Role of S-Phase Fraction in Differentiating Aplastic Anemia from Hypoplastic Myelodysplastic Syndrome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4118-4118
Author(s):  
Anil Tripathi ◽  
Payal Tripathi ◽  
Ashutosh Kumar ◽  
Rizwan Ahmad ◽  
Anil Balapure ◽  
...  

Abstract Among the patients with bone marrow hypoplasia, differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (HMDS) can be a difficult and challenging task because of the considerable clinical, cytological and histological similarities between these two disorders. The distinction between AA and HMDS is important because the clinical course and management of these two entities differ. There is a higher risk of progression to acute leukemia in patients with HMDS compared with AA. Various attempts have been made in the past to differentiate these entities. Different patterns of proliferation of bone marrow cells in AA and HMDS have been reported in past using proliferating cell nuclear antigens (PCNA). S-Phase Fraction (SPF) reflects the cellular proliferation and has been proven to be a useful diagnostic and prognostic marker in various hematological malignancies and solid tumors. In the present study, we examined whether flow cytometric analysis of SPF could be used as a tool to differentiate AA from HMDS. The study group comprised of 25 consecutive patients with AA, 18 patients with HMDS diagnosed on the basis of peripheral blood and bone marrow findings along with 30 age and sex matched healthy controls. The mean age of AA patients and HMDS patients was 27.1 ± 12.7 years (range 13–65 years with median age of 23 years) and 38.8 ± 20.6 years (range 15–75 years with median age of 32.5 years) respectively. The most common clinical presentation in patients with AA and HMDS was anemia. Other manifestations were bleeding and pyrexia. No etiological association could be made in any of these cases. Peripheral blood leucocytes were stained with propidium iodide and analyzed for SPF through flow cytometry using Modfit-LT V 3.0 software. The mean SPF value in the patients with AA and HMDS was 0.49 ± 0.33% and 0.79 ± 0.28% respectively. The mean SPF value in control subjects was 0.67 ± 0.22%. The SPF value in patients with AA was significantly lower than that of control (p=0.01) whereas there was no significant difference in SPF values in patients with HMDS and control subjects. The SPF value was statistically significant higher in HMDS patients as compared to AA (p=0.003). During follow-up, 3 patients (12%) with AA have revealed the evidence of dysplasia on repeat bone marrow examination. These patients had high SPF values as compared to the median SPF value in AA patients. We conclude that SPF value may be an important parameter in patients with AA to predict their propensity to evolve into HMDS. SPF value may also be useful in the early diagnosis of HMDS before morphologically evidence of dysplasia is apparent.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4233-4233
Author(s):  
Anil Tripathi ◽  
Payal Tripathi ◽  
Ashutosh Kumar ◽  
Rizwan Ahmad ◽  
A.L. Vishwakarma ◽  
...  

