Predictors of Survival in CLL: Multivariate Analyses Reveal Significant Correlation with IgVH Gene Mutation Status, Clinical Stage, and Cellular CD38 (but Not Zap-70) Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5010-5010
Author(s):  
Alicia D. Volkheimer ◽  
Marc C. Levesque ◽  
Bethany E. Beasley ◽  
Louis Diehl ◽  
Youwei Chen ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Doubling Time ◽  
Multivariate Analyses ◽  
Medical Center ◽  
Clinical Stage ◽  
Leukemia Cell ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Binet Stage ◽  
Univariate Analyses

Abstract One of the complexities of chronic lymphocytic leukemia (CLL) is that some patients die early from the disease, while others identically staged by conventional means may live more than two decades. This has led to a search for prognostic indicators that correlate better with eventual survival. Candidate markers include Rai stage, Binet stage, lymphocyte doubling time (DT), immunoglobulin heavy chain V region (IgVH) mutation status, and leukemia cell CD38 and Zap-70 expression. To determine which of these markers correlate best with survival in univariate and multivariate analyses, we examined these parameters in 150 CLL patients from a VA medical center and a university medical center. CLL cells were purified from patients not receiving active treatment with WBC >20,000/uL by deleting T cells, monocytes, neutrophils, and erythrocytes using antibodies against CD2, CD3, CD16, CD36, CD56, and glycophorin A, and centrifugation over ficoll-Hypaque (CLL purity > 97%). In univariate analyses, patients with advanced stage on presentation had shorter survival than those with low stage [14.0 yr for high modified Rai stage vs. 25.3 yr for low stage (p = 0.013), and 13.8 yr, 13.4, and 25.3 yr for Binet stages C, B, and A, respectively (p = 0.033)]. Patients with a lymphocyte DT >3 yr survived twice as long (22.6 yr) as those with a DT <3 yr (11.3 yr) (p = 0.004). There was a strong relationship of IgVH mutation status with survival (median survival 22.6 yr for mutated, 9.4 yr for unmutated; p = 0.0006). Likewise, cellular CD38 expression significantly correlated with survival (CD38 neg 25.3 yr, CD38 pos 13.4 yr, p = 0.008). Zap-70 expression determined by quantitative immunoblot [Zap-70/actin ratio (anti-Zap-70 antibody from Upstate; clone 2F3.2)] was not significantly related to survival (Zap-70 pos 20.8 yr, Zap-70 neg 22.6 yr). Other parameters found not to be related to eventual survival were WBC on presentation, maximum WBC reached before treatment, and time from diagnosis to initial treatment. IgVH mutation status was significantly related to lymphocyte DT, CD38 expression, and Zap-70 expression. In multivariate analyses using the proportional hazards model, IgVH mutation status (p = 0.001), cellular CD38 expression (p = 0.025), and Binet stage (p = 0.026) were significantly associated with survival (with p = 0.0002 overall for these three parameters in the model), but Zap-70 had no significant relationship to survival in the model. Thus, in contrast to other reports, cellular Zap-70 expression does not correlate with various parameters of disease severity (including survival) in our cohort of CLL patients. In summary, our univariate analyses show significant correlations of advanced clinical stage, short lymphocyte doubling time, high CD38 expression, and unmutated IgVH with short survival. However, multivariate analyses show that only IgVH gene mutation status, clinical stage at presentation, and cellular CD38 expression correlate significantly with survival.

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1840-1847 ◽  
Author(s):  
Rajendra N. Damle ◽  
Tarun Wasil ◽  
Franco Fais ◽  
Fabio Ghiotto ◽  
Angelo Valetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Risk Category ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Staging Systems ◽  
V Genes ◽  
V Gene

Abstract Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

Familial Chronic Lymphocytic Leukemia(CLL): The Mayo Clinic Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1906-1906
Author(s):  
Tufia C. Haddad ◽  
Tait D. Shanafelt ◽  
Susan L. Slager ◽  
Robert L. Phyliky ◽  
Clive S. Zent ◽  
...  
Keyword(s):  
B Cell ◽  
Gene Mutation ◽  
Mayo Clinic ◽  
Lymphocytic Leukemia ◽  
Time Interval ◽  
Degree Relative ◽  
Mutation Status ◽  
Cytogenetic Abnormalities ◽  
Cd38 Expression ◽  
Second Degree

