Gender Mismatch Research Articles

Clinical Characteristics and Outcomes of Renal Transplantation in Elderly Recipients

BackgroundElderly renal transplant candidates constitute one the fastest-growing populations among end-stage renal disease patients. Since the impacts of advanced recipient age have not yet been fully defined, we evaluated the clinical characteristics and outcomes of elderly renal transplant recipients. MethodsAmong 564 adult renal transplant recipients, at our center between 2000 and 2009, 64 were at least 60 years of age (Elderly group), and 500 were younger than 60 years (Young group) at the time of the procedure. We compared their clinical features and surgical management. ResultsThere were significant differences in mean donor age (55.6 years vs. 53.2 years, P = .030) and gender mismatch (77.0% vs. 63.4%, P = .035). However, there were no significant differences between the two groups in patient and graft survivals (P = .177 and P = .365, respectively). Malignancy after transplantation was a significant risk factor upon univariate evaluation but only ABO incompatibility upon multivariate analysis of patient and graft survival. The main cause of graft loss among the Elderly group was death with a functioning graft due to heart failure. ConclusionsRenal transplantation is a feasible, safe option for the elderly and should be actively implemented. However, screening for cancer and heart disease should be mandatory to improve outcomes.

Effects of talker gender and spatial location on sentence recognition for young and old listeners with normal hearing

This study aimed to determine the effect of gender and spatial difference between two talkers on the sentence recognition of young and old listeners with normal hearing. Gender difference was manipulated using gender-matched (i.e., male-male or female-female) or gender-mismatched (i.e., male-female or female-male) sentence pairs. Four spatial separation conditions (-45/45°, -90/90°, -135/135°, 180° azimuth) were presented through eight directional speakers. The ability of sentence recognition was identified by key word scoring. Overall, young normal-hearing (YNH) listeners performed better than old normal-hearing listeners (ONH) in all conditions. The gender mismatch between two talkers was beneficial to recognize closed-set sentences by creating the release from informational masking, more for the ONH group compared to the YNH group. The effect of spatial separation was not significant in both groups. Year of education for ONH listeners significantly affected their two-talker speech recognition. Results of individual differences in ONH listeners suggest that the ability to use acoustic cues given by gender and spatial difference between two competing talkers appears to be related to their cognitive ability.

Influence of Gender Donor-Recipient Combinations on Survival After Human Lung Transplantation

Background In the current practice of lung transplantation, donor and recipient genders are neither directly considered nor matched. However, some data have suggested a possible effect of gender combinations on survival following lung transplantation. Methods A total of 249 adult lung transplant recipients at a single center between February 1988 and December 2008, were analyzed retrospectively for donor-recipient gender matching. We compared the mortality by calculating one-term survival rates after transplantation using the Kaplan-Meier method with comparisons using the log-rank (Mantel-Cox) test. Statistical significance of the mean effects of size matching was assessed by paired Student t tests and Wilcoxon signed rank tests. Results Kaplan-Meier survival analysis shown that male compared to female recipients did not have an effect on outcomes after lung transplantation at 5 years ( P = .5379), 10 years ( P = .107), 15 years ( P = .0841), 20 years ( P = .0711). No effect of gender on lung transplantation outcomes was observed with donor-recipient gender mismatches at 5 years ( P = .1804), 10 years ( P = .1457), 15 years ( P = .0731), or 20 years ( P = .0629). Similarly, no differences were observed for each gender combination. The degree of size matching was defined as the ratio of donor-to-recipient predicted total lung capacity. The ratios were similar for the donor-recipient gender match and significantly different for the donor-recipient gender mismatch. Conclusions These analyses suggested that gender was not a significant independent risk factor affecting survival after lung transplantation. Size mismatch caused by gender mismatch did not increase mortality.