Abstract Aplastic anemia (AA) has variable course and may transform in some patients into paraxysmal nocturnal hemoglobinuria (PNH), myelodysplasia (MDS), or acute myeloid leukemia (AML). Attempts are made to find out indicators that might suggest its future course in order to make prognostic and therapeutic decisions.A proportion of patients with AA may develop cytogenetic abnormalities in due course which may herald the conversion into MDS or AML. The objective of this study was to assess the role of S phase fraction (SPF) and aneuploidy in the early detection of clonal abnormalities in hemopoietic cells. The study group comprised of 30 patients with AA diagnosed on the basis of peripheral blood and bone marrow findings and 15 healthy controls. All patients were put on cyclosporin (3–5 mg/kg/d) as no one was able to afford either anti-thymocyte globulin or bone marrow transplantation. The patients were followed up periodically for the response to treatment, side effects, and the development of cytogenetic abnormalities. The SPF, aneuploidy, and cytogenetic studies were performed at the start of the study and after 6 months. Peripheral blood cells were stained with propidium iodide and analyzed for SPF and aneuploidy through flow cytometry using Modfit-LT software. Cytogenetic study was performed by conventional method using peripheral blood/bone marrow cells. The mean age of the patients was 26.8±12.4 years (range 13–58 yrs) and male to female ratio was 4 to 1. The most common clinical presentation was anemia. Other manifestations were bleeding and pyrexia. No etiological association could be made in any of these cases. Seven patients (23 %) had aneuploidy at the time of diagnosis whereas 3 patients (10%) developed aneuploidy at six months of follow up. The mean SPF value in the controls was 0.47±0.35%. No control subject had aneuploidy. The mean SPF in patients who did not show aneuploidy (n=20) was 0.53 ±0.01% and it was not significantly different from that of controls. The mean SPF value in patients (n=7) who had shown aneuploidy at the time of diagnosis was 3.91 ±0.24% and in patients (n=3) who later on developed aneuploidy was 7.17± 0.38%. The SPF values in both these groups were significantly higher (p=<.001) than in patients without aneuploidy. One patients with aneuploidy later on developed cytogenetic abnormalitity in the form of trisomy 8 and another with aneuploidy developed dysplastic changes in the bone marrow. Out of 20 patients (without aneuploidy) 6 (30%) had shown partial response to treatment whereas 2 (20%) patients with aneuploidy responded. Patients who developed marrow dysplasia or trisomy 8 did not respond to treatment. We suggest that the measurement of SPF and aneuploidy in patients with AA can be helpful in the prognostic assessment in terms of their propensity to develop dysplasia, cytogenetic abnormalities, or malignancy. Therefore patients with high SPF or aneuploidy may not be advised to undergo immunosuppressive therapy as they may more commonl;y develop into malignancy.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3999-3999
Author(s):  
Ben Zion Katz ◽  
Shahar Karni ◽  
Hadar Shimoni ◽  
Amit Natan ◽  
Amir Shaham ◽  
...  

