scholarly journals The role of prognostic factors in assessing ‘high-risk’ subgroups of patients with chronic lymphocytic leukemia

Leukemia ◽  
2007 ◽  
Vol 21 (9) ◽  
pp. 1885-1891 ◽  
Author(s):  
N E Kay ◽  
S M O'Brien ◽  
A R Pettitt ◽  
S Stilgenbauer
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia

Chronic Lymphocytic Leukemia: Evaluation of Cytogenetic Markers as Prognostic Factors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4860-4860
Author(s):  
Jose Carda ◽  
Patricia Sousa ◽  
Patricia Olim ◽  
Emília Magalhães ◽  
Luis Rito ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Retrospective Study ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progressive Disease ◽  
Risk Group ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Intermediate Risk

Abstract Abstract 4860 Backgroud: Chronic lymphocytic leukemia (CLL) is one of the most frequent chronic lymphoproliferative disorders in Europe. It is characterized by persistent monoclonal lymphocitosis with localized or generalized lymphadenopathy. Despite the initial clinical presentation, it has a heterogeneous natural history, with the majority of patients living 10–12 years, but with some patients dying rapidly, within 2–3 years of diagnosis. Beside clinical prognostic factors, novel cytogenetic markers are recognized to be useful in predicting disease free and overall survival in CLL. AIMS: In a retrospective study throughout 10 years (1999-2009), we analyzed the clinical and biological presentation and compared the evolution and survival of patients with B-CLL using different cytogenetic markers. METHODS: We identified 112 cases (63 males and 49 females) of B-CLL with cytogenetic study by fluorescence in situ hybridization (FISH). RESULTS: Amongst 112 patients, the male to female (M/F) ratio was 1.3:1 and the median age was 70 (43-96) years. At diagnosis, the median lymphocyte count was 15.5 G/L (5.4-173). Fifty five patients (49%) had lymphadenopathies and seventeen (15%) had splenomegaly and/or hepatomegaly at presentation. By the revised Rai staging system seventy (63%) patients were included in low risk group, thirty (27%) in intermediate risk group and twelve (10%) in high risk group. The expression of ZAP-70 and CD38 by flow citometry was performed in 75 patients and revealed 13 (17%) patients CD38+ and 12 (16%) ZAP70+. The study of chromosomal aberrations with FISH showed thirty six patients (32%) with no abnormality, thirty six (32%) with isolated 13q deletion, fifteen (14%) with 12 trisomy, twelve (11%) with 11q deletion and thirteen (11%) with 17p deletion. Forty (36%) patients showed progressive disease in a median time of sixteen months (0-120), thirteen with 13qdel, seven with 17pdel and five with 12 trisomy. After treatment two patients showed progressive disease, six maintain a stable disease and thirty two obtain a remission, nine in complete remission. The Overall Survival (OS) at ten years was 70%. By the revised Rai staging system the OS at ten years was 80% for low risk, 70% for intermediate risk and all the high risk patients died during follow up. The OS at five years for the del13q-, 12 trisomy, del11q- and del17p- was 90%, 88%, 58% and 60%, respectively. SUMMARY: Chronic lymphocytic leukemia is currently considered a chronic disorder with a favourable outcome, but with a variable evolution to progressive disease. This retrospective study allowed the characterization of patient with CLL in our department and the acknowledgement that our results are quite similar to the published data. Disclosures: No relevant conflicts of interest to declare.

Occurrence of Chromosomal Translocations as Independent Prognostic Factor in Chronic Lymphocytic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2084-2084
Author(s):  
Christine Mayr ◽  
Cathrine Schulz ◽  
Stephan Stilgenbauer ◽  
Alexander Kröber ◽  
Hartmut Döhner ◽  
...  
Keyword(s):  
Risk Factor ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Chromosomal Translocations ◽  
Study Cohort ◽  
Binet Stage