Abstract 16802: Gender Match Does Not confer Survival Advantage in Pediatric Heart Transplantion

Background: In adult heart transplant recipients, a survival advantage for male recipients with donor-recipient gender match has been shown. We determined if similar effects of recipient gender, donor gender, and donor-recipient mismatch exist in pediatric heart transplantation. Methods: We reviewed the United Network for Organ Sharing (UNOS) database for 3630 first time heart transplant recipients younger than age eighteen years transplanted between January 1994 and May 2008. We determined mortality rates based on recipient gender, donor gender, and donor recipient gender match with and without adjustment for known risk factors, including presence of congenital heart disease, assist device, race, donor or recipient age, era, elevated bilirubin or creatinine, mechanical ventilation, and dialysis. Results: Female recipients (F) had increased mortality compared to male recipients (M) with adjusted hazard ratio (HR) = 1.27 (1.12-1.44, p < .001). Donor gender had no effect on mortality. Gender mismatch conferred no survival disadvantage for male recipients with adjusted HR = 1.09 (0.92-1.29, p= .330) nor female recipients with HR= 1.12 (0.93-1.36, p=0.330). The largest survival effect was between M to M and M to F groups (HR=1.38; 1.17-1.63, p< .001). However, 5 year conditional survival was similar between all groups (M to M, F to F, M to F, F to M) (log rank p =.1077 for 30 day and p=.0595 for 1 year survivors). Conclusion: In pediatric heart transplant recipients, unlike adult patients, gender match does not confer survival advantage. Female recipients have increased mortality compared to male recipients. Gender specific recipient risk factors post transplant should be investigated.

Increasing Genetic Complexity Predicts for Inferior Outcomes Following Reduced-Intensity Conditioning Allogeneic Transplant for Chronic Lymphocytic Leukemia

Abstract 3090Several biologic markers have been identified which predict an unfavorable course in CLL. Reduced-intensity conditioning (RIC) allogeneic transplant may be able to overcome some of these. This retrospective analysis evaluates the effect of cytogenetics, including metaphase cytogenetics, on outcomes with RIC-allogeneic SCT.From 2005–2011, 51 RIC-allogeneic SCTs were performed at The Ohio State University for CLL. There were 38 males (74.5%) and 13 females (25.5%) with a median age of 58 (range 37–73). The median interval between diagnosis and SCT was 48 months (range 9–270). Before SCT, a median 4 lines of chemotherapy were given (range 1–11). One patient was in CR at the time of SCT, 39 were in PR, and 11 had stable or progressive disease; the median CMI was 3 (range 0–7). Fifty-nine percent of patients had del17; 53% had 3 or more abnormalities on metaphase cytogenetics, and 37% had 5 or more abnormalities. The source was PBSC in 48 (94%), BM in 1 (2%) and CB in 2 (4%). Of the PB or BM SCTs, 19 donors (39.6%) were related and 29 (60.4%) were volunteer; 45 (92%) were matched and 4 (8%) had a 1 allele mismatch. There were 21 (41%) pairs with an ABO mismatch and 16 (31.4%) pairs with a gender mismatch. Conditioning was Flu/Bu +/− ATG in 42 patients (82.2%), FluCamTBI in 6 (11.8%), FluCy in 1 (2%), and FluCyTBI-based in 2 receiving CB (4%). Following transplant, 34 (66.6%) developed AGVHD (gr 1–2: 28, gr 3–4: 6) and 27 of 48 evaluable patients (56.3%) developed CGVHD (limited: 7, extensive: 20). With a median follow-up of 17.3 months (range 1–60), the estimated 3-year OS and PFS following transplant were 56.5% and 42.9% respectively. Table 1 lists variables which had a p-value of ≤0.1 on univariate analysis. The presence of del13 and ≥5 karyotype abnormalities remained significant on multivariate analysis for OS while ≥5 karyotype abnormalities and conditioning with an alemtuzumab-containing regimen were significant for PFS (Table 2). The estimated 3 year OS for patients with del13 was 32.2% and 23% for patients with ≥5 karyotype abnormalities, compared with 72.7% and 73.5% for those without, respectively. The estimated 3-year PFS was 21.5% for patients with ≥5 karyotype abnormalities and 0% for patients with an alemtuzumab-containing regimen and 53.9% and 49.3% for those without, respectively.TableVariables included in multivariate analysis model.Variablelogrank p-valuePFSOSAge ≥550.0072*…Del13 ≥4.7%0.0039*Del17p ≥5.7%0.0019*0.0878Karyotype abnormalities ≥50.0002*0.0138*Karyotype abnormalities ≥30.0186*0.0623Largest node ≥4 cm0.0277*…Marrow involvement ≥50%0.0752…Alemtuzumab conditioning…0.0001*GVHD prophylaxis0.0001*0.0374*HLA mismatch<0.0001*…*statistically significant at p<0.05Table 2Multivariate analysis of OS, PFS.OSVariableHR95% CIp-valueDel13q<4.7%1≥4.7%3.581.36 to 9.420.01Karyotype<41≥55.161.97 to 13.560.001PFSVariableHR95% CIp-valueConditioningno alemtuzumab1alemtuzumab9.83.28 to 29.290Karyotype<41≥54.351.67 to 11.280.002Due to small numbers, the alemtuzumab data should be interpreted with caution, but are consistent with previous reports. Increasing genomic complexity is known to predict for diminished chemosensitivity. Accordingly, the presence of 5 or more abnormalities on metaphase cytogenetics was demonstrated to be a poor prognostic indicator for both PFS and OS following SCT. There was substantial, but not universal, overlap among patients with del17, del13, and highly complex karyotype; this interplay merits further consideration. Better understanding of the evolution of genetic complexity will better define how to time transplant to allow for maximum benefit to those patients likely to evolve. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Association Between Genetic Variants in Immune Response Genes and Outcomes After Hematopoietic Cell Transplantation