Abstract Background: Complete Blood Count (CBC) analytical capacity is falling short of recognizing informative RBC morphology or WBC dysplastic morphological changes. Current morphologic peripheral blood smear (PBS) analysis is performed manually using a semi-quantitative scale on a limited number of cells introducing high degree of subjectivity and low sensitivity. The novel Full-Field Morphology (FFM) technology developed by Scopio Labs performs PBS analysis on a significantly larger scale of 1000 fields of 100X view in a routine manner, allowing a precise and highly sensitive automated quantification of cellular and sub-cellular morphological parameters. Current diagnosis of myelodysplastic syndrome (MDS) is based on invasive bone marrow aspirate, followed by subjective morphological analysis. In this study, we applied this digital morphometric approach to compare PBS morphology of MDS patients with age-matched controls. Methods: 32 MDS (average age 80+10, [range 41-97] y, F:M ratio 14:18) and 30 age-matched control (average age 79+9, [range 65-100] y, F:M ratio 13:17) PBS were scanned by the Scopio Labs system, and evaluated according to three distinct morphological features with known significance in MDS: blast percentage per 100 or 1000 WBC; neutrophil cytoplasmic granulation per 1000 neutrophils; RBC morphology of at least 150,000 RBC. Quantitative determination of neutrophils granulation, was measured by Granulation Index (GI, between 0-1) and GI Distribution Width (GIDW, between 0-1). RBC measurements included the quantitative measurements of RBC size, namely macro- and microcytosis, and RBC contour changes (deformation), i.e. the percent of RBC that deviate from normal RBC shape. Results: The mean GI of MDS samples was 0.36+0.15, [range 0.14-0.63] (Fig. 1A middle, Fig. 1E), significantly (p<10 -4) lower compared with the mean GI of age-matched control samples 0.53+0.10, [range 0.24-0.64] (Fig. 1A top, Fig. 1E). Mean GI were highly diverse among MDS samples compared with age-matched controls (Fig. 1E), but with no significant differences in GIDW (not shown). Interestingly, two sub-populations of neutrophils were detected in some of the MDS samples, differ in their mean GI (0.26 for one sub-population, 0.52 for the second one, Fig. 1A bottom). Such fingerprint, suggesting the presence of an abnormal and normal clones, was not detected in the control samples. Percentage of blasts was determined per 100 or 1000 WBC counts/sample (Fig. 1B). Blasts were detected in 13/32 (41%) of MDS samples compared with 1/30 (3%) of age-matched controls, when counts were performed per 100 WBC. However, when 1000 WBC were analysed, blasts were detected in 27/32 (84%) of MDS samples compared with 6/30 (20%) of age matched controls, a highly significant difference (p<10 -6). The percentage of blasts per 1000 WBC counts/sample of MDS samples was 0.92+1.35, [range 0-5] %, significantly (P<0.0008) higher compared with the percentage of blasts per 1000 WBC counts/sample of age-matched control samples 0.02+0.05, [range 0-0.2] % (Fig. 1E). RBC analysis revealed significant differences between MDS and age-matched samples (Fig. 1C). As expected, mean RBC size (49+4, [range 41-59] mm 2 MDS; 45+3, [range 40-51] mm 2 age matched) and % of macrocytosis (17+15, [range 2-60] % MDS; 3+4, [range 0-15] % age matched) were significantly (p<10 -5) higher in the MDS samples compared with the age matched controls (Fig. 1E). We found that MDS PBS contained significantly (p<10 -6) higher number of abnormally-shaped RBC (8+1, [range 5-12] %), compared with age-matched controls (6+1, [range 5-8] %) (Fig. 1E). Representative summaries of morphometric analyses of MDS and age-matched control are shown in figure 1D. Representative PBS scans of MDS and control samples are available in https://demo.scopiolabs.com/?_org=VCdaE756rjYwZW3Z#/scans. Conclusion: Our study demonstrates that FFM-based digital PBS analysis enables the detection and quantification of unique WBC and RBC morphologic alterations associated with MDS. The expanding therapeutic options for MDS, including for patients at early disease stages, makes the establishment of an accurate diagnosis of MDS, even at early stages, to be highly important. The proposed novel digital imaging technology opens the opportunity to screen patients, diagnose them early, based on peripheral blood morphology, and potentially, monitor their responsiveness to therapy. Figure 1 Figure 1. Disclosures Katz: Scopio Labs: Consultancy. Karni: Scopio Labs: Current Employment. Shimoni: Scopio Labs: Current Employment. Natan: Scopio Labs: Current Employment. Shaham: Scopio Labs: Current Employment. Pozdnyakova: Scopio Labs: Consultancy. Mittelman: Janssen · Roche · Novartis · Takeda · Medison / Amgen · Neopharm / Celgene / BMS · Abbvie · Gilead: Research Funding; Novartis · Takeda · Fibrogen · Celgene / BMS · Onconova · Geron: Other: Clini; Onconova · Novartis · Takeda · Silence: Membership on an entity's Board of Directors or advisory committees; MDS HUB: Consultancy; Celgene / BMS · Novartis: Speakers Bureau. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1993-1993
Author(s):  
Xiaohui Zhang ◽  
Alan F List ◽  
Jeffrey E. Lancet ◽  
Song Jinming ◽  
Lynn C. Moscinski ◽  
...  