Abstract Background: The course of chronic lymphocytic leukemia (CLL) is highly variable. Therefore, there is a need for prognostic factors that are readily performed and have a high predictive power. Methods: The occurrence of translocations, a recently identified prognostic factor in CLL (Blood2006;107:742–751), was studied in 148 previously untreated, mostly early-stage patients and compared with respect to treatment-free survival (TFS) to several prognostic factors (Binet stage, mutational status of immunoglobulin genes, CD38, thymidine kinase serum concentration and cytogenetic aberrations detected by interphase FISH). To investigate chromosomal translocations, we applied a new method, CpG oligodeoxynucleotide stimulation that allows efficient preparation of metaphase spreads from CLL cells. Results: The occurrence of translocations classified the majority of patients with poor prognosis. If translocations were investigated in addition to the currently used prognostic factors they identified those patients who were classified to be in a low-risk group based on traditionally used criteria, who had in fact a high risk for progression. Vice versa, patients in the high-risk groups for progression who did not have translocations had a long TFS. There was a substantial overlap of patients who had translocations and additional risk factors. But when we omitted patients who had translocations in addition to a given risk factor, we found that the respective risk factor lost its prognostic significance for the remaining patients. The two factors that retained their prognostic power in these patients were translocations and the Binet stage. This could suggest that the prognostic significance of the currently used factors derives from their frequent co-occurrence with translocations. Finally, multivariate analyses demonstrated that Binet stage (p=0.02) and translocations (p=0.0005) are the factors with the highest impact on TFS in our study cohort. Conclusion: We present a method for efficient preparation of metaphase spreads in CLL cells in order to investigate chromosomal translocations. The occurrence of translocations is an independent prognostic marker in CLL. Finally, translocations occur not as a late event in the course of the disease and may define a new biological subgroup in this disease entity.

Characteristic Proinflammatory Serum Cytokine Profiles In Patients with B-Cell Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3595-3595
Author(s):  
James J. Harding ◽  
Raymond Yeh ◽  
Yan Nikhamin ◽  
Mark Frattini ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Regulatory Role ◽  
Healthy Controls ◽  
Β2 Microglobulin ◽  
Cd38 Expression

Abstract Abstract 3595 Background: Cytokines are posited to play a critical regulatory role on the survival of the B-cell neoplastic clone in Chronic Lymphocytic Leukemia (CLL). AIM: The primary goals of this study were 1) to define additional relevant cytokines, growth factors and chemokines in CLL pathophysiology and 2) to correlate abnormal cytokine levels with disease stage, relevant hematological data and multiple prognostic factors. METHODS: A novel bead-based protein array system was employed to simultaneously measure 38 proinflammatory cytokines in the sera of CLL patients (N=116) and healthy age and sex matched controls (N=30). These results were correlated with Rai stage, β2-microglobulin level, LDH, CD38 expression and cytogenetic abnormalities. RESULTS: We first confirmed previous observations that TNFα, IL-1α, IL-1RA, IL-10, sIL-2Rα, VEGF and sCD40 ligand are significantly elevated in patients with CLL as compared with healthy controls. Expanding on the current literature, we demonstrated perturbations in an additional 15 serum cytokines in affected individuals. Compared to healthy controls, CLL patients had an increase in serum levels of IL-3 (p=0.002), IL-7 (p=0.008), INF-2α (p<0.0001), MCP-1 (p<0.0001), MIP-1β (p=0.002), MDC (p<0.0001), Fractakine (p<0.0001), EGF (p<0.0001), FGF-2 (p<0.0001), GRO (p<0.0001), Eotaxin (p<0.0001) and FLT-3 ligand (p<0.0001). Patients with CLL also exhibited significantly lower levels of INF-γ (p<0.01), IL-6 (p<0.005) and IL-8 (p<0.002) when compared to healthy individuals. Advanced Rai stage and high risk chromosomal abnormalities (del 11q and del 17p) strongly correlated with higher serum levels of TNFα, soluble IL-2Rα, IL-10, MCP-1, MIP-1α, MIP-1β and IP-10. Finally, serum levels of TNFα, MIP-1α and MIP-1β correlated with other adverse prognostic markers, including total white blood cell count, serum β2-microglobulin and LDH levels as well as CD38 expression. CONCLUSION: We have demonstrated numerous previously unrecognized cytokine abnormalities in patients with CLL and described a unique cytokine signature associated with advanced disease. Supported by the current understanding of cytokine biology and CLL pathophysiology, our observations suggest an important regulatory role for hematopoietic cytokines, such as IL-3 and IL-7, in promulgating survival of the aberrant B-cell clone. Likewise, the profoundly high levels of chemokines (i.e. MCP-1, MIP-1α, MIP-1β, IP-10) and their association with high risk prognostic factors argue for their role in sustaining the neoplastic microenvironment. Finally, the altered levels of IL-10, IL-6 and INF-γ observed in patients with CLL likely contribute to the immunosuppressive phenotype of the disease state. Disclosures: No relevant conflicts of interest to declare.

Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

2006 ◽  
Vol 24 (3) ◽  
pp. 437-443 ◽  
Author(s):  
John C. Byrd ◽  
John G. Gribben ◽  
Bercedis L. Peterson ◽  
Michael R. Grever ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Interphase Cytogenetics ◽  
Mutational Status ◽  
The Impact

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig VH mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig VH mutational status to classify risk, there was no association between complete response rate with either unmutated Ig VH mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig VH unmutated patients as compared with the Ig VH mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. Conclusion These data demonstrate that high-risk CLL patients characterized by Ig VH unmutated (≥ 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig VH mutational status and interphase cytogenetics on treatment outcome.

Gene Expression Profile of Protein Kinases Reveals a Distinctive Signature of Chronic Lymphocytic Leukemia (CLL) and Points to a Role of Second Generation Protein Kinase Inhibitors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2794-2794
Author(s):  
Simona Tavolaro ◽  
Sabina Chiaretti ◽  
Monica Messina ◽  
Francesca R. Mauro ◽  
Ilaria Del Giudice ◽  
...  
Keyword(s):  
Gene Expression ◽  
Prognostic Factors ◽  
Protein Kinase ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Kinase Activity ◽  
Lymphocytic Leukemia ◽  
P Value

Abstract Background. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of relatively mature B cells and by a very variable clinical course. This clinical heterogeneity is sustained by different biologic parameters, such as the mutational status of the immunoglobulin variable genes (IgVH), CD38 and ZAP-70 expression. In order to investigate the potential role of protein kinase (PK) inhibitors in CLL, we evaluated the gene expression profile of 1324 probesets annotated as PK using the HGU133 Plus2.0 Affymetrix arrays. Methods. We evaluated 44 CLL and 137 acute lymphocytic leukemia (ALL) patients. Two additional sets of CLL (49 cases) were utilized to validate the results obtained. Probesets identified as PK genes were used for all the analyses, namely unsupervised clustering, Analysis of Variance (ANOVA) and t-test analysis. ANOVA was performed using a p-value of ≤0.001: further selection was performed retaining only those probesets whose mean expression level was ≥300 in at least one group and showed a fold change difference of ≥1.5 across all groups. Finally, to specifically identify genes differentially expressed between different subclasses of CLL, a t-test was applied: probesets were required to have a p-value ≤0.05 and a fold change>1.5. Results. Unsupervised analysis, performed on CLL samples and different ALL subgroups, highlighted in CLL a unique and very homogeneous pattern characterized by the overexpression of a large set of PK; these results were further confirmed by ANOVA. Moreover, we identified 16 PK genes that were highly expressed in all 3 CLL sets analyzed. These genes codify for proteins with tyrosine kinase activity (SYK, LYN, BLK, LCK, JAK1, CSK and FGR), serin-threonin kinase activity (PIM2, PFTK1, TLK1, MAP4K1, PDPK1, PRKCB1 and STK10) or both (GRK6 and WEE1). Some of the selected genes are members of important protein kinase families, involved in cellular signaling, such as Src kinases (SFK), MAPK and JAK kinase family. PK expression was also analyzed in different CLL subclasses, subdivided according to different prognostic factors; in particular, we compared IgVH mutated vs unmutated patients, CD38+ vs CD38- cases and, finally, ZAP-70+ vs ZAP-70- patients in the 3 experimental CLL sets. Comparison between IgVH mutated vs unmutated cases highlighted a differential expression of ZAP-70 in all the 3 sets analyzed. Contrariwise, no PK was associated with the other prognostic parameters. Thus, these analyses did not show a specific signature associated with the abovementioned biologic features, suggesting that PK overexpression is specific of the disease itself rather than of CLL subclasses. Conclusions. Our results show that CLL is characterized by a very peculiar PK signature and identify some potential molecular targets. Moreover, our findings indicate that a common mechanism of PK-mediated deregulation is operational in CLL cells, independently of other prognostic factors. Based on these pre-clinical data, we propose that second generation PK inhibitors may have a role in the management of all CLL patients.