Abstract 3049 Background:Despite rapid advances in allogeneic hematopoietic cell transplant (HCT) techniques, the procedure continues to be associated with a high morbidity and mortality with transplant related mortality (TRM) ranging from 15% to as high as 50%. Acute graft versus host disease (GvHD) remains a major cause of morbidity and an important cause of early TRM in patients undergoing allogeneic HCT. Though variations in major histocompatibiliy (MHC) genes are well known determinants of acute GvHD, there is increasing evidence that genetic variation in immune/cytokine response pathways also contributes significantly to the pathogenesis of acute GvHD. Methods:We evaluated the association of single nucleotide polymorphisms (SNPs) in non-MHC dependent immune/cytokine response pathways (n= 77 SNPs in recipients and donors) with acute GvHD and TRM at one year in a cohort of 425 recipient-donor pairs who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota between 1998 and 2007. We used a Fine and Gray proportional hazards model adjusted for competing risk to evaluate the association between the genetic variants and time to acute GvHD and time to TRM. Results:After adjustment for recipient age at transplant, race, diagnosis, disease status at transplant, gender mismatch, CMV serostatus of recipient and donor, recipient and donor sex, donor type, conditioning regimen (myeloablative or reduced intensity) and year of transplant, one recipient SNP, rs646005 in the TIRAP gene and one donor SNP, rs2232596 in the LBP gene were marginally associated with increased risk for grade II-IV acute GvHD (Hazard ratio (HR) = 1.33 (95% Confidence interval (CI): 1.07 – 1.62) and 1.32 (1.07 – 1.66) respectively; p =0.01). Similar analyses for TRM showed recipient SNP rs5498 in the ICAM1 gene was associated with a decreased risk of TRM (HR: 0.67(95% CI: 0.50 – 0.89); p=0.0006) while recipient SNPs rs1739654 in the LBP gene and rs3804100 in the TLR2 gene were associated with an increased TRM risk (HR: 1.86 (95% CI: 1.16 – 2.97) and 1.66 (95% CI: 1.11 – 2.48) respectively; p =0.01). Conclusions:These findings are consistent with previous reports that support a role for genetic variants in the innate immune response pathways among both recipients and donors can influence the risk of acute GvHD and TRM among patients undergoing allogeneic HCT. These findings indicate that a systematic search for genetic variants in the innate immune response pathways may identify novel biomarkers that can be used to identify patients at high risk for acute GvHD and TRM. Disclosures:Weisdorf:Genzyme: Consultancy, Research Funding.