Abstract Background: Pancytopenia and bone marrow aplasia/hypoplasia are caused by a heterogeneous group of disorders, most commonly aplastic anemia (AA), hypoplastic myelodysplastic syndrome (MDS), paroxysmal nocturnal hemoglobinuria (PNH), and T-cell large granular lymphocytosis (T-LGL). Clinical and morphological distinction among these entities is often challenging, particularly between AA and hypoplastic MDS. This study is to examine the clinicopathological and genetic features of a group of AA and hypoplastic MDS patients, with or without concurrent T-LGL and/or PNH, in order to better understand and differentiate the two entities. Methods and Materials: We retrieved 45 cases with cytopenias and hypoplastic bone marrow at Moffitt Cancer Center. Peripheral blood complete blood counts, bone marrow morphological findings, flow cytometric analyses for LGL and PNH, and cytogenetics data were extracted from electronic medical records. Targeted next-generation sequencing (54 myeloid neoplasm related genes) was performed on the bone marrow. Results: The 45 patients showed peripheral blood cytopenias and bone marrow aplasia or marked hypocellularity. There were 26 cases diagnosed with AA with no morphologic evidence of dysplasia or increased blasts in the bone marrow, and 19 cases diagnosed with hypoplastic MDS based on morphological and cytogenetic criteria. In the meantime, distinct T-LGL population was identified in 2 of 11 cases with AA (18.2%) and 3 of 11 cases with hypoplastic MDS (27.3%); PNH clones were identified in 8 of 17 cases with AA (47%) and 3 of 11 cases with hypoplastic MDS (27.3%). Clonal cytogenetic abnormalities were found in 2 of 25 cases with AA (8%) and 11 of 18 cases with hypoplastic MDS (61.1%). Twelve of 26 cases of AA (46%) showed one or more gene mutations with allele burden ranging from 7% to 52%, and most of these cases (9 of 12; 75%) involved only one gene. In contrast, 15 of 19 cases of hypoplastic MDS (78.9%) had one or more gene mutations with allele burden ranging from 19% to 53%. Seven of the 15 cases (46.7%) had two or more gene mutations. The most common mutated genes in the two groups in this study were ASXL1 and TET2. Conclusion: Although there are overlapping clinical and morphological features between AA and hypoplastic MDS, differences are present between the two entities including presence of PNH clones, cytogenetic changes, and gene mutation frequencies. These features may help to make differential diagnosis and identify the cases with more progression potential. Clinical outcomes with different treatment and larger scale studies are needed to better characterize and define the two different entities. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3902-3902
Author(s):  
Adam Albitar ◽  
Danielle Townsley ◽  
Wanlong Ma ◽  
Ivan De Dios ◽  
Vincent Funari ◽  
...  

Abstract Background:We have reported that peripheral blood cell-free DNA (cfDNA) is reliable for detecting bone marrow molecular abnormalities in patients with hematologic neoplasms. However, not clear is whether cfDNA is sufficient to detect mutations present at low variant allele frequency (VAF). Since patients with aplastic anemia (AA usually have relatively small clones in blood and bone marrow (BM), we compared mutations detected in BM cells with those detected in peripheral blood cfDNA from patientswith this disease. Methods: A total of 120 paired BM aspirate and PB plasma samples were tested by the commercially available TruSight Myeloid Sequencing Panel (Illumina; San Diego, CA). We extracted DNA from bone marrow aspirate using the QIAamp DNA Mini Kit. We used NucliSenS EasyMAG automated platform for extracting total nucleic acid from PB plasma collected in EDTA. All paired BM and plasma samples were tested by the commercially available TruSight Myeloid Sequencing Panel (Illumina; San Diego, CA), which covers hot spot mutations in 54 genes. The average depth of sequencing was 10,000X. Results: One hundred twenty paired BM and cfDNA samples from 96 patients with aplastic anemia were tested. Of the 96 patients, 33 (34%; equivalent to 48 samples, 40%) had one or more mutations. We identified 54 different somatic mutations in these patients, of which 45 were unique. There was no significant difference (P=0.71, Sign test) in allele frequency between cfDNA and BM. The median mutant allele frequency was 10.9% in cfDNA and 12.6% in BM cells, and 40 of the 54 mutations had allele frequency ≤20% in BM cells, while 45 samples had allele frequency ≤20 in cfDNA. Six of the 33 patients with somatic mutations (18%) showed mutations in plasma cfDNA but not in BM. In contrast, 2 patients (6%) showed mutations in BM cells and not in cfDNA. One of these two patients had a mutation in ASXL1 gene detected in BM cells but not in cfDNA and a subsequent sample showed the same ASXL1mutation in BM cells and not in cfDNA, and a second clone with a different ASXL1 mutation detected in both BM cells and cfDNA. Overall concordance between BM cells and cfDNA in the 120 samples was 92% and there was no statistically significant difference between the two sample types (P=0.6). Summary and Conclusions: Seven samples (from 7 patients) of the 120 tested samples showed mutations in cfDNA and not in BM cells while 3 samples (from 2 patients) showed mutations in BM and not in cfDNA. VAF of mutations in cfDNA were similar to those in BM cells. Therefore, peripheral blood cfDNA should be tested in addition to BM cells for detecting mutations in patients with AA. Peripheral blood cfDNA can be used as a reliable means for monitoring patients with AA. cfDNA testing can be used as an alternative testing to bone marrow even when mutant allele frequency in bone marrow is <20%. cfDNA may be an especially valuable source of mutation detection in marrow failure, in which marrow aspirates may not contain sufficient cells for accurate mutation analysis. Disclosures Albitar: Neogenomics Laboratories: Employment. Townsley:Novartis: Research Funding. Ma:Neogenomics Laboratories: Employment. De Dios:Neogenomics Laboratories: Employment. Funari:Neogenomics Laboratories: Employment. Young:GSK/Novartis: Research Funding. Albitar:Neogenomics Laboratories: Employment, Equity Ownership.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yixuan Liu ◽  
Suhong Xie ◽  
Lei Li ◽  
Yanhui Si ◽  
Weiwei Zhang ◽  
...  

