT. The 5-year probability of overall survival was 55% after NIMA-matched UCBTs versus 38% after NIMA-mismatched UCBTs (P = .04). When faced with the choice of multiple HLA-mismatched UCB units containing adequate cell doses, selecting an NIMA-matched UCB unit may improve survival after mismatched UCBT.