Fludarabine, Melphalan and Low Dose Total Body Irradiation for Reduced Intensity Conditioning (RIC) Prior to Allogeneic Hematopoietic Cell Transplantation (AlloHCT)

Abstract 4570RIC AlloHCT can provide a curative option for patients with hematologic diseases who are not candidates for myeloablative AlloHCT. However, this approach is limited by high relapse rates, especially with aggressive myeloid malignancies. We hypothesized that achieving greater cytoreduction by increasing conditioning intensity would increase the efficacy of a RIC regimen. Therefore, we utilized fludarabine (40 mg/m2/day × 4 days on days -5 to -2), melphalan 50 mg/m2 (day -2) and TBI (total of 400 cGy in 2 fractions on day -1) (FluMelTBI) in a pilot trial of RIC for hematologic disorders. Forty-nine patients who were not eligible for myeloablative transplantation accrued between March 2009 and June 2011. Tacrolimus (0.015 mg/kg oral every 12 hours, starting on day -1, titrated to 5–15 ng/ml), mycophenolate mofetil (1000 mg oral every 8 hours, starting on day -1) and methotrexate (2.5 mg/m2 IV on days 1, 3 and 6) were used for Graft-versus-Host Disease (GvHD) prophylaxis in all patients. Patient and donor characteristics are presented in Table A. All 49 patients engrafted neutrophils at a median 16 days (range 10–39). One patient did not nadir platelets <20 × 109/L; of the remaining 48 patients, two died before platelet recovery on days +14 and +50, while 46 achieved platelet recovery at a median 17 days (range, 11–73). At day +100 post-RIC AlloHCT, 71% were in CR, with 2 patients too early to evaluate. The transplant related mortality (TRM) was 10% at day +100 and 22% at 1 yr. The incidence of acute GvHD grade 2–4 was 49% and grade 3–4 was 23%. Chimerism data are presented in Table B. At a median follow-up of 364 days (range 17–821), the 1 yr OS and PFS are 58% (95% CI: 42–72%) and 50% (95% CI: 34–64%), respectively. Factors that were significantly related to lower OS were older age (p=0.02) and gender mismatch (p=0.03). In conclusion, FluMelTBI is a well-tolerated RIC regimen with low TRM, achieves early complete donor chimerism and a good early disease response. Longer follow-up is needed to determine long term survival and disease control.Table A:Patient and donor characteristicsAge: median (range)N=4958 yrs (5-72)Gender: male female45% 55%Disease: AML or ALL MDS or MPD NHL other51% 20% 14% 10%Disease status prior to transplant: CR1 CR>1 No prior CR Untreated MDS/MPD/SAA 1st relapse or CML blast crisis27% 12% 27% 20% 14%Related Unrelated33% 67%HLA matched 10/10 HLA mismatched (<10/10)75% 25%ABO compatible incompatible49% 51%Gender matched mismatched61% 39%Peripheral blood hematopoietic cells Bone marrow hematopoietic cells84% 16%CD 34+ cell dose: median (range) × 106/kg5.24 (0.82-40.72)Table B:Chimerism results post AlloHCTN evaluableDay+30Day+100Day+365383614N (%) complete (>95% donor) myeloid chimerism36 (95%)34 (94%)13 (93%)N (%) complete (>95% donor) lymphoid chimerism34 (89%)33 (92%)14 (100%) Disclosures:Hahn:Novartis

Parameters of donor–recipient size mismatch and survival after bilateral lung transplantation

The purpose of this study was to investigate the relationship between donor-recipient height, gender and predicted estimates of total lung capacity (pTLC) mismatches and post-transplant survival. The lung transplant databases at three programs were reviewed. The pTLC ratios (donor pTLC/recipient pTLC) and height ratios (donor height/recipient height) were calculated retrospectively. Patients were grouped according to pTLC ratio ≤1.0 or >1.0 and height ratio ≤1.0 or >1.0, and according to gender (mis-)matching. A time-to-event analysis was performed for risk of death after transplantation conditional on 30-day survival using Kaplan-Meier survival and Cox proportional hazard models. There were 211 adult bilateral lung transplant recipients who qualified for the analysis. Mean follow-up was comparable for all cohorts (range 2.21 to 3.85 years). In the univariate Cox proportional hazard models, a pTLC ratio >1.0 (HR 0.43, p = 0.002) and a height ratio >1.0 (HR 0.61, p = 0.03) were associated with better survival, and a female-donor-to-male-recipient gender mismatch (F-to-M) was associated with worse survival (HR 2.35, p = 0.01). In the multivariate Cox proportional hazard model accounting for F-to-M gender mismatch and height ratio >1.0, a pTLC ratio >1.0 remained associated with survival (HR 0.38, p = 0.015). However, accounting for a pTLC ratio >1.0, a height ratio of >1.0 and F-to-M mismatch were not associated with survival. A pTLC ratio >1.0 is associated with improved survival after bilateral lung transplantation. The pTLC ratio might better reflect allograft-thorax mismatch than the height ratio, as it also accounts for effects of gender on lung and thoracic volumes.

