Is there any impact of HLA-DPB1 disparity in 10/10 HLA-matched unrelated hematopoietic SCT? Results of a French multicentric retrospective study.

We retrospectively analyzed the impact of HLA-DPB1 mismatches in a large cohort of 1342 French patients who underwent 10/10 HLA-matched unrelated HSCT. A significant impact of HLA-DPB1 allelic mismatches (2 vs 0) was observed in severe acute GVHD (aGVHDIII-IV) (risk ratio (RR)=1.73, confidence interval (CI) 95% 1.09-2.73, P=0.019) without impact on OS, TRM, relapse and chronic GVHD (cGVHD). According to the T-cell epitope 3 (TCE3)/TCE4 HLA-DPB1 disparity algorithm, 37.6% and 58.4% pairs had nonpermissive HLA-DPB1, respectively. TCE3 and TCE4 disparities had no statistical impact on OS, TRM, relapse, aGVHD and cGVHD. When TCE3/TCE4 disparities were analyzed in the graft-vs-host or host-vs-graft (HVG) direction, only a significant impact of TCE4 nonpermissive disparities in the HVG direction was observed on relapse (RR=1.34, CI 95% 1.00-1.80, P=0.048). In conclusion, this French retrospective study shows an adverse prognosis of HLA-DPB1 mismatches (2 vs 0) on severe aGVHD and of nonpermissive TCE4 HVG disparities on relapse after HLA-matched 10/10 unrelated HSCT.

[Impact of anti-HLA antibodies on outcomes of allogeneic stem cell transplantation: a report by the SFGM-TC]. / Impact des anticorps anti-HLA sur le devenir de l'allogreffe de cellules souches hématopoïétiques : un rapport par la SFGM-TC.

The role of anti-HLA antibodies in allogeneic stem cell transplantation setting is still unclear. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This article offers the recommendations of the group that considered the impact that have anti-HLA antibodies on outcomes in allogeneic stem cell transplantation.

[Allogeneic stem cell transplantation from an HLA-haploidentical related donor: SFGM-TC recommendations (Part 1)]. / Greffes de cellules souches hématopoïétiques à partir d'un donneur haplo-identique : recommandations de la SFGM-TC (première partie).

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part one of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.

[Allogeneic stem cell transplantation from an HLA-haploidentical related donor: SFGM-TC recommendations (part 2)]. / Greffes de cellules souches hématopoïétiques à partir d'un donneur haploidentique : recommandations de la SFGM-TC (deuxième partie).

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part two of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.

The emerging role of Twist proteins in hematopoietic cells and hematological malignancies.

Twist1 and Twist2 (Twist1-2) are two transcription factors, members of the basic helix-loop-helix family, that have been well established as master transcriptional regulators of embryogenesis and developmental programs of mesenchymal cell lineages. Their role in oncogenesis in epithelium-derived cancer and in epithelial-to-mesenchymal transition has also been thoroughly characterized. Recently, emerging evidence also suggests a key role for Twist1-2 in the function and development of hematopoietic cells, as well as in survival and development of numerous hematological malignancies. In this review, we summarize the latest data that depict the role of Twist1-2 in monocytes, T cells and B lymphocyte activation, and in associated hematological malignancies.

ENTPD1/CD39 is a promising therapeutic target in oncology.

Regulatory T cells (Tregs) are a subpopulation of CD4(+) T cells that are essential for maintaining the homeostasis of the immune system, limiting self-reactivity and excessive immune responses against foreign antigens. In cancer, infiltrated Tregs inhibit the effector lymphocytes and create a favorable environment for the growth of the tumor. Although Tregs mediate immunosuppression through multiple, non-redundant, cell-contact dependent and independent mechanisms, a growing body of evidence suggests an important role for the CD39-CD73-adenosine pathway. CD39 ectonucleotidase is the rate-limiting enzyme of a cascade leading to the generation of suppressive adenosine that alters CD4 and CD8 T cell and natural killer cell antitumor activities. Here, we review the recent literature supporting CD39 as a promising therapeutic target in oncology. In vitro and in vivo experiments involving knockout models and surrogate inhibitors of CD39 provide evidence in support of the anticancer activity of CD39 inhibition and predict a favorable safety profile for CD39 inhibitory compounds. In addition, we report the ongoing development of CD39-blocking monoclonal antibodies as potential anticancer drugs. Indeed, CD39 antagonistic antibodies could represent novel therapeutic tools for selectively inhibiting Treg function without depletion, a major limitation of current Treg-targeting strategies.

