Serum 2-Hydroxyglutarate Level Is a Prognostic Marker in Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1433-1433
Author(s):  
Jing-Han Wang ◽  
Wen-Lian Chen ◽  
Tian-Lu Chen ◽  
Yong-Mei Zhu ◽  
Wei-Na Zhang ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Conflicts Of Interest ◽  
Methylation Status ◽  
Gene Mutations ◽  
Serum Levels ◽  
Hematologic Malignancies ◽  
High Serum ◽  
Independent Prognostic Marker ◽  
High Level ◽  
The Impact

Abstract Abstract 1433 BACKGROUND High levels of 2-HG in serum were found among AML cases with IDH1/IDH2 mutations. However, the impact of 2-HG levels on biological characteristics and clinical outcomes has not been systematically evaluated in a large cohort of AML patients. METHODS Serum 2-HG levels in 699 patients with hematologic malignancies, including 405 AML patients, were measured by GC-TOFMS. Clinical prognostic power of 2-HG and genetic risk factors associated with 2-HG were also evaluated in AML patients. RESULTS Among all patients with hematopoietic malignancies investigated, high serum 2-HG levels were observed only in AML group. 64 out of 405 (15.8%) AML patients displayed aberrantly higher levels (7.14±2.11μg/ml) of 2-HG. Compared to cases with normal 2-HG (3.65±1.02μg/ml), these patients showed a higher prevalence in AML-M0/M1 subtypes, a closer correlation with mutated IDH1/2 genes, a distinct gene expression profile and an aberrant DNA methylation status in bone marrow blasts. Additionally, the patients with high 2-HG were associated with higher serum levels of α-ketoglutarate (α-KG) and glutamate, suggesting presence of impaired metabolic pathway involved in the biosynthesis of 2-HG. Univariate and multivariate analyses indicate that high level of 2-HG is among the most significant negative indicators for complete remission (CR) rate, overall survival (OS) and event-free survival (EFS) either in all AML cases or in cases with cytogenetically normal AML (CN-AML). CONCLUSIONS Serum 2-HG is an independent prognostic marker in AML. Patients with high 2-HG had significantly higher frequency of IDH1/IDH2 gene mutations and unfavorable prognosis compared to those with normal 2-HG. Disclosures: No relevant conflicts of interest to declare.

scholarly journals POS0329 GASTROINTESTINAL INVOLVEMENT IN SYSTEMIC SCLEROSIS: PATHOGENETIC ROLE OF GUT MICROBIOME, CYTOKINES AND ADIPOKINES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 392.1-392
Author(s):  
E. Pigatto ◽  
M. Schiesaro ◽  
M. Caputo ◽  
M. Beggio ◽  
P. Galozzi ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Gut Microbiome ◽  
Serum Levels ◽  
High Serum ◽  
Healthy Population ◽  
Gastrointestinal Involvement ◽  
Degrading Bacteria ◽  
Gi Symptoms ◽  
Low Levels ◽  
The Impact