Donor-Recipient Gender Mismatch Affects Early Graft Loss After Kidney Transplantation

Background We sought to determine the risk factors influencing the occurrence of early graft loss among kidney transplant recipients. Study design One hundred forty-six potential donors and 230 kidney recipients were included in the study. Prior to organ procurement we collected demographic data as well as hemodynamic data of mean arterial pressure, central venous pressure, pulmonary capillary wedge pressure, systemic vascular resistance index acquired by means of a thermodilution method. The recipient data included age, gender, prior hemodialysis period, panel-reactive antibodies, cold ischemia time, renal insufficiency cause, and donor-recipient gender mismatch. We assessed the influence of the data on graft loss at 30 days after renal transplantation. To confirm the relationships, we performed statistical analyses using chi-square, Fisher exact, and V. Cramer tests. Results There were no significant relationships between the analyzed parameters and early graft loss in the study group except for gender mismatch. The 71 female recipients of male kidneys showed the lowest graft survival: donor/recipient male/female 89%; donor/recipient female/male 97%; no mismatch 97% ( P = .01). Conclusions Female recipients of male kidneys may experience a greater risk of early graft loss compared with all other gender combinations.

Abstract PL07-01: Linkage disequilibrium-based analysis of DNA repair and GST genes in malignant gliomas: A unique tool in defining the association between genetic diversity and survival

Abstract Inherited genetics are increasingly being identified as a significant factor that contributes to both treatment outcome and treatment-associated toxicities in cancer patients undergoing therapy. The specific SNPs and genes involved are, however, still poorly understood. In this study, we exploited the unique advantages of a linkage disequilibrium-based approach to examine the relationship between genetic diversity in regions of DNA repair and GST genes with survival in adults with anaplastic astrocytoma and glioblastoma multiforme treated on temozolomide and carmustine-based protocols. We genotyped a subset of 1,267 tagging SNPs within or near haplotype blocks of 27 genes in 301 patients. The SNPs were selected to be in high LD with and, thus, to be predictive of the diversity of the target region containing the gene and 20 kb flanking 3′ and 5′ of it. Genotyping was conducted on a high-throughput customized Affymetrix platform. Associations between genotypes and survival was performed using the Fisher's exact test, after testing for Hardy-Weinberg conformity and gender mismatches. The results identified several tSNPs in and around the loci of 11 genes (EXO1, DDB2, LIG1, MGMT, MSH2, MSH4, PAN3, RAD52, TDG, XRCC1, and XRCC5) to be highly associated with survival. Several other SNPs showing a statistical tendency to be associative. Although, a number of SNPs/genes was associated with survival in both anaplastic astrocytoma and GBM, a subset of genes and SNPs were associative in GBMs but not in AAs and vice versa. We then examined 28 SNPs in all eight members of the GST family (A1, M1, M3, P1, O1, S1, T and Z) allowing the identification of seven specific SNPs that were highly associated with treatment outcome/survival. The identification of highly polymorphic regions associated with the loci of DNA repair and GST genes as determinants of alkylating agent-based therapy in malignant gliomas is consistent with the established role of enhanced DNA repair and drug metabolism in tumor resistance to these agents. Ongoing studies are directed at these associative SNPs to gain insight into the biology underlying their association with treatment outcome. Supported by grants RO1 CA 153050, RO1 CA127872, RO1 CA 112519 and P30-CA114236 from the NIH, USA. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL07-01.

Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis

AbstractSeveral risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from transplantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]:85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability.

528 Does Gender Mismatch Increase the Risk of Antibody-Mediated Rejection (AMR) after Heart Transplantation?

528 Does Gender Mismatch Increase the Risk of Antibody-Mediated Rejection (AMR) after Heart Transplantation?

579 Do Boys and Girls Match? – The Effect of Gender Mismatch in Cardiac Transplantation

The effect of gender matching after cardiac transplantation is still controversial. There is no data about the effect of gender matching on acute rejection and graftvasculopathy. This analysis examines the impact of gender matching on immunological complications after cardiac transplantation.

Gender Differences in Liver Donor Quality Are Predictive of Graft Loss

Some studies have found that donor-recipient gender mismatch predicts posttransplant outcomes but whether this is independent of donor quality is unknown. To evaluate the association between gender mismatch and graft loss, 11 508 females (F) and 16 714 males (M) who underwent liver transplant from March 1, 2002 to December 31, 2007 were studied. Of 11 donor characteristics, clinically relevant differences between F and M donors were median age (47 vs. 39 years), height (165 vs. 178 cm) and proportion dying of stroke (59 vs. 35%) (p < 0.001 for all). The donor risk index was significantly lower for F than M donors (1.3 vs. 1.6, p < 0.001). Recipients of gender-mismatched grafts had an 11% higher risk of graft loss (p < 0.001). Compared to M→M donor-recipient-matched transplants in univariable analysis, F→M mismatch was associated with a 17% increased risk of graft loss (95% CI = 1.11-1.24, p < 0.001), whereas M→F mismatch was not (HR = 1.02; 95% CI = 0.96-1.09; p = 0.46). However, adjustment for significant recipient and donor factors eliminated the association between F→M mismatch and graft loss (HR = 0.95; 95% CI = 0.89-1.02; p = 0.18). In conclusion, donor quality differs significantly between female and male donors-female donors are older, shorter and die more frequently of stroke-and gender differences in donor quality, rather than gender mismatch are predictive of graft loss.

Clinical Significance of Polymorphisms During Hepatopoietic Stem Cell Transplantation.

AbstractAbstract 3497Conidtioning plays an important part in hematopoietic stem cell transplantation (HSCT) and is a major cause of early mortality. Most of conditioning regimens include the ionizing radiation and alkylating agent. The tissue damage made by chemotherapy or radiation is the major cause of acute toxicity and the development of graft versus host disease (GvHD). DNA repair and drug metabolism gene polymorphisms influence the transplantation associated mortality and GvHD by causing incomplete DNA repair and interference with metabolism of drugs. To explore whether these polymorphisms influence clinical implication and the adverse outcomes related to chemo-radiotherapy, we analyzed total 12 polymorphisms in DNA repair (ERCC1, ERCC2, XRCC1, XRCC3, XRCC4, XPC, MGMT and OGG1) and drug metabolizing pathway (GST T1, GST P1, CYP1A1 rs1048943 and CYP1A1 rs4646903).The total 175 patients were assessed from a HLA identical sibling (n=122, 69.7%) and unrelated donors (n=53, 30.3%). Patients have either acute leukemia (n=123, 70.3%), MDS (n=18, 10.3%), CML (n=15, 8.6%) or others (n=19, 10.8%). We evaluated the association between SNPs with adverse effects such as venoocclusive disease (VOD), mucositis, treatment related mortality and acute/chronic GvHD. Multivariate analysis was performed adjusting for clinical factors; recipient age, donor type, diagnosis, disease status, gender mismatch, HLA mismatch, stem cell source, conditioning regimen and GvHD prophylaxis. Three SNPs were associated with clinical significance. XRCC4 (rs1056503) was associated with increased risk of acute gut GvHD (RR:6.84, 95% CI:1.69-28.2, p=0.007), CYP1A1 (rs1048943) with mucositis (RR:3.12, 95% CI:1.22-7.96, p=0.017) and XPC (rs2228001) with VOD (RR:38.23, 95% CI:2.08-702.18, p=0.014).Our findings show that the acute adverse events after allogeneic HSCT were correlated DNA repair and drug metabolism gene polymorphisms and these findings suggest that XRCC4, CYP1A1 and XPC might provide useful information for the risk stratification of HSCT Disclosures:No relevant conflicts of interest to declare.