High Expression of Haematopoietic Cell Specyfic Lyn Substrate-1 (HS1) Predicts Survival of B-Cell Chronic Lymphocytic Leukemia Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2853-2853
Author(s):  
Aleksandra Butrym ◽  
Miroslaw Majewski ◽  
Justyna Dzietczenia ◽  
Tomasz Wrobel ◽  
Kazimierz Kuliczkowski ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Patient Survival ◽  
Clinical Course ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Mutational Status ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Abstract 2853 B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in adults in western countries. It is characterized by B lymphocyte accumulation in peripheral blood, bone marrow, lymph nodes and other lymphatic organs. Leukemic cells derive most commonly from B lymphocytes, rarely from T or NK cells. B-CLL is known from its heterogeneous clinical course from indolent to very aggressive. In spite of many known prognostic factors (such as immunoglobulin heavy chain gene mutational status – IgVH, expression of ZAP70 and CD38), is still difficult to classify a single patient to particular risk group and to predict CLL clinical course. That is why new prognostic factors are still needed. HS1 (hematopoietic cell specific Lyn substrate-1) is an intracellular protein, which expression occurs mainly in hematopoietic cells. HS1 plays an important role in regulating T cell immune synapse and affects many functions of NK cells, including the lysis of target cells, adhesion, chemotaxis and clustering of actin in the lytic synapse. The role of HS1 in B cells is poorly understood. This protein was identified in B cells as the primary receptor substrate for phosphorylation by BCR after antigenic stimulation. Other studies have confirmed the role of HS1 in the process of clonal expansion and deletion induced by antigen-receptor interaction in B cells and T. HS1 is rapidly phosphorylated in B cells in the vicinity of tyrosine residues and is a substrate for tyrosine kinases: the Src family and Syk, including Lyn, FGR, Fyn and Lck. It has been shown that HS1 interacts with the cell cytoskeleton in both: normal and leukemic B cells. HS1 protein is an important regulator of motility, migration and adhesion of leukemic cells and is involved in cytoskeleton rearrangement. HS1 can have impact on homing and migration of CLL cells. It can indirectly promote disease progression and influence patient survival. The aim of this study was to evaluate HS1 expression in CLL patients in connection with other known prognostic factors and patient survival. Material and methods: 92 untreated CLL patients (45 women and 47 men), aged between 42 and 88 years (median age 67 years), were included into the study. Diagnosis was made basing on typical clinical, hematological and immunophenotypical picture. The control group was consist of 28 healthy matched people (11 men and 17 women), aged between 36 and 79 years (median age 59 years). HS1 protein expression was determined by western blot. Comparative semi-quantitative indication of the degree of saturation of the bands analyzed by densitometry using the gel documentation system Gel-Doc (Bio-Rad) and a computer program to analyze the 1-D Quantity One (Bio-Rad). Assuming conventional units [AU - arbitrary units], depending on the saturation band, patients were divided into four groups with the expression of HS1 protein expressed in value from 0 to 3. Lack of expression was expressed as 0 [AU], and expression of the strongest, with the highest saturation band measured as 3 [AU]. Mutational status of IgVH, as well as CD38 and ZAP70 expression were also analyzed. Results: HS1 expression was significantly higher in CLL patients comparing to controls. Positive correlation was shown between HS1 and: age (p=0.0454), Rai stage (p=0.0412), leukocytosis (p=0.0129) and β2-microglobulin (p=0.0342). There was negative correlation between HS1 and hemoglobin level (p=0.0464) and platelet count (p=0.0310). Patients with lymphocyte doubling time shorter or equal to 6 months had higher expression of HS1. Expression of HS1 significantly influenced survival of CLL patients. Patients with higher HS1 expression had shorter survival than those with lower HS1 expression (p=0.0329). Conclusions: 1. Higher HS1 expression is observed in more advanced CLL stages. 2. Expression of HS1 in CLL cells is matched with shorter patient survival The relationship between expression of HS1 and survival of patients with B-CLL. Disclosures: No relevant conflicts of interest to declare.