Abstract Background This study investigates the effect of autologous bone marrow transfusion (BMT) on the reconstruction of both bone marrow and the immune system in patients with AIDS-related lymphoma (ARL). Methods A total of 32 patients with ARL participated in this study. Among them, 16 participants were treated with conventional surgery and chemotherapy (control group) and the remaining 16 patients were treated with chemotherapy followed by autologous bone marrow transfusion via a mesenteric vein (8 patients, ABM-MVI group) or a peripheral vein (8 patients, ABM-PI group). Subsequently, peripheral blood and lymphocyte data subsets were detected and documented in all patients. Results Before chemotherapy, no significant difference in indicators was observed between three groups of ARL patients. Unexpectedly, 2 weeks after the end of 6 courses of chemotherapy, the ABM-MVI group, and the ABM-PI group yielded an increased level of CD8+T lymphocytes, white blood cells (WBC), and platelet (PLT) in peripheral blood in comparison to the control group. Notably, the number of CD4+T lymphocytes in the ABM-PI group was significantly higher than that in the other two groups. Additionally, no significant difference in haemoglobin levels was observed before and after chemotherapy in both the ABM-MVI and ABM-PI groups, while haemoglobin levels in the control group decreased significantly following chemotherapy. Conclusions Autologous bone marrow transfusion after chemotherapy can promote the reconstruction of both bone marrow and the immune system. There was no significant difference in bone marrow recovery and reconstruction between the mesenteric vein transfusion group and the peripheral vein transfusion group.


1974 ◽  
Vol 77 (2) ◽  
pp. 401-407 ◽  
Author(s):  
J. A. Mahoudeau ◽  
A. Delassalle ◽  
H. Bricaire

ABSTRACT Plasma levels of testosterone (T) and 5α-dihydrotestosterone (DHT) were determined by radioimmunoassay in 29 patients with benign prostatic hypertrophy (BPH) and in 56 control men of various ages. No significant difference was found in T, DHT nor DHT/T ratio between BPH and control subjects of similar age. Plasma DHT was higher in the prostatic than in the peripheral veins in 8/9 patients with BPH during laparotomy, indicating a prostatic secretion of DHT. No difference in the mean T nor the mean DHT was found in peripheral plasma before and after adenomectomy.


2018 ◽  
Vol 159 (42) ◽  
pp. 1710-1719
Author(s):  
Krisztián Kállay ◽  
Judit Csomor ◽  
Emma Ádám ◽  
Csaba Bödör ◽  
Csaba Kassa ◽  
...  