Background:Gastrointestinal (GI) involvement is very common in patients with Systemic Sclerosis (SSc). The pathophysiology of GI manifestations has not yet been defined. Cell-mediated immunological reactions appear to lead to endothelial damage resulting in fibrosis. The risk of developing malnutrition reinforces the need to better understand GI pathophysiology in these patients.Objectives:The study aimed to evaluate GI symptoms (GIT 2.0) and malnutrition status (MUST) and to determine specific bacterial changes in gut microbiome by investigating the possible presence of positive hot spots in bacterial species in SSc patients and their potential role in the disease progression. We also evaluated serum levels of adipokines and cytokines involved in the pathogenesis of SSc and their role, in addition to gut microbiome, in predicting the onset of GI involvement and malnutrition in SSc patients.Methods:We enrolled 25 scleroderma patients (EULAR/ACR 2013 criteria). UCLA-SCTC GIT 2.0 questionnaire to evaluate GI symptoms and MUST to investigate the risk of malnutrition were used. Gut microbiome was analyzed and the samples were subjected to extraction for the 16S rRNA gene (Earth Microbiome Project and the NIH-Human Microbiome Project). The microbiome was investigated at phenotypic and genotypic level. Serum levels of cytokines and adipokines (adiponectin and leptin) were evaluated by ELISA.Results:79.9% of patients had GERD and 63.5% abdominal distension at GIT 2.0 questionnaires. 48% of patients had moderate risk of malnutrition (MUST=2) and 12% had high risk (MUST=3). Gut microbioma: 19 patients (76%) had low similarity and 11 (44%) low diversity compared to the healthy population. The prevailing enterotypes of gut microbiome was Bacteroides (80%) and Prevotella (20%). The genotypic evaluation showed a reduced concentration of: gluten-digesting (Lactobacillus); lactose-digesting (Faecalibacterium); vitamin K-producing (Enterococcus, Desulfovibrio and Veillonella); acetaldehyde-degrading bacteria. 24 patients (96%) showed a reduction in bacteria devoted to maintaining weight control (Bifidobacterium and Ruminococcus). The patients had an altered intestinal permeability with less mucolytic bacteria (Bacteroides) and reduced production of LPS (Enterobacter and Escherichia). Low levels of butyrate (Eubacterium and Clostridium), acetate and propionate were found for SCFA-producing bacteria. Potentially pathogenic bacteria were also investigated: Salmonella was found in 14 (56%), Klebsiella in 9 (36%) and Enterococcus Faecalis in 3 (12%) patients. 11 (44%) patients had elevated serum levels of IL10 and IL12; 4 (16%) had high value of leptin. Correlation was found in patients who had a reduced concentration of gluten-digesting bacteria and MUST. Elevated MUST was correlated with serological increase in IL17A and IFN-α. Serum levels of IL12 and IL10 were found to correlate with specific bacteria alterations: high concentration of acetaldehyde-producing bacteria and low levels of acetaldehyde-degrade bacteria (also correlated with high serum levels of IL6), mucolytic bacteria and producers of hydrogen sulphide, acetate and propionate. Finally, reduced levels of mucolytic bacteria and acetate producing bacteria correlated with high serum leptin levels.Conclusion:The relationship between the gut microbiome and SSc seems to be multifactorial. In our study genotypic changes of gut microbioma might play a role in damaging the permeability of the mucosa and increasing risk of malnutrition. The evaluation of gut microbiome and cytokine profile is probably going to be of value in the follow-up of SSc. However, further studies are needed to clarify the impact of GI dysbiosis on the immune system in SSc.References:[1]Patrone V. et al. Gut microbiota profile in systemic sclerosis patients with and without clinical evidence of gastrointestinal involvement, Sci Rep. 2017; 7: 14874Disclosure of Interests:None declared

scholarly journals A Versatile Macromer-Based Glycosaminoglycan (sHA3) Decorated Biomaterial for Pro-Osteogenic Scavenging of Wnt Antagonists

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1037
Author(s):  
Mathis Gronbach ◽  
Franziska Mitrach ◽  
Stephanie Möller ◽  
Sandra Rother ◽  
Sabrina Friebe ◽  
...  
Keyword(s):  
Serum Levels ◽  
Bone Defects ◽  
High Serum ◽  
Qualitative And Quantitative Analysis ◽  
Negative Effects ◽  
Bone Defect Healing ◽  
2D System ◽  
Surface Decoration ◽  
The Impact ◽  
Regeneration Of Bone

High serum levels of Wnt antagonists are known to be involved in delayed bone defect healing. Pharmaceutically active implant materials that can modulate the micromilieu of bone defects with regard to Wnt antagonists are therefore considered promising to support defect regeneration. In this study, we show the versatility of a macromer based biomaterial platform to systematically optimize covalent surface decoration with high-sulfated glycosaminoglycans (sHA3) for efficient scavenging of Wnt antagonist sclerostin. Film surfaces representing scaffold implants were cross-copolymerized from three-armed biodegradable macromers and glycidylmethacrylate and covalently decorated with various polyetheramine linkers. The impact of linker properties (size, branching) and density on sHA3 functionalization efficiency and scavenging capacities for sclerostin was tested. The copolymerized 2D system allowed for finding an optimal, cytocompatible formulation for sHA3 functionalization. On these optimized sHA3 decorated films, we showed efficient scavenging of Wnt antagonists DKK1 and sclerostin, whereas Wnt agonist Wnt3a remained in the medium of differentiating SaOS-2 and hMSC. Consequently, qualitative and quantitative analysis of hydroxyapatite staining as a measure for osteogenic differentiation revealed superior mineralization on sHA3 materials. In conclusion, we showed how our versatile material platform enables us to efficiently scavenge and inactivate Wnt antagonists from the osteogenic micromilieu. We consider this a promising approach to reduce the negative effects of Wnt antagonists in regeneration of bone defects via sHA3 decorated macromer based macroporous implants.