Germline Genes Specific to Chronic Lymphocytic Leukemia (CLL) and Genes Common to CLL, Lymphoplasmacytic Lymphoma/Waldenström’s Macroglobulinemia, and Other Non-Hodgkin Lymphomas Are Important in Susceptibility

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3127-3127
Author(s):  
Ola Landgren ◽  
Sigurdur Y Kristinsson ◽  
Xueying Sharon Liang ◽  
Ingemar Turesson ◽  
Magnus Bjorkholm ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Population Based ◽  
Case Control ◽  
Lymphocytic Leukemia ◽  
Lymphoplasmacytic Lymphoma ◽  
Population Based Study ◽  
First Degree Relatives ◽  
Germline Genes

Abstract Background. Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in chronic lymphocytic leukemia (CLL). Population-based studies have found CLL and non-Hodgkin lymphomas (NHLs) to aggregate in families. The aim of this study was to expand our understanding on the role of susceptibility genes in CLL and other lymphoproliferative malignancies. Methods. Using the population-based Swedish Population-, Cancer-, and Multigenerational registries, we identified all CLL patients (n=9,717) diagnosed from 1958–2004 with linkable first-degree relatives (N=26,947). We also obtained information on 38,159 matched controls and their 107,223 first-degree relatives. Cancer risks in relatives of CLL patients were compared with those in relatives of controls using marginal survival models. In parallel, we conducted a candidate gene association study in unrelated familial lymphoma cases (44 CLL, 71 Waldenström’s macroglobulinemia (WM)) from our clinical studies of high risk families (which were selected for having multiple cases of either CLL or WM) compared to 107 spouses from the same families. We tested 1536 single nucleotide polymorphisms (SNPs) in 152 candidate genes in several pathways including apoptosis, DNA repair, immune response, and oxidative stress using a custom Illumina genotyping platform. Results. In our population-based study, we found relatives of CLL patients to have an increased risk for CLL (relative risk [RR]=8.5, 95%CI=6.1–11.7), lymphoplasmacytic lymphoma (LPL)/WM (RR=4.0, 95%CI=2.0–8.2) and other NHLs (RR=1.7, 95%CI=1.4–2.2), but not for Hodgkin lymphoma, multiple myeloma, or other hematologic tumors. In our SNP-based study, we found several genes (e.g., IL-10, BCL-2, TRAIL, and TRAILR1) to be significantly associated with both familial CLL and WM. In particular, a SNP in the promoter region of IL-10 (rs1800890, −3575T&gt;A), which has been previously detected in other NHL case-control studies, was associated with both CLL and WM. Conclusions. We conclude that germline genes specific to CLL and genes common to CLL, LPL/WM and other NHLs are important in susceptibility. We found consistent patterns in both our population-based study and our clinical high-risk families. Our findings for BCL-2, TRAIL, and TRAILR1 highlight the important role of apoptosis pathways in the etiology of these lymphomas. Better characterization of early genetic lesions will ultimately provide clues to pathogenesis and allow identification of novel molecular targets.

Complex analysis of prognostic factors in chronic lymphocytic leukemia

2007 ◽  
Vol 148 (16) ◽  
pp. 737-743
Author(s):  
Béla Kajtár ◽  
Pál Jáksó ◽  
László Kereskai ◽  
Ágnes Lacza ◽  
Gábor Méhes ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Complex Analysis ◽  
Lymphocytic Leukemia

Bevezetés: Az utóbbi években felfedezett számos új prognosztikai faktor segítséget nyújthat a várható túlélés meghatározásához krónikus lymphocytás leukémia esetében. Célok: Jelen tanulmány célja e prognosztikai faktorok gyakoriságának, valamint egymással való összefüggésének meghatározása volt 419 beteg mintáin. Módszerek: 160 esetben végezték el az immunglobulin-nehézláncgén mutációs vizsgálatát. Eredmények: Az esetek 62%-ában nem mutált immunglobulin gént találtak, a nehézlánc géncsaládok használata különbözött a mutációs státusz függvényében. A CD38 expresszió 78%-os konkordanciát mutatott a mutációs státusszal, a ZAP-70-expresszió tekintetében korrelációt nem figyeltek meg. Citogenetikai abnormalitást 76%-ban láttak, a leggyakoribb eltérések a del(13q) (57%), a 12-es triszómia (15%), a del(11q) (12%) és a del(17p) (6%) voltak. A del(11q)-t hordozó esetek 95%-a nem mutált, az egyedül del(13q)-t hordozó esetek 74%-a mutált IgH-gént tartalmazott. Következtetések: A vizsgált paraméterek nem függetlenek egymástól, ezért alkalmazásuk a klinikai gyakorlatban gondos tervezést igényel.

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