[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.

Reduced intensity conditioning: enhanced graft-versus-tumor effect following dose-reduced conditioning and allogeneic transplantation for refractory lymphoid malignancies after high-dose therapy.

Non-myeloablative regimens have been proven to allow engraftment following allogeneic stem cells transplantation (allo-SCT) with minimal procedure-related toxicity. Conventional allo-SCT may produce remissions in patients with relapsed and refractory lymphoid malignancies (LM) but these good results may be achieved at the cost of high treatment-related morbidity and mortality. Application of allo-SCT using less intensive regimens may temper the frequency of these complications, allowing a potent graft-versus-tumor effect (GVT). We present our data on 11 patients with LM receiving allo-SCT with a reduced regimen. Ten patients had received previous high-dose therapy, and were at high risk for toxicity, thus precluding the use of allo-SCT. A fludarabine and low-dose busulfan combination facilitated engraftment while exerting GVT. Hematological recovery was quick, and full donor T cell chimerism preceded acute GVHD. GVHD and infections were the major problems. Spontaneous acute GVHD occurred in eight patients (72%). Five patients (45%) achieved complete remission, and the GVT effect was closely associated with GVHD. These results support the concept that GVT is effective against LM in patients who have been heavily pretreated. Further studies are needed to investigate strategies to generate more specific alloreactive effects providing optimal GVT and an acceptable risk of GVHD and infections.

Outcomes in patients with incipient undifferentiated arthritis.

OBJECTIVE: To determine outcomes in patients with onset within the last year of peripheral inflammatory arthritis that does not meet classification criteria for any specific disease. METHODS: Symptoms and laboratory tests were evaluated at baseline and 14 to 60 months later in 43 patients, 32 women and 11 men, with a mean age of 50 years. RESULTS: At baseline, a presumptive clinical diagnosis was made in 16 of the 43 patients. Diagnoses at last follow-up were undifferentiated inflammatory arthritis in seven cases, mild rheumatoid arthritis in 18, psoriatic arthritis in two, Sjögren's syndrome in two, lupus in one, and paraneoplastic syndrome in one. The remaining 12 patients were free of inflammatory joint symptoms; three had symptoms of osteoarthritis and nine were asymptomatic. Factors present at baseline and predictive of progression to definite rheumatoid arthritis were a positive test for rheumatoid factor, presence of an HLA DRB1*04 allele, and a presumptive clinical diagnosis of rheumatoid arthritis. CONCLUSION: 55% of our patients developed a specific inflammatory joint disease, and 42% developed rheumatoid arthritis, which was consistently mild. Resolution of all inflammatory joint symptoms occurred in 28% of cases. A number of clinical laboratory, and genetic findings of use for predicting the outcome of undifferentiated arthritis were identified.

Detection of antigen receptor gene rearrangements in lymphoproliferative malignancies by fluorescent polymerase chain reaction.