Gvhd Severity Is Regulated by the Adoptive Transfer Low Numbers of NKT Cells by a Mechanism Distinct From CD4+CD25+ Regulatory T Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 229-229
Author(s):  
Dennis Leveson-Gower ◽  
Janelle Olson ◽  
Emanuela I Sega ◽  
Jeanette Baker ◽  
Robert Zeiser ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Adoptive Transfer ◽  
Conflicts Of Interest ◽  
Serum Levels ◽  
Nkt Cells ◽  
Donor Type ◽  
Ifn Γ ◽  
The Impact

Abstract Abstract 229 NKT cells, a subset of which are CD1d reactive, play an important immunoregulatory role in suppressing dysfunctional immune reactions, including graft-versus-host disease (GVHD). To explore the biological activity and mechanism of donor-type NKT in suppression of GVHD, we utilized highly purified (>95%) populations of donor (C57Bl6; H-2b) NKT (DX5+TCR+CD4+) cells adoptively transferred into lethally irradiated recipient (Balb/c; H-2d) animals with T cell depleted bone marrow (TCD-BM). Highly purified (>95%) NKT cells (5.5×105) from luciferase positive (luc+) C57BL/6 mice were infused into lethally irradiated Balb/c recipients with TCD-BM(5×106) from wild-type (WT) C57BL/6 mice, and the animals were monitored by bioluminescence imaging (BLI). By day 4 after transfer, an NKT derived signal was observed in spleen and lymph node (LN) sites, and between days 7 and 10, NKT had also migrated to the skin. Total photons emitted peaked near day 25 after transplantation, followed by a steady decline. To assess the impact of donor-type NKT cells on GVHD induction by conventional CD4+ and CD8+ T cells (Tcon), we co-transferred various doses of highly purified WT NKT at day 0 with TCD-BM, followed by 5×105 luc+Tcon/animal on day 2. As few as 2.5×104 NKT cells significantly improved survival of mice receiving 5×105 Tcon. Animal survival with Tcon only was 20% and for Tcon with NKT cells was 74%(p=0.0023). In contrast to what is observed with CD4+CD25+FoxP3+ regulatory T cells (Treg), the NKT cells did not suppress Tcon proliferation assayed by both in vivo BLI and in a mixed-leukocyte reaction. Analysis of serum cytokines with or without 2.5×104 NKT, following HCT with TCD-BM and Tcon, indicated the addition of NKT cells resulted in elevated levels of INF-γ, IL-5, and IL-6 in serum; significant differences were not observed in serum levels of IL-2, IL-4, IL-10, IL-17, or TNF-α. Intracellular levels of cytokines in Tcon were analyzed from the same groups. At 8 days after HCT, mice receiving NKT had fewer TNFα-positive cells in LNs (CD4: 45% to 27%; CD8 36% to 24%); by day 11, however, TNFαa levels between groups were equivalent. IFN-γ levels, which were high in both NKT treated and untreated groups at day 8 (85%-95%), decreased significantly in NKT treated mice by day 11 (CD4: 40%; CD8: 43%), but were abundant in Tcon only mice (CD4: 78%; CD8: 80%) (p=.0001). No significant changes were found in the intracellular levels of IL-2, IL-4, IL-5, IL-10, or IL-17 of Tcon in the presence or absence of NKT cells. NKT from both IL-4 -/- and IFN-γ -/- mice were less effective at suppressing GVHD than WT NKT, implicating these cytokines in the suppressive mechanism. Finally, we found that NKT do not have a major impact on the graft-versus-tumor effect of Tcon against a luc+ BCL-1 tumor. These studies indicate that NKT persist in vivo upon adoptive transfer and suppress GVHD, even at extremely low cell numbers, which is important given the relative paucity of this cell population. The mechanisms of GVHD suppression appear to be distinct to those of Treg and involve the production of IL-4 and IFN-γ by NKT resulting in a decrease in Tcon, which produce pro-inflamatory cytokines. Disclosures: No relevant conflicts of interest to declare.

Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 661-661
Author(s):  
Jon J van Rood ◽  
Cladd E Stevens ◽  
Jacqueline Smits ◽  
Carmelita Carrier ◽  
Carol Carpenter ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hla Antigens ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Leukocyte Antigens ◽  
Grade Ii ◽  
The Impact ◽  
Related Mortality

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

Interventional Strategies to Contain Colonization and Infections Caused By Carbapenemase Producing Klebsiella Pneumonia in Haematological Malignancies

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2647-2647
Author(s):  
Alessandra Malato ◽  
Francesco Acquaviva ◽  
Rosaria Felice ◽  
Silvana Magrin ◽  
Maria Grazia Donà ◽  
...  
Keyword(s):  
Hand Hygiene ◽  
Conflicts Of Interest ◽  
Hematologic Malignancies ◽  
Healthcare Personnel ◽  
Klebsiella Pneumonia ◽  
Multiresistant Pathogens ◽  
Control Effort ◽  
Patient Reported ◽  
Plan B ◽  
The Impact

Abstract Background and Aim: The emergence and dissemination of Carbapenemase producing Klebsiella pneumoniae (KPC) represent a serious threat to public health and is associated with high mortality rates in patients with hematologic malignancies. Several risk factors (prior exposure to or current use of antibiotics, extended stay in hospital, neutropenia, sharing a room with a know carrier etc) have been identified for colonization in hematological patients. However, data on how to contain their spread in haematological setting are still surprisingly limited. We carried out a prospective investigation to assess the prevalence of KPC colonization among hematologic patients, the impact of a strategy control to limit the spread and to evaluate the efficacy of an implementation of more extensive active surveillance. Methods: Infections caused by multiresistant pathogens have been recorded in our Unit from January 2012 through June 2014. From January 2012 to July 2013, we developed an intensive control infection program, (Plan A): 1. Weekly colonization screening for KPC; 2. Educate healthcare personnel about KPC; 3. Promotion of hand hygiene 4. Physical separation of carriers from non-carriers 5. A double-carbapenem plus colistin therapeutic empiric regimen was given for blood stream infections. Since July 2013, we decided to implement additional measures, including (Plan B): 1. Drastic reduction in the number of beds. 2. 2% chlorhexidine body washing for colonized patients. 3. Ensure access to adequate hand hygiene stations (i.e., clean sinks and/or alcohol) and ensure they are well stocked with supplies (e.g. towels, soap, etc.) 4. Donning gown and gloves before entering the affected patient’s room and removing the gown and gloves and performing hand hygiene prior to exiting the affected patient’s room. Results: Since January 2012 perianal swabs were detected weekly from 607 consecutive patients affected by hematologic malignancies, for a total of 1079 admissions and 12.284 days of hospital stay.KPC colonization was present in 47 out of 607 (7.7%) screened patients at some time during their (often multiple hospitalizations); 11 bloodstream infections were reported in 9 patients (23%). Three deaths (3/11, 27%) due to KPC were reported before implementation screening (overall mortality rate was 6.3 % of colonized patients). KPC-decolonisation was achieved in 13/47 pts (28 %) after a median duration of 88 days (range 20-118).Most patients who recovered from KPC infection or were just colonized by KPC went on to receive additional chemotherapy without any life threatening KPC infection occurring (only one patient reported two septic episodes). Since screening cultures or further clinical cultures identified a progressive increase KPCcolonized or -infected patients, we decided to implement additional measures (Plan B). Therefore, from fourth trimester 2013 of study, we have observed a progressive decrease in rate of new colonization: 2 patients (4.17%) vs 15 patients (30%) in the third trimester, and a very low rate was maintained until the second trimester of 2014( 3 patients -4%). Conclusions: The prevalence of KPC colonization in our hospital is high among patients with hematologic diseases.An implementation of additional measures, sharing the patients in single bed-rooms and consequently limiting transfer of cases from other wards, was able to contain KPC colonization and infection.However, the success of our preliminary interventions should be monitored constantly; besides, to prevent the emergence and further spread of CRE, a coordinated regional control effort among healthcare facilities should be recommended. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3503-3503 ◽  
Author(s):  
Alan P. Venook ◽  
Fang-Shu Ou ◽  
Heinz-Josef Lenz ◽  
Omar Kabbarah ◽  
Xueping Qu ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Molecular Subtype ◽  
Progression Free Survival ◽  
Molecular Data ◽  
Tumor Location ◽  
Tumor Burden ◽  
Independent Prognostic Marker ◽  
Molecular Features ◽  
Metastatic Sites ◽  
The Impact

