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ABSTRACT: Bronchiolitis obliterans (BO) is a late non-infectious pulmonary complication after allogeneic hematopoietic SCT. Among 982 patients after myeloablative hematopoietic SCT between January 2000 and October 2010, 68 were diagnosed with BO according to NIH criteria. The median onset of BO was 18 months post transplant, 5-year cumulative incidence was 5.8% and 5-year mortality 41%. BO prevalence rate was 10% among all long-term surviving hematopoietic SCT recipients and 12% among chronic GVHD-patients. Chronic GVHD, peripheral SCT and ABO blood group incompatibility were identified as risk factors associated with BO. IgG levels were significantly decreased at the onset of BO (6.7 g/L±0.7, P=0.001), the mean exhaled NO concentrations were lower in BO-patients than in stem cell recipients without BO (14 p.p.b.±0.9 vs 20 p.p.b.±2.1) or healthy controls (25 p.p.b.±2.4, P<0.001). Hypoxia-inducible factor 1 alpha (HIF-1α) was significantly elevated in BO as compared with healthy controls or GVHD-patients without lung involvement (340±61 vs 127±22 vs 140±32, P=0.02). Calculated 5-year survival was superior in female than in male BO-patients (86 vs 45%, P=0.04). These results emphasize the relevance of BO as serious late complication with substantial mortality and point to essential pathophysiological changes due to regulatory responses to hypoxia.Bone Marrow Transplantation advance online publication, 25 February 2013; doi:10.1038/bmt.2013.17.
Bone marrow transplantation 02/2013; · 3.00 Impact Factor
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Bone marrow transplantation 10/2012; · 3.00 Impact Factor
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ABSTRACT: Bei Leukämien, fortgeschrittenen Lymphomen und anderen hämatologischen Erkrankungen stellt die Transplantation autologer (eigenen)
oder allogener (nichteigenen) Stammzellen (SZT) eine etablierte und in ihrer Bedeutung wachsende Therapieoption dar. Integriert
in moderne Gesamtbehandlungskonzepte werden allogene SZT überwiegend bei akuten Leukämien mit ungünstigem Risikoprofil in
kurativer Intention durchgeführt. Der antineoplastische Effekt einer myelotoxischen bzw. myeloablativen Konditionierungstherapie
wird mit einem hoch wirksamen immunologischen antileukämischen Effekt nichteigener gewebeverträglicher Stammzellen kombiniert.
Demgegenüber werden autologe SZT nach hoch dosierter Radiochemotherapie überwiegend bei fortgeschrittenen lymphatischen Neoplasien
zur Verbesserung der Remissionsqualität eingesetzt. Die Indikationsstellung zur kurativen allogenen SZT muss aufgrund der
mit diesem Verfahren verbundenen Morbidität und Mortalität durch akute und chronische Toxizitäten sowie immunologische Unverträglichkeitsreaktionen
(Transplantat-gegen-Wirt-Reaktion: „graft-versus-host disease“, GvHD) gegen risikoärmere, aber auch ineffektivere Therapieoptionen
sorgfältig abgewogen werden.
Transplantation of autologous (self) or allogeneic (not-self) haematopoietic stem cells for leukaemia, advanced lymphoma,
and other selected haematological diseases is an established treatment modality that is increasingly performed worldwide.
Allogeneic stem cell transplantation (SCT) is mainly performed in acute leukaemia patients with high-risk profiles and is
integrated into modern therapeutic concepts with curative intention. The antineoplastic efficacy of the myelotoxic or myeloablative
conditioning regimens preceding SCT is combined with an immunological, highly effective antileukaemic effect of histocompatible
donor stem and immune cells. In contrast, autologous SCT after high-dose chemotherapy is performed as consolidation therapy
to improve the quality of remission, preferably in advanced neoplasias of the lymphatic system. The indication for a curative
allogeneic SCT, which is associated with significant acute and chronic toxicities as well as immunological complications,
must be carefully balanced against conventional, but less effective, treatment options.