Abstract Background: Over the last decade, increasing numbers of families with at least 2 cases of CLL or other B-cell lymphoproliferative disorders have been described. Methods: Families seen at Mayo Clinic with at least one individual diagnosed with CLL and one or more first or second degree relative diagnosed with CLL or a B-cell lymphoproliferative disorder(LPD) were identified. Clinical characteristics and risk stratification test results (cytogenetic abnormalities by FISH, level of CD38 expression, and IgVH gene mutation status) were extracted and reviewed. Serum, intracellular and CLL B cell secreted levels of pro- and anti-angiogenic cytokines (VEGF, BFGF, and TSP) were also compared between cases of familial and sporadic CLL. Results: Seventy-one families seen at Mayo Clinic were identified meeting criteria for familial CLL. Of the 71 index CLL families, 78.9% (n=56) had at least one other first or second-degree relative with CLL or a B cell LPD, 15.5% (n=11) had 2 other affected members, and 5.6% (n=4) had 3 or more affected members. Of affected family members with B-cell LPDs other than CLL, 64% (n=25) had non-Hodgkin lymphoma, 21% (n=8) had Hodgkin disease, 10% (n=4) had multiple myeloma or Waldenstrom macroglobulinemia, and 5% (n=2) had another lymphoid leukemia (1 ALL, 1 hairy cell leukemia). The median age was 62, with 63% males and 37% females. The majority of individuals had an early Rai stage at diagnosis (stage 0–66%, stage I-19%). Results of cytogenetic testing by FISH, CD38 status, IgVH gene mutation status appear similar in familial and sporadic CLL cases seen at Mayo clinic during the same time interval. No clear pattern of IgVH gene mutation status, IgVH gene family usage, level of CD38 expression, or cytogenetic abnormalities by FISH was seen among multiple affected members from the same family. There were also no significant differences noted in serum, intracellular, and CLL B cell secreted levels of VEGF, BFGF or TSP in the familial samples when compared to a cohort of non-familial samples. Conclusions: Expression of cytogenetics by FISH, immunophenotype, IgVH mutation status and levels of serum, intracellular and cytoplasmic pro- and anti-angiogenic factors(VEGF, BFGF, and TSP) were similar in individuals with familial and sporadic CLL.

Rel a Is a Novel Prognostic Marker in CLL That Is Independent of VH Gene Mutation Status, CD38 Expression and ZAP-70 Expression

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4153-4153
Author(s):  
Saman Hewamana ◽  
Thet Thet Lin ◽  
Clare Rowntree ◽  
Kamaraj Karunanithi ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Dna Binding ◽  
Prognostic Marker ◽  
Prognostic Significance ◽  
Hazard Ratio ◽  
Response To Therapy ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Binet Stage ◽  
Time To First Treatment

Abstract We recently demonstrated that the NF-kB subunit Rel A is associated with in vitro survival and clinical disease progression in CLL. We therefore hypothesized that Rel A would have prognostic significance in this disease. Rel A DNA binding was quantified in nuclear extracts derived from 131 unselected CLL patient samples using a quantitative DNA binding ELISA-based method. We tested the ability of Rel A to predict for the requirement for treatment and survival and compared our findings with other established prognostic markers. Rel A DNA binding was strongly associated with advanced Binet stage (P<0.0001) but did not correlate with IgVH mutation status (P = 0.25), CD38 expression (P = 0.87) or ZAP-70 expression (P = 0.55). It was predictive of time to first treatment (P = 0.02) and time to subsequent treatment (P = 0.0001). In addition, Rel A was the most predictive marker of survival both from date of diagnosis (hazard ratio 9.1, P = 0.01) and date of entry into the study (hazard ratio 3.9, P = 0.05) and retained prognostic significance in multivariate analysis for both time to first treatment and overall survival in the presence of Binet stage, IgVH mutation status, CD38 and ZAP-70. Take together our data shows that Rel A is an independent prognostic marker of survival in CLL and appears to have the unique capacity to predict the duration of response to therapy. Prospective assessment of Rel A as a marker of clinical outcome and as a therapeutic target is now clearly warranted.