3503 Background: 80405 found no OS or Progression Free Survival (PFS) difference when bevacizumab (BV) or cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in All RAS wild type (wt) mCRC pts. There was a significant 1° side by biologic interaction (P int: OS = 0.008, PFS = 0.001) favoring pts with left-sided (L) 1°. Analyses of 1° tumors beyond All RAS includes Consensus Molecular Subtype (CMS), BRAF and MSI. (CMS results - see Lenz et al; BRAF -see Innocenti et al) We asked whether 1° tumor location - L vs right (R) - is an independent prognostic marker when these other molecular features are considered. Methods: We used a Cox proportional hazard model stratified by prior XRT and +/- adjuvant chemo; adjusted for age, gender, synchronous vs metachronous, CMS, MSI and BRAF status. Pts with transverse (T) tumors were excluded in this analysis. Results: Sidedness was determined in 782 pts (L - 472; R - 256; T -54). Molecular data from 728 pts (with L - and R-sided 1°s) was available as follows: KRAS -- 291, NRAS -393, BRAF - 393, MSI - 378, CMS - 533. L vs R mOS: 32.9 v 19.6 months (mo) (p < 0.0001). See Table for OS results in All RAS / BRAF wt and BRAF mutant (mut) pts. Sidedness (R vs L) is an independent prognostic marker even after adjusting for all these molecular features: HR = 1.392 (1.032, 1.878), p = 0.031. Conclusions: Primary tumor location is an independent prognostic factor when adjusted for age, gender, synchronous/metachronous, CMS, MSI and BRAF status. We are exploring clinical variables such as tumor burden, metastatic sites and measurability of disease in an attempt to explain the impact of sidedness. Support: U10CA188021, U10CA180882. Eli Lilly and Co, Genentech/Roche, Pfizer, Sanofi. Clinical trial information: NCT002655850. [Table: see text]

A Sequence Variation in the Promoter Region of PTPN22 Gene Predicts Relapse After HLA-Fully-Matched Unrelated Bone Marrow Transplantation for Hematologic Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3088-3088
Author(s):  
Luis J. Espinoza ◽  
Akiyoshi Takami ◽  
Katsuya Nakata ◽  
Makoto Onizuka ◽  
Yasuo Morishima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Promoter Region ◽  
Conflicts Of Interest ◽  
Hematologic Malignancies ◽  
Negative Regulator ◽  
Ptpn22 Gene ◽  
Transplant Outcomes ◽  
The Impact

Abstract Abstract 3088 The protein tyrosine phosphatase non-receptor 22 (PTPN22), also known as LYP, is an intracellular phosphatase ubiquitously expressed with particularly high expression in hematopoietic tissues that is a critical negative regulator of signaling through the T cell receptor and has emerged as the strongest common genetic risk factor for human autoimmunity outside the major histocompatibility complex. In this study we analyzed the impact of the polymorphism rs2488457 (1123G>C) in the promoter region of PTPN22 gene on transplant outcomes in patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The PTPN22 rs2488457 genotypes were retrospectively analyzed in a cohort of 663 patients with hematologic malignancies and their unrelated donors. The presence of the C/C or C/G genotype in the donor side was associated with a significantly lower incidence of relapse compared to the donor G/G genotype (28% vs. 34% 5-years, P =0.05) (Fig.1). No difference was noted in transplant-related mortality, or graft-versus-host disease in relation to the rs2488457 polymorphism. The donor C/C or C/G genotype remained statistically significant for relapse in the multivariate analyses (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.43 to 0.85; P =0.004). These differences in relapse did not significantly affect on overall survival (OS) (48% vs. 49% 5-years, P =0.85). The recipient PTPN22 genotypes did not significantly influence the transplant outcomes. These results suggest an association of the donor C/C or C/G genotype with lower disease relapse. These could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic BMT. Disclosures: No relevant conflicts of interest to declare.