Retracted: Deficiency of Either P-Glycoprotein or Breast Cancer Resistance Protein Protect against Acute Kidney Injury

The kidney has a high capacity to regenerate after ischemic injury via several mechanisms, one of which involves bone marrow-derived (stem) cells. The ATP binding cassette transporters, P-glycoprotein and breast cancer resistance protein, are determinants for the enriched stem and progenitor cell fraction in bone marrow. Because they are upregulated after acute kidney injury, we hypothesized that both efflux pumps may play a role in protecting against renal injury. Surprisingly, transporter-deficient mice were protected against ischemia-induced renal injury. To further study this, bone marrow from irradiated wild-type mice was reconstituted by bone marrow from wild-type, P-glycoprotein- or breast cancer resistance protein-deficient mice. Four weeks later, kidney injury was induced and its function evaluated. Significantly more bone marrow-derived cells were detected in kidneys grafted with transporter-deficient bone marrow. A gender mismatch study suggested that cell fusion of resident tubular cells with bone marrow cells was unlikely. Renal function analyses indicated an absence of renal damage following ischemia-reperfusion in animals transplanted with transporter-deficient bone marrow. When wild-type bone marrow was transplanted in breast cancer resistance protein-deficient mice this protection is lost. Furthermore, we demonstrate that transporter-deficient bone marrow contained significantly more monocytes, granulocytes, and early outgrowth endothelial progenitor cells.

Incidence, Risk Factors, and Clinical Outcomes of Atrial Fibrillation and Atrial Flutter After Heart Transplantation

Atrial fibrillation (AF) and atrial flutter (AFL) after heart transplantation (HT) has been associated with increased mortality. Diverse incidence rates have been reported to date, with no clear classification according to the time of onset of such arrhythmias. We determined the incidence of AF/AFL using the time of onset after HT and analyzed the associated risk factors and outcomes. We performed a retrospective study of 228 HT recipients (March 1996 to July 2007), including donor and recipient demographics, gender mismatch, ischemia time, surgical anastomosis, time of onset of AF/AFL, acute cellular rejection, left ventricular systolic function, and all-cause mortality. The mean age of the donors (81% men) was 30 +/- 12 years and of the recipients (78% men) was 53 +/- 11 years. AF/AFL occurred in 45 patients (20%): 24 (11%) in the first 30 days, 10 (4%) within the 31 days to 1 year, and 11 (5%) after 1 year. When the patients with AF/AFL were compared to those with sinus rhythm, the significant difference was the older mean age of the donors (p = 0.001) and the recipients (p = 0.02). The all-cause mortality rate was 43% for those with AF/AFL compared to 23% for those with sinus rhythm (hazard ratio 2.45; 95% confidence interval 1.2 to 4.8), mostly driven by the greater mortality in the later-onset AF/AFL group (>30 days after HT). In conclusion, AF and AFL have an incidence of 20% after HT and are associated with increased overall mortality compared to that in patients in sinus rhythm. AF/AFL is more common within the first 30 days of HT, with an overall incidence of 20%. Older donor and recipient age is a risk factor associated with AF/AFL.

Donor-Recipient Gender and Size Mismatch Affects Graft Success after Kidney Transplantation

Female recipients of male kidneys have an inferior graft survival, and patients receiving larger kidneys relative to their body size may have a graft survival advantage. Thus, graft survival may be affected by both gender and kidney size mismatches. The objective of this study was to analyze the possible confounding effect of body mass mismatch (body mass as proxy for kidney size) between female recipients of male donor kidneys. A total of 668 kidney transplantations between 1996 and 2005 at our center were studied retrospectively. Graft and patient survival were determined by Kaplan-Meier estimation. Multivariate Cox proportional analyses were performed to determine the hazards of graft loss. There were 146 female recipients of male kidneys. Compared with all other gender combinations, this group had the lowest unadjusted graft survival (86%, 79%, and 78% vs 92%, 88%, and 86% at 1, 2, and 3 years, respectively; log-rank p = 0.01). Donor body mass index (BMI) correlated with donor kidney size (p < 0.001). Male kidneys were a risk factor of graft loss for female recipients (hazard ratio [HR] 3.45, 95% CI 1.40 to 8.51, p = 0.01), but male donors with a larger BMI relative to female recipients' significantly reduced the risk (HR 0.19, 95% CI 0.05 to 0.67, p = 0.01). The inferior graft survival for female recipients of male donor kidneys is mitigated by male donors with a larger BMI.