Der Onkologe 04/2012; 15(6):564-574. · 0.17 Impact Factor
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O Ringdén,
M Labopin, D W Beelen,
L Volin,
G Ehninger,
J Finke,
H T Greinix,
S Kyrcz-Krzemien,
D Bunjes,
L Brinch,
D Niederwieser,
R Arnold,
M Mohty,
V Rocha
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ABSTRACT: Ringdén O, Labopin M, Beelen DW, Volin L, Ehninger G, Finke J, Greinix HT, Kyrcz-Krzemien S, Bunjes D, Brinch L, Niederwieser D, Arnold R, Mohty M, Rocha V, for the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) (Karolinska University Hospital Huddinge, Sweden; CEREST-TC EBMT, Paris, France; University of Duisburg-Essen, Germany; Helsinki University Central Hospital, Helsinki, Finland; University Hospital, Dresden, Germany; University Hospital, Freiburg, Germany; Medical University Vienna, Vienna, Austria; Medical University of Silesia, Katowice, Poland; University Hospital, Ulm, Germany; Rikshospitalet, Oslo, Norway; University Hospital, Leipzig, Germany; Charité University Hospital, Berlin, Germany; Université de Nantes, Nantes, France; and Hôpital Saint-Louis, Paris, France). Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients. J Intern Med 2012; 272: 472-483. Background. No survival benefit of using blood stem cells instead of bone marrow (BM) has been shown in matched unrelated donor (MUD) transplantation. Design and methods. In a retrospective registry analysis, we compared the use of blood stem cells (n = 1502) and BM (n = 760) from unrelated donors in patients aged 18-60 years with acute myeloid leukaemia (AML) undergoing myeloablative conditioning between 1997 and 2008. The blood stem cell recipients were older (P < 0.01), had more advanced disease (P < 0.0001) and received less total body irradiation (P < 0.0001) and more antithymocyte globulin (P = 0.01). Results. Recovery of neutrophils and platelets was faster with blood stem cells (P < 0.0001). The incidence of acute graft-versus-host disease (GVHD) was similar, but there was more chronic GVHD in the blood stem cell group [hazard ratio (HR) = 1.29, P = 0.02]. There were no significant differences in nonrelapse mortality (NRM), relapse incidence and leukaemia-free survival (LFS) between the two groups amongst patients with AML in remission. In patients with advanced leukaemia, NRM was lower (HR = 0.61, P = 0.02) and LFS was prolonged (HR = 0.67, P = 0.002) when blood stem cells were used. At 3 years, LFS for all patients, regardless of remission status, was 41% for both treatment groups. The outcome was not affected after multivariable analysis adjusted for confounders. Conclusion. Blood stem cells compared with BM in MUD transplantation for patients with AML in remission resulted in the same rates of LFS. In patients with advanced leukaemia, the blood stem cell group had reduced NRM and improved LFS.
Journal of Internal Medicine 04/2012; 272(5):472-483. · 5.48 Impact Factor
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J Casper,
J Holowiecki,
R Trenschel,
H Wandt,
K Schaefer-Eckart,
T Ruutu,
L Volin,
H Einsele,
G Stuhler,
L Uharek, [......],
A R Zander,
K Larsson,
M Markiewicz,
S Giebel,
T Kruzel,
H A Mylius,
J Baumgart,
U Pichlmeier,
M Freund, D W Beelen
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ABSTRACT: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The safety and efficacy of this new conditioning regimen has been investigated prospectively in patients with AML. A total number of 75 patients with AML in CR were treated with 3 × 14 g/m(2) treosulfan and 5 × 30 mg/m(2) fludarabine, followed by matched sibling or unrelated SCT. Patients were evaluated for engraftment, adverse events, GVHD, and for non-relapse mortality, relapse incidence, overall and disease-free survival (DFS). All patients showed primary engraftment of neutrophils after a median of 20 days. Non-hematological adverse events grade III-IV in severity included mainly infections (59%) and gastrointestinal symptoms (7%). Acute GVHD grade II-IV occurred in 21% and extensive chronic GVHD occurred in 16% of the patients. After a median follow-up of 715 days, the 2-year overall and DFS estimates were 61% and 55%, respectively. The 2-year incidences of relapse and non-relapse mortality reached 34% and 11%, respectively. In summary, our data confirm promising safety and efficacy of the treosulfan-based conditioning therapy in AML patients, ClinicalTrials.gov Identifier: NCT01063660.