Abstract: Introduction: Acquired bone marrow failures are rare but fatal diseases in childhood. Since 2013, Hungary has been participating as a full member in the work of the European Working Group on uniform diagnostics and therapy in patients with acquired bone marrow failure syndromes. Hypocellular refractory cytopenia of childhood has been emphasized as a frequent entity, transplanted by reduced intensity conditioning with excellent outcomes. Aim: To analyse and compare the results of treatment before and after our joining. Method: A total of 55 patients have been treated in the 8 centres of the Hungarian Pediatric Oncology Network during 5 years between 2013 and 2017 (severe aplastic anemia: 9, myelodysplastic syndrome: 41, juvenile myelomonocytic leukemia: 5 patients). Allogeneic hematopoietic stem cell transplantation was performed in severe aplastic anemia in 7 cases, while antithymocyte globulin was administered in one case and one patient died before diagnosis. In patients with myelodysplastic syndromes, watch and wait strategy was applied in 4, while transplantation in 37 cases. Reduced intensity conditioning was used in 54 percent of these cases. Transplantation was the treatment of choice in all 5 patients with juvenile myelomonocytic leukemia. Results: In the whole patient cohort, the time from diagnosis to treatment was median 92 (3–393) days, while in severe aplastic anemia median 28 (3–327) days only. Grade II–IV acute graft versus host disease occurred in 22.6%, grade III–IV in 6.8% and chronic in 11.2%. All the patients treated with severe aplastic anemia are alive and in complete remission (100%). The overall estimated survival rate is 85.1% in myelodysplastic syndrome, while 75% in juvenile myelomonocytic leukemia. The median follow-up was 30.4 (1.1–62.5) months. There was a remarkable increase in overall survival comparing the data before (1992–2012) and after (2013) joining the international group, 70% vs. 100% (p = 0.133) in severe aplastic anemia and 31.3% vs. 85.1% (p = 0.000026) in myelodysplastic syndrome. Conclusion: Due to a change in the paradigm of the conditioning regimen in hypocellular refractory cytopenia of childhood, the overall survival rate has significantly increased. Orv Hetil. 2018; 159(42): 1710–1719.


2019 ◽  
Vol 141 (7-8) ◽  
pp. 233-237

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and cytopenia in peripheral blood, where about a third of patients may develop acute myeloid leukemia (AML). The diagnosis of MDS requires the analysis of peripheral blood and bone marrow. Depending on the percentage of blasts in the bone marrow, the number of cytopenias and cytogenetic abnormalities, determination of the prognostic indices is possible (IPSS – „International Prognostic Scoring System“, R-IPSS-„Revised International Prognostic Scoring System“, WPSS – „WHO Prognostic Scoring System“). Until today, numerous studies have been conducted on the molecular mechanisms and epigenetic pathways in myelodysplastic syndrome, and their prognostic and therapeutic importance, but there are few studies analyzing the importance of microRNAs (miRNAs) in MDS. In the last few years, there have been numerous results on the impact of aberrant miRNA expression in malignant disorders where the miRNA represent tumor suppressor genes or oncogenes. Several miRNAs have been recognized as diagnostic and prognostic parameters and possible therapeutic targets. In this paper, we present the overview of recent results on the role of miRNA in MDS.


Author(s):  
Mustafa Can ◽  
Muhammet Kocabaş ◽  
Melia Karakose ◽  
Hatice Caliskan Burgucu ◽  
Zeliha Yarar ◽  
...  

Abstract Purpose: In our study, we aimed to determine the frequency of thyroid nodules in patients with acromegaly according to the American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS) classification and its relationship with acromegaly disease activity. Methods: A total of 56 patients with acromegaly and age, sex, and body mass index matched with 56 healthy control subjects were included in our study. Thyroid-stimulating hormone, free thyroxine, and anti-thyroperoxidase antibody levels of patients and control subjects were measured. In addition, patients and healthy controls were evaluated by ultrasonography to determine thyroid structure, thyroid volume, and thyroid nodules and to make ACR TI-RADS classification. Results: Thyroid nodules were present in 31 (55.4%) of 56 patients in the acromegaly group and 20 (35.7%) of 56 subjects in the control group, and the frequency of thyroid nodules was significantly higher in the acromegaly group (p=0.038). The mean number of nodules in the acromegaly group and control group was 1.27±1.43 and 0.48±0.73, respectively, and the mean number of nodules was significantly higher in the acromegaly group (p=0.003). The number of patients with TI-RADS 1, TI-RADS 2, and TI-RADS 4 nodules in the acromegaly group was higher than the control group (p=0.026, p=0.049, p=0.007, respectively). No difference was found in terms of cytological findings between those who have undergone FNAB in the acromegaly group and control group. Conclusion: In our study, we found that the frequency of thyroid nodules, the number of thyroid nodules, and the number of TI-RADS 1, TI-RADS 2, and TI-RADS 4 nodules increased in patients with acromegaly. There was no significant difference between acromegaly disease activity and thyroid nodule frequency, number of thyroid nodules, and TI-RADS classifications.


Sign in / Sign up

Export Citation Format

Share Document