Monoclonal rearrangements of antigen receptor genes in lymphoproliferative diseases are characterized by the specific sequence and the length of their junctional region, which can be used as markers of the proliferating clone. PCR techniques have greatly simplified routine detection of monoclonal rearrangements. But on the one hand, identification of the sequences requires sequencing methods and on the other hand, sizing of rearrangements by conventional analysis of PCR products on agarose or nondenaturing polyacrylamide gels may be uncertain. We have developed an approach based on amplification of rearranged IGH, TCRG and TCRD locus by fluorescent PCR associated to a computerized analysis of generated PCR products allowing their objective sizing. We tested this method on DNA samples from patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia, whose pattern of IGH and TCRG rearrangements had been previously identified by Southern blot techniques. TCRG-PCR assay allowed detection of 100% of rearranged samples. No false-negative results were found but a high rate (60%) of Southern-negative and PCR-positive samples were identified. TCRD PCR-assay detected VD1-JD1 or VD2-D2/3 rearrangements in both acute lymphoblastic leukemia and chronic lymphocytic leukemia samples. IGH PCR assay permitted detection of all known rearranged samples. The sensitivity of these three different PCR assays (1% leukemic cells) was equivalent to that of other published PCR protocols. These results show the validity and reliability of the fluorescent PCR method for routine detection of IGH, TCRG and TCRD rearrangements. Sizing of PCR products by computerized analysis was also validated. It provides additional information on rearrangement patterns in lymphoproliferative diseases, as clonal rearrangements can be recognized by their size. This can be of great interest in various circumstances, particularly for detection and follow-up of oligoclonality.

Lethal acute graft-versus-host disease in a liver transplant recipient: relations with cell migration and chimerism.

We report herein the case of a patient who developed fatal acute graft-versus host disease (GvHD) after liver transplantation (LT). GvHD occurred 18 days after LT and was characterized by skin epidermolysis, diarrhea and leucopenia. Skin biopsy showed epidermal dyskeratosis with epithelial necrosis, a lesion consistent with GvHD. Despite immunosuppressive therapy, the patient died within 24 days. In our observation, GvHD occurred although five HLA compatibilities were identified between the donor and the recipient, an apparently favorable and uncommon situation. This case further supports the qualification that LT may be complicated by GvHD and strongly suggests that minor rather than major histocompatibility antigens are the main target of allogenic interactions of GvHD. The involvement of chimerism in GvHD is controversial and requires further investigation.

Generic HLA-DRB1 gene oligotyping by a nonradioactive reverse dot-blot methodology.

HLA-DRB1 allelic specificities can be determined using SSOs annealing to their complementary PCR-amplified target DNA. To perform HLA-DR oligotyping routinely for donors and recipients of bone marrow transplantation, a "reverse" dot-blot technique has been developed that consists in the hybridization of labeled PCR-amplified target DNA to SSOs that have been first attached to nitrocellulose membranes. The 15 oligonucleotides chosen enabled the following HLA-DRB1 "generic" specificities to be defined: DR1, BON, 2, 3, 4, 11, 11 JVM, 12, 13, 13 HAG, 14, 7, 8, 9, 10. The genomic DNA was amplified by asymetric PCR with incorporation of biotinylated deoxynucleotides predominantly to generate labeled single-stranded DNA. Hybridization between specific immobilized oligoprobes and target DNA was nonradioactively detected by a colorimetric reaction using alkaline phosphatase. The reverse dot-blot methodology was successfully tested, first, for the determination of HLA-DR4 subspecificities, and then the procedure was routinely applied to the generic HLA-DR oligotyping of bone-marrow donors and recipients.

[Hemorrhagic necrosis of the mesenteric lymph nodes in adult celiac disease. Physiopathologic interpretation of 1 case]. / Nécrose hémorragique des ganglions mésentériques dans la maladie coeliaque de l'adulte. Interprétation physiopathologique à propos d'un cas.

The authors report the case of a 35 year old woman dead of cachexia in the course of a refractory adult coeliac disease. The autopsy revealed multiple lymphadenopathies exclusively found in the small intestinal mesentery; all these lymph nodes were destroyed by an extensive haemorrhagic necrosis. There was neither lymphoma nor cavitation. These original findings are interpreted as the consequence of a localized intravascular coagulation, and probably a step towards cavitation or atrophy.