Bone marrow transplantation 12/2011; 47(9):1171-7. · 3.00 Impact Factor
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International journal of laboratory hematology 06/2011; 34(1):e3-5. · 1.30 Impact Factor
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ABSTRACT: We evaluated the influence of gene polymorphisms of TLR9 (T1237C; T1486C), IL23R (A1142G), and NOD2 SNP8 (R702W), SNP12 (G908R) and SNP13 (1007fs) on outcome of hematopoietic SCT in a homogenous group of 142 AML patients after non-T-cell-depleted myeloablative transplantation from HLA-identical sibling donors. In our retrospective study, we found that TLR9 gene variant at 1486 influenced transplant outcome. Estimated 5-year OS in patients with the CC gene variant of TLR9 was 70.2% compared with 44.8% (P<0.027) in patients with TC/TT of TLR9 gene. No significant influences on 5-year OS were found for gene polymorphisms of NOD2 or IL23R (A1142G) in this study group. The 5-year treatment-related mortality was lowest in patients with CC gene variant of TLR9 (7.8 vs 23.1%; NS). Acute GVHD grade III-IV was higher in patients with NOD2 gene variants (28 vs 12.8%; P=0.065). In contrast, patients transplanted from donors with the gene variant of IL23R had no occurrence of severe acute GVHD grade III-IV (0 vs 18.4%; P<0.048). However, multivariate analysis confirmed the influence of NOD2 gene variants on the occurrence of acute GVHD grade II-IV after transplant. These results suggest that the gene variants of TLR9, NOD2 and Il23R had influence on the outcome of transplant.
Bone marrow transplantation 05/2011; 46(5):702-8. · 3.00 Impact Factor
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ABSTRACT: Myelodysplastic syndromes (MDSs) often occur in older adults with significant comorbidities. Therefore, a reduced-toxicity conditioning regimen may be more suitable than standard conditioning regimens before allogeneic blood stem cell transplantation. Here, we retrospectively compare the outcome of a treosulfan-based conditioning regimen with standard myeloablative TBI-based conditioning regimens in patients (pts) with MDS. A total of 48 pts with MDS were included in the study, of which 29 (60%) pts received TBI-based and 19 (40%) pts received a treosulfan-based conditioning regimen. A significantly lower relapse incidence (5% vs 34% at 3 years, P=0.019) resulting in a better, but not statistically significant relapse-free survival (RFS) (57% vs 31%, P=0.086) was observed after treosulfan-based conditioning. In pts with increased risk for significant side effects due to comorbidities (haematopoietic stem cell transplantation specific comorbidity index), the estimated 3-year RFS was significantly better in the treosulfan group: 54% (95% confidence interval (CI), 17-90%) compared with pts in the TBI group: 11% (95% CI, 0-44%; log-rank test P=0.0455). Treosulfan-based conditioning therapy is a feasible and effective regimen for pts with MDS, especially in pts with preexisting comorbidities.
Bone marrow transplantation 04/2011; 46(4):502-9. · 3.00 Impact Factor
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Bone marrow transplantation 03/2009; 44(4):265-6. · 3.00 Impact Factor
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ABSTRACT: Toll-like receptor 9 (TLR9) is part of the innate immune system, which is activated by CpG oligonucleotides (ODNs) and produces potent Th1-type innate and adaptive immune responses. It is reported that TLR9 gene variants, T1486C and T1237C, are associated with a reduced TLR9 expression compared with the wild-type gene. In two cohort analyses, we evaluated the influence of these gene variants on the outcome of transplant in 413 patients and donors. A retrospective analysis of the first cohort (n=293) showed that the homozygous CC gene variant of TLR9 (1486) compared with TC/TT gene variants was significantly associated with a markedly improved 5-year TRM (11.7 versus 36.4%, P<0.003), 5-year OS (86.1 vs 48.3%, P<0.001) and a lower relapse rate (13.2 vs 33.3%, P<0.007), whereas the occurrence of acute GVHD was not different. A prospectively performed analysis of the second cohort (n=120) and multivariate analyses confirmed the influence of the CC gene variant on these end points. Compared with patients with TC/TT gene at position 1486 of TLR9, patients with the homozygous CC gene variant had a lower TLR9 mRNA expression and a delayed T-cell immune reconstitution after transplant, which might prevent them from overwhelming immune responses as sepsis or systemic inflammatory response syndrome (SIRS) associated with an increased TRM. In vitro studies using CpG-rich ODNs showed an upregulation of TLR9 expression in cell lines with CC gene variant, but not in cell lines with wild-type gene.