Prior Treatment Relates More Strongly to Richter’s Transformation Than ZAP-70, CD38, IgVH Gene Mutation Status, and Cytogenetic Abnormalities: Findings of an Observational Cohort Study of 962 Patients with CLL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2777-2777
Author(s):  
Kami Maddocks-Christianson ◽  
Clive S. Zent ◽  
Susan Slager ◽  
Susan Schwager ◽  
Megan Reinalda ◽  
...  
Keyword(s):  
Cohort Study ◽  
Gene Mutation ◽  
Mayo Clinic ◽  
Leukemia Cell ◽  
Observational Cohort Study ◽  
Prognostic Parameters ◽  
Mutation Status ◽  
Treatment History ◽  
Increased Risk ◽  
Observational Cohort

Abstract BACKGROUND: Studies have suggested that patients with CLL are at a significantly increased risk of developing other lymphoid malignancies. Whether the risk of developing a 2nd lymphoproliferative disorder (LPD) is more strongly related to characteristics of the leukemia cell or to other factors such as prior chemotherapy is unknown. This distinction is important given increasing momentum to pursue early treatment of CLL patients based on recently identified prognostic markers, e.g. ZAP-70, IgVH mutation status. We used the Mayo Clinic CLL Database (DB) to conduct an observational cohort study to evaluate the relationship between clinical, biologic, and treatment characteristics and the risk of secondary LPD. METHODS: The Mayo Clinic CLL DB was established in 1999 and included 962 patients at the time of the present analysis. Clinical information regarding date of diagnosis, prognostic parameters, treatment history, disease-related complications, and co-morbidities was abstracted from clinical records on all patients at the time of study enrollment and maintained on an ongoing basis. For the present study, cases of secondary LPD were identified by chart review and cross referencing patient clinic numbers from the CLL DB with the Mayo Clinic Lymphoma and Leukemia/Myelodysplasia databases. Additionally, all clinic numbers were cross-referenced with an electronic hematopathology database that has recorded results of all bone marrow and lymph node biopsies of all Mayo Clinic patients since 1992. RESULTS: A second LPD was identified in 26 (2.7%) of the 962 CLL patients during a median follow-up of 7.12 years (range 0.1–21.0). The median time from diagnosis to development of secondary LPD was 4.4 years (range 0–19 years). Diffuse large B-cell lymphoma was the most common subtype of secondary LPD (12 of 26 cases). Gender was associated with increased risk of developing 2nd hematologic cancer where 1% of women compared to 3.4% of men (p=0.051) developed a 2nd LPD. Treatment history was also related to development of a 2nd LPD. 2nd LPD developed among 4% of previously treated CLL patients compared to 2% of untreated patients (p=0.08). Among the 362 patients who were treated for CLL prior to developing a second LPD, the median time to first treatment was shorter for those who developed a 2nd LPD (2.43 years vs. 6.22 years; p<0.001). No statistically significant association was observed between other clinical or biologic leukemia cell characteristics and development of 2nd LPD including IgVH gene mutation status, ZAP-70 status, CD38 status, cytogenetic abnormalities by FISH, B2M, stage at diagnosis, or ALC at diagnosis. CONCLUSIONS: In this observational cohort study, prior treatment demonstrated a stronger correlation with the risk of developing a 2nd LPD than did leukemia cell characteristics including IgVH gene mutation status, FISH, ZAP-70, B2M, and CD38. This finding suggests Richter’s transformation may relate more to therapy than characteristics of the leukemia cell itself. Until the results of clinical trials evaluating the role of early treatment based on prognostic parameters are available, this result underscores the importance of delaying administration of chemotherapy until patients meet established criteria for treatment.