Abstract 4656: DNA repair polymorphisms as predictors of Graft-versus-Host Disease after allogeneic hematopoietic cell transplants

Abstract Graft versus host disease (GVHD) remains a major source of morbidity and mortality among patients undergoing hematopoietic cell transplants (HCT). Tissue damage as a result of treatment is the initiating event in the pathogenesis of GVHD and variations in DNA repair can influence the amount of tissue damage in response to treatment modalities used in HCT. Since DNA damage caused by therapeutic agents such as alkylating agents and ionizing radiation used frequently in pre- HCT conditioning regimens is commonly repaired by the base excision repair (BER) pathway we hypothesized that genetic polymorphisms in the BER pathway will be associated with GVHD after HCT. We evaluated the association between single nucleotide polymorphisms (SNPs) (n= 179) in the BER pathway with acute GVHD and chronic GVHD in a cohort of 470 recipients who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota. After adjustment for donor type, diagnosis, disease status at transplant and gender mismatch, two SNPs in RFC1 (Replication Factor C) gene (rs1057807 and rs4975003) were associated with a decreased risk of grade II-IV acute GVHD (HR:0.74-0.77; p≤0.01) and one SNP, rs6844176, in RFC1 gene was associated with increased risk of grade II-IV acute GVHD (HR:1.39, p=0.001). The rs3730914 SNP in the LIG1 (Ligase I) gene was also associated with a decreased risk of grade III-IV acute GVHD (HR: 0.38; p=0.005). One SNP, rs1805410, in the PARP1 (poly ADP-ribose polymerase 1) gene was associated with increased risk of chronic GVHD (HR: 1.44; p=0.01) post HCT. These findings suggest that SNPs in the BER pathway can be used as genetic biomarkers to predict individuals at high risk for GVHD. If these findings are confirmed, modulation of pre-transplant conditioning may alter risk in these patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4656.

Gender differences in specialty preference and mismatch with real needs in Japanese medical students

BackgroundThe shortage of doctors and maldistribution among specialties are of great concern in the Japanese health care system. This study investigated specialty preference in medical students of one university, and examined gender differences and compared their preference with real needs.MethodsWe conducted a self-administered questionnaire including specialty preference in all students of one medical university. Preference was assessed by the five-level probability of their future choice: 1 = very low, 2 = low, 3 = moderate, 4 = high, and 5 = very high. The proportion of 4 or 5 was calculated as the preference rate. The real needs (magnitude of doctor shortage) in the prefecture were drawn from two different surveys. The relationship between the sex-specific preference rate by specialty and real needs was assessed by Spearman's correlation coefficient.ResultsInternal medicine showed the highest preference rate, followed by general surgery, pediatrics, and emergency medicine. There was no significant correlation between the preference rates of men and women (r = 0.27, p = 0.34). The preference rates for general surgery, orthopedics, neurosurgery, and emergency medicine were significantly higher in men than in women, while those of obstetrics & gynecology, pediatrics, and dermatology were significantly higher in women. The magnitude of doctor shortage by specialty from two surveys were significantly correlated with the total preference rate and men's preference rate (r = 0.54 to 0.74), but not with women's preference rate (r = 0.06 and 0.32).ConclusionsThis study elucidated not only gender differences in specialty preference but also the relationship to real needs. Critical gender differences and mismatch with real needs were found in women. In addition to traditional gender roles and insufficient support for women's participation in Japan, gender differences and mismatch influence the current and future maldistribution of specialties. Systematic changes in the working environment in medical society are required to solve these problems.