Bone marrow transplantation 03/2009; 44(5):295-302. · 3.00 Impact Factor
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ABSTRACT: Polymorphisms in cytokine genes can influence immune responses and inflammation and thereby affecting the outcome of hematopoietic stem-cell transplantation. We analyzed a single-nucleotide polymorphism in the gene for the interleukin-23 receptor (IL-23R) (1142G>A) in a cohort of 221 transplant recipients and their human leukocyte antigen (HLA)-identical sibling donors and in a second cohort of 186 transplant recipients and their HLA-identical unrelated donors. Genotypes were tested for an association with graft-versus-host disease (GVHD) by multivariate analysis. The donor's IL-23R genotype was significantly associated with a reduced risk of acute GVHD in both cohorts for patients after transplant. Analysis of all 407 transplant recipients showed that IL-23R (1142G>A, Arg381Gln) genotype of the donor was associated with a decreased risk of grades 2-4 acute GVHD (31.6 compared to 51.0%, P=0.02) and grades 3-4 severe acute GVHD (3.9 compared to 23.4%, P=0.003). Death in remission was significantly lower in patients transplanted from donors with variant IL23-R (11.7 versus 27.7%, P=0.028), whereas overall survival or relapse rates were not influenced significantly by the IL-23R genotype. Among recipients of hematopoietic cells from HLA-identical donors, the IL-23R (Arg381Gln) gene variant on the donor side has a protective effect on the occurrence of acute GVHD in recipients after transplantation.
Bone Marrow Transplantation 06/2008; 41(9):821-6. · 3.75 Impact Factor
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ABSTRACT: The polymorphic gene expression of CYP2C19 causes individual variability in drug metabolism and thereby in pharmacologic and toxicologic responses. We genotyped 286 patients and their donors for the CYP2C19 gene who underwent allogeneic transplantation for various diseases and analyzed their outcome. Patients were classified as: poor metabolizers (PMs; 3.1%), intermediate metabolizers (IMs; 24.5%) and extensive metabolizers (EMs; 72.5%). Patients genotyped as PMs had significant higher hepato- and nephrotoxicities compared to IMs or EMs. Maximum bilirubin and serum creatinine levels measured after transplant were approximately twofold higher than those of EMs or IMs. The increased toxicity resulted in an increased 4-year estimate for transplant-related mortality (TRM) with 50+/-18.6% for PMs compared to 25.1+/-3.7% for EMs (P<0.018) and 22.7 +/-5.6% for IMs (P<0.042), whereas no significant influence for relapse rate, overall survival or incidence of acute graft-versus-host disease grade 2-4 were found between the groups. Multivariate analysis including all potential factors that might influence TRM confirmed that the genotype of CYP2C19 is an independent factor, which influenced TRM significantly. These results suggest that genotyping for CYP450 2C19 can help to identify patients with higher risk for TRM.
Bone Marrow Transplantation 10/2007; 40(7):659-64. · 3.75 Impact Factor
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ABSTRACT: RNA interference is referred to as the recently discovered process of sequence-specific, post-transcriptional gene silencing that is initiated by double-stranded RNA molecules known as small interfering RNAs (siRNA). We herein present a first report on the in vivo application of targeted non-virally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome-positive chronic myeloid leukaemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic haematopoietic stem cell transplantation. We found a remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells. In vivo siRNA application was well tolerated without any clinically adverse events. Our findings imply that the clinical application of synthetic siRNA is feasible, safe and has real potential for genetic-based therapies using synthetic non-viral carriers.
Clinical and Experimental Medicine 07/2007; 7(2):47-55. · 1.58 Impact Factor
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M Schmidt-Hieber,
I W Blau,
R Trenschel,
R Andreesen,
G Stuhler,
H Einsele,
L Kanz,
U Keilholz,
O Marinets, D W Beelen,
A A Fauser,
L Volin,
T Ruutu,
L Uharek,
T Fietz,
W Knauf,
W Hopfenmüller,
E Thiel,
M Freund,
J Casper
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ABSTRACT: In recent years, reduced-intensity conditioning (RIC) regimens before allogeneic stem cell transplantation (SCT) are increasingly used in patients not eligible for conventional conditioning. We did a retrospective, multicenter analysis to assess the feasibility of conditioning with fludarabine and treosulfan before allogeneic SCT in multiple myeloma patients. Thirty-four patients with a median age of 51.5 years were included in the analysis. All patients underwent myeloablation after conditioning followed by stable engraftment, and 29 of 31 evaluable patients (94%) showed early complete hematopoietic chimerism. Non-hematological toxicities were limited and encompassed mainly fever in neutropenia and infections. Grade II-IV acute and chronic graft-versus-host disease was observed in 33 and 39%, respectively. With a median follow-up of 708 days (range 60-1729 days), the median progression-free survival was 180 days. The treatment-related mortality was 10% on day 100 and 25% after 1 year. The median overall survival has not yet been reached. Our data indicate that conditioning with fludarabine and treosulfan before allogeneic SCT is feasible in intensively pretreated multiple myeloma patients and leads to stable engraftment and complete hematopoietic chimerism. Randomized trials are warranted to determine if this approach might be incorporated in an algorithm of multiple myeloma treatment.