The Utilization of JAK2 Molecular Testing at the University of Minnesota Medical Center

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
Pawel Mroz ◽  
Cade Arries
Keyword(s):  
Gene Mutation ◽  
Detection Rate ◽  
Medical Center ◽  
Single Gene ◽  
Myeloproliferative Neoplasm ◽  
Pathogenic Mutation ◽  
Molecular Testing ◽  
Mutation Status ◽  
Clinical Indications ◽  
Patient Presentation

Abstract Objectives JAK2 gene mutation status is included in the 2017 WHO diagnostic criteria of a myeloproliferative neoplasm (MPN) and therefore indicated in the diagnostic workup. Overutilization and inappropriate testing, however, can cause harm and lead to medical errors, and most importantly, it can significantly drive up the costs of patients’ care. Here we report an attempt to evaluate the success rate and the associated costs of JAK2 testing as well as to correlate it with clinical indications and patient presentation. Methods We conducted the analysis of next-generation testing orders/results performed at out institution between 9/2/2015 and 7/13/2018. We reviewed the rate of positive results as well as the type of order submitted to laboratory and compared the costs of individual tests. Results We analyzed 3,474 NGS orders/results performed at our institution. Of those, 1,203 were submitted for JAK2 testing, making this the most commonly ordered NGS test. Out of 1,203 results, there were 820 unique patient specimens and 118 tested positive (15%). The JAK2 testing was primarily ordered as part of the NGS MPN panel, which includes JAK2, CALR, and MPL mutation hotspots (70%), the custom panel (23%), JAK2 single gene (5%), or as part of comprehensive myeloid panel (2%). The mutation detection rate was 15%, 12%, 11%, and 15%, respectively. Conclusion Testing for JAK2 gene mutation status is the most commonly ordered NGS test in our laboratory. The detection rate for pathogenic mutation, irrespective of the type of genetic panel ordered, was 11% to 15%. Our analysis of the JAK2 ordering and reporting suggests that the JAK2 testing may be somewhat overutilized at our institution. An ongoing analysis of clinical indications, patient presentation, and associated costs will help to fully elucidate the true utility of this testing and will be included in the poster presentation.

Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers

Blood ◽  
2008 ◽  
Vol 112 (9) ◽  
pp. 3807-3817 ◽  
Author(s):  
Chris Pepper ◽  
Thet Thet Lin ◽  
Guy Pratt ◽  
Saman Hewamana ◽  
Paul Brennan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Prognostic Markers ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Vh Gene

Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P < .001), lymphocyte doubling time (P = .01), VH gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and VH gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 1840-1847 ◽  
Author(s):  
Rajendra N. Damle ◽  
Tarun Wasil ◽  
Franco Fais ◽  
Fabio Ghiotto ◽  
Angelo Valetto ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Mutation ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Risk Category ◽  
Mutation Status ◽  
Cd38 Expression ◽  
Staging Systems ◽  
V Genes ◽  
V Gene

Cellular immunophenotypic studies were performed on a cohort of randomly selected IgM+ B-chronic lymphocytic leukemia (B-CLL) cases for which Ig VH and VL gene sequences were available. The cases were categorized based on V gene mutation status and CD38 expression and analyzed for treatment history and survival. The B-CLL cases could be divided into 2 groups. Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (≥30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%). Patients in both the unmutated and the ≥30% CD38+ groups responded poorly to continuous multiregimen chemotherapy (including fludarabine) and had shorter survival. In contrast, the mutated and the <30% CD38+ groups required minimal or no chemotherapy and had prolonged survival. These observations were true also for those patients who stratified to the Rai intermediate risk category. In the mutated and the <30% CD38+ groups, males and females were virtually equally distributed, whereas in the unmutated and the ≥30% CD38+ groups, a marked male predominance was found. Thus, Ig V gene mutation status and the percentages of CD38+B-CLL cells appear to be accurate predictors of clinical outcome in B-CLL patients. These parameters, especially CD38 expression that can be analyzed conveniently in most clinical laboratories, should be valuable adjuncts to the present staging systems for predicting the clinical course in individual B-CLL cases. Future evaluations of new therapeutic strategies and drugs should take into account the different natural histories of patients categorized in these manners.

scholarly journals Relevance of comorbidities and antithrombotic medication as risk factors for reoperation in patients with chronic subdural hematoma

2021 ◽  
Author(s):  
Alexander Younsi ◽  
Lennart Riemann ◽  
Cleo Habel ◽  
Jessica Fischer ◽  
Christopher Beynon ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Multivariate Analyses ◽  
Independent Predictor ◽  
Perioperative Complications ◽  
Chronic Subdural Hematoma ◽  
Western Society ◽  
Increased Risk ◽  
Surgical Evacuation ◽  
Antithrombotic Medication ◽  
Univariate Analyses