Significant Impact of IL-17A Gene Polymorphism On Transplant Outcomes After HLA-Fully-Matched Unrelated Bone Marrow Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2305-2305
Author(s):  
Akiyoshi Takami ◽  
J. Luis Espinoza ◽  
Makoto Onizuka ◽  
Takakazu Kawase ◽  
Takamasa Katagiri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Conflicts Of Interest ◽  
Chronic Gvhd ◽  
Hematologic Malignancies ◽  
Chemokine Production ◽  
Transplant Outcomes ◽  
The Impact ◽  
Standard Risk

Abstract Abstract 2305 Poster Board II-282 IL-17 plays an active role in autoimmune diseases and organ transplant rejection through its mediating proinflammatory responses and inducing inflammatory cytokine and chemokine production. This study examined the impact of donor and recipient polymorphism in the IL-17A gene on the clinical outcomes in unrelated HLA-fully-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donor Program. The IL-17A polymorphism (rs2275913, G197A) was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. In patients with standard risk disease, the donor IL-17A-197A genotype was associated with significantly improved OS (adjusted HR, 0.32; 95% CI, 0.13-0.79; p=0.01) and reduced transplant related mortality (TRM) (adjusted HR, 0.27; 95% CI, 0.11-0.67; p=0.005), but no impact on disease relapse or the development of grades II-IV acute GVHD or chronic GVHD. Patients with standard risk disease receiving transplants from donors with the 197A genotype had better 5-year OS (71% vs. 40%, p=0.02; Figure) and lower 5-year TRM rate (27% vs. 60%, p=0.02). The IL-17A polymorphism did not significantly influence the transplant outcomes in patients with high risk disease. These results suggest transplantation from IL-17A-197A positive donor is advantageous in improving OS and reducing TRM after HLA-matched unrelated BMT for standard risk hematologic malignancies. Disclosures: No relevant conflicts of interest to declare.

A Minor Genetic Variation In the Granzyme B Gene Predicts Relapse After HLA-Fully-Matched Unrelated Bone Marrow Transplantation for Hematologic Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 681-681
Author(s):  
Luis J. Espinoza ◽  
Akiyoshi Takami ◽  
Kayoko Yamada ◽  
Mayu Yamada ◽  
Yuki Motohashi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Conflicts Of Interest ◽  
Granzyme B ◽  
Hematologic Malignancies ◽  
Effector Cells ◽  
Transplant Outcomes ◽  
A Minor ◽  
The Impact

Abstract Abstract 681 Granzyme B (GZMB) is a serine protease with important roles mediating target-cell apoptosis induced by natural killer cells and cytotoxic CD8+ T cells. The polymorphism rs8192917 (A55G) in the GZMB gene has been reportedly associated with the ability of effector cells to secrete GZMB. In this study we analyzed the impact of GZMB polymorphism on transplant outcomes in patients undergoing unrelated HLA-fully-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donation Program. The GZMB genotypes were retrospectively analyzed in a cohort of 360 pairs of patients with hematologic malignancies and their unrelated donors. The presence of the G/G genotype in the donor side was associated with a significantly higher incidence of relapse (62% vs. 32%, P=0.04; Fig 1). Multivariate analysis revealed that the donor G/G genotype, which is expected to produce lower levels of GZMB after stimulation, (Girnita et al, Transplantation 2009) was an independent risk factor for relapse (hazard ratio, 4.17; 95% confidence interval, 1.63 to 10.70; P=0.003). The host GZMB genotypes did not significantly influence the transplant outcomes. These results suggest an association of low GZMB secretors with disease relapse. These could therefore be useful in selecting the donor and creating therapeutic strategies for improving the final outcome of allogeneic BMT. Disclosures: No relevant conflicts of interest to declare.

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