Bone Marrow Transplantation 05/2007; 39(7):389-96. · 3.75 Impact Factor
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ABSTRACT: Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).
Histology and histopathology 05/2007; 22(4):365-72. · 2.48 Impact Factor
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Clinical and Experimental Medicine 04/2006; 6(1):45-7. · 1.58 Impact Factor
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O Maywald,
M Pfirrmann,
U Berger,
L Breitscheidel,
A Gratwohl,
H-J Kolb, D W Beelen,
A Tobler,
G Metzgeroth,
S U Gnad,
A Hochhaus,
J Hasford,
R Hehlmann,
A Reiter
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ABSTRACT: We investigated the impact of a cytogenetic response (CyR) to IFN prior to and at the time of allogeneic hematopoietic stem cell transplantation (HSCT) on transplant-related mortality (TRM), relapse rate and survival probability after HSCT in 162 transplanted patients with chronic myeloid leukemia. One-hundred-one patients (62.3%) achieved a CyR prior to HSCT. Survival probabilities were higher in patients, who achieved any CyR prior to HSCT than in patients without CyR (63.6 vs 49.2%: P = 0.019). Survival probabilities in patients, who achieved a major CyR were better than in patients with minimal and minor CyR or in patients with no CyR (69.4 vs 58.8% vs 49.2%: P = 0.040). TRM and survival of chronic phase patients without CyR at the time of HSCT were similar to that of patients transplanted in advanced phase. Both groups combined had an outcome inferior to patients with at least minimal CyR (TRM, Gray test: P = 0.016, survival, log-rank test: P = 0.002). Univariate and multivariate analyses identified CyR prior to or at HSCT as a strong and independently favorable prognostic factor. We therefore conclude that allogeneic HSCT in CyR should be investigated prospectively as an alternative treatment option in defined patient groups.
Leukemia 04/2006; 20(3):477-84. · 9.56 Impact Factor
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J Thiele,
H M Kvasnicka,
H Dietrich,
G Stein,
M Hann,
A Kaminski,
N Rathjen,
K A Metz, D W Beelen,
M Ditschkowski,
A Zander,
N Kroeger
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ABSTRACT: Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.
Histology and histopathology 08/2005; 20(3):879-89. · 2.48 Impact Factor
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Bone Marrow Transplantation 07/2005; 35(12):1211. · 3.75 Impact Factor
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R Trenschel,
M Ditschkowski,
A H Elmaagacli,
M Koldehoff,
H Ottinger,
N Steckel,
M Hlinka,
R Peceny,
P-M Rath,
H Dermoumi, D W Beelen
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ABSTRACT: Caspofungin (CAS) is the first of a new class of antifungal agents, the echinocandins, that interfere with fungal cell wall synthesis by inhibition of glucan synthesis. Here, we report the results of 31 patients treated with CAS following allogeneic SCT. CAS was administered as a second-line agent to patients with invasive fungal infection (IFI) (n=15) or fever of unknown origin (n=16) who were recalcitrant to or intolerant of prior antifungal therapy. Unsuccessful first-line regimes included amphotericin B (n=17), liposomal amphotericin B (n=5), fluconazole (n=3), itraconazole (n=1), and voriconazole (n=2). All patients received concomitant immunosuppressive therapy for graft-versus-host disease. In 23 patients, cyclosporin A (CSA) and CAS were administered concurrently without any major side effects detected. Observed increases in GPT were not clinically significant. Normalization of serum creatinine and significant reductions in C-reactive protein were observed in response to CAS. Favorable outcome to CAS were documented in eight of 15 patients with IFI and in 15 of 16 patients with fever of unknown origin. CAS is a promising alternative in patients with IFI and fever of unknown origin in the setting of allogeneic SCT.
Bone Marrow Transplantation 04/2005; 35(6):583-6. · 3.75 Impact Factor