AbstractIn an aging Western society, the incidence of chronic subdural hematomas (cSDH) is continuously increasing. In this study, we reviewed our clinical management of cSDH patients and identified predictive factors for the need of reoperation due to residual or recurrent hematomas with a focus on the use of antithrombotic drugs. In total, 623 patients who were treated for cSDH with surgical evacuation between 2006 and 2016 at our department were retrospectively analyzed. Clinical and radiological characteristics and laboratory parameters were investigated as possible predictors of reoperation with univariate and multivariate analyses. Additionally, clinical outcome measures were compared between patients on anticoagulants, on antiplatelets, and without antithrombotic medication. In univariate analyses, patients on anticoagulants and antiplatelets presented significantly more often with comorbidities, were significantly older, and their risk for perioperative complications was significantly increased. Nevertheless, their clinical outcome was comparable to that of patients without antithrombotics. In multivariate analysis, only the presence of comorbidities, but not antithrombotics, was an independent predictor for the need for reoperations. Patients on antithrombotics do not seem to necessarily have a significantly increased risk for residual hematomas or rebleeding requiring reoperation after cSDH evacuation. More precisely, the presence of predisposing comorbidities might be a key independent risk factor for reoperation. Importantly, the clinical outcomes after surgical evacuation of cSDH are comparable between patients on anticoagulants, antiplatelets, and without antithrombotics.

scholarly journals Prevalence of Epiretinal Membrane among Subjects in a Health Examination Program in Japan

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 93
Author(s):  
Hiroshi Shimizu ◽  
Ryo Asaoka ◽  
Takashi Omoto ◽  
Yuri Fujino ◽  
Shingo Mitaki ◽  
...  
Keyword(s):  
Epiretinal Membrane ◽  
Multivariate Analyses ◽  
Multiple Logistic Regression Analysis ◽  
Body Height ◽  
Older Age ◽  
Health Examination ◽  
Multiple Logistic Regression ◽  
Older Subjects ◽  
Fundus Photographs ◽  
Univariate Analyses

The prevalence of an epiretinal membrane (ERM) was elucidated using a dataset from a health examination program database in Japan. From the cohort database, 5042 eyes of 2552 subjects were included. The presence of an ERM, cellophane macular reflex (CMR), or preretinal macular fibrosis (PMF) was detected using color fundus photographs, and crude and age-standardized prevalence were obtained. To further assess the possible risk factors of ERM, background parameters were compared between ERM+ and − groups, and multiple logistic regression analysis was performed. ERM was detected in fundus photographs of 275 eyes (eye-based prevalence of 5.5%) from 217 subjects (subject-based prevalence of 8.5%). CMR was detected in 169 eyes (3.4%) of 138 subjects (5.4%), and PMF was detected in 106 eyes (2.1%) of 97 subjects (3.8%). By univariate analyses, compared with ERM− eyes or subjects, higher Scheie’s H grade (p < 0.0001), S grade (p < 0.0001), and glaucoma prevalence (p = 0.0440) were found in ERM+ eyes, and older age (p < 0.0001), more frequent histories of hypertension (p = 0.0033) and hyperlipidemia (p = 0.0441), and more frequent uses of medication for hypertension (p = 0.0034) and hyperlipidemia (p = 0.0074), shorter body height (p = 0.0122), and higher systolic blood pressure (p = 0.0078), and thicker intimal medial thickness (p = 0.0318) were found in ERM+ subjects. By multivariate analyses, older age (p < 0.0001, estimate = 0.05/year) was the only significant factor of ERM prevalence. Age-standardized prevalence of ERM was calculated to be 2.4%, 6.7%, and 13.3% for all ages, subjects older than 40 years, and subjects older than 65 years, respectively. We reported the prevalence of ERM and its subclasses in Japanese subjects. Since its prevalence is remarkably high in older subjects, an ERM can be seen as an important cause of visual impairment in Japan and in areas of the world where individuals live to an advanced age.

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