Bone marrow infiltration patterns and their prognostic significance in chronic lymphocytic leukemia: correlations with clinical, immunologic, phenotypic, and cytogenetic data.

1984 ◽  
Vol 2 (6) ◽  
pp. 562-570 ◽  
Author(s):  
T Han ◽  
M Barcos ◽  
L Emrich ◽  
H Ozer ◽  
R Gajera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Bone Marrow Infiltration ◽  
Clinical Staging ◽  
Bone Marrow Biopsies

Bone marrow biopsies were prospectively performed on 75 patients with chronic lymphocytic leukemia (CLL). There was a highly significant relationship (p less than 0.002) between clinical stages and bone marrow infiltration patterns. Ten (50%) of 20 patients with diffuse patterns died; the estimated median survival time for these patients was 87 months. In contrast, only six (11%) of 55 patients with nondiffuse patterns died; the estimated median survival time for these patients could not be computed. When both clinical stage and infiltration pattern were evaluated for survival, a highly significant association between clinical stage and survival time was still observed (p less than 0.003) whereas bone marrow infiltration pattern was no longer significant. A significant association was also observed between bone marrow infiltration patterns and absolute lymphocyte counts (p less than 0.0005), Fc-receptor-positive cells (p less than 0.002), 3H-thymidine uptake of leukocytes (p less than 0.01), serum alkaline phosphatase levels (p less than 0.05), monoclonal urinary-free light chain status (p less than 0.05), and cytogenetics of leukemic cells (p less than 0.05). These observations lead to the conclusion that in an overall prognostic evaluation of patients with CLL, although bone marrow histopathology may have no additional value over a well-established clinical staging system, as a whole, it may be of clinically predictive value in disease progression of patients with stage I and II.

The Prognostic Significance of Autoimmune Cytopenias in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2361-2361
Author(s):  
Carol Moreno ◽  
Kate E Hodgson ◽  
Pau Abrisqueta ◽  
Gerardo Ferrer ◽  
Montse Elena ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Stage ◽  
Lymphocytic Leukemia ◽  
Bone Marrow Infiltration ◽  
Clinical Staging ◽  
Immune Disease ◽  
Advanced Clinical Stage ◽  
Positive Direct ◽  
Autoimmune Cytopenia

Abstract Abstract 2361 Poster Board II-338 Clinical staging systems are the backbone for assessing prognosis in patients with chronic lymphocytic leukemia (CLL). Clinical stages, however, are assigned without taking into consideration the mechanisms of the disease. In this regard, the prognosis of patients with advanced (Binet C, Rai III, IV) stage due to immune cytopenia is controversial. To address the prognosis of patients with CLL in advanced clinical stage due to immune mechanisms, we studied two groups of patients with and without autoimmune cytopenia. The first group consisted of 62 patients (39 men, median age 65 yrs; range 33-89) with advanced stage due to autoimmune cytopenia (stage C “immune”). Autoimmune hemolytic anemia (AIHA) was defined as a hemoglobin level <10g/dL and either a positive direct antiglobulin test (n=37) or indirect signs of hemolysis including a high reticulocyte count, low haptoglobin levels, increased LDH and bilirrubin levels (n=7). Immune thrombocytopenia (ITP) was defined as a platelet count < 100.000/mm3 with normal megakaryocytes in bone marrow or no reticulocytopenia, no enlarged spleen and no chemotherapy within the last month from study entry (n=18). The control group included 96 patients (59 men, median age 68 yrs; range 28-90) with stage C disease with no signs of immune-mediated cytopenia. Demographics, clinical characteristics and duration of follow-up were similar in both groups. When considered from the time of diagnosis, patients with stage C “immune” disease had a significantly better survival than those in stage C due to bone marrow infiltration (median survivals: 89 months vs. 45 months; p=0.04). In contrast, the prognosis of 12 patients who developed immune cytopenia during the course of the disease was not different from that of 42 patients who had progressed to stage C with no evidence of autoimmunity, neither when considered from the time of diagnosis (median survivals: 110 months vs. 101 months; p=0.71) nor from the point at which cytopenia (either autoimmune or infiltrative in origin), was detected (median survivals: 51 months vs. 63 months; p=0.102). When the analysis was restricted to the 62 patients with autoimmune cytopenia, no significant differences in survival were observed according to the time at which the autoimmune disorder was detected, i.e. at diagnosis or during the course of the disease (median survivals: 89 months vs.103 months; p=0.38). Of note, 11 out of the 18 patients with stage C “immune” disease at diagnosis responded to corticosteroids and, as a result, switched to stage A, whereas only 8 out of 53 patients with stage C due to bone marrow infiltration had a similar response to chemotherapy. In summary, this study shows that the outcome of patients with CLL who present with advanced clinical stage differs according to the origin of the cytopenia (i.e., immune vs. infiltrative) and emphasizes the importance of determining the origin of the cytopenia when evaluating patients with CLL and “advanced” clinical stage. These results also make a case for including a stage C “immune” group in the prognostic categorization of patients with CLL. Disclosures: No relevant conflicts of interest to declare.

CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease

Blood ◽  
2002 ◽  
Vol 99 (3) ◽  
pp. 1023-1029 ◽  
Author(s):  
Terry J. Hamblin ◽  
Jenny A. Orchard ◽  
Rachel E. Ibbotson ◽  
Zadie Davis ◽  
Peter W. Thomas ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Surrogate Marker ◽  
Variable Region ◽  
Lymphocytic Leukemia ◽  
Prognostic Indicators ◽  
Cd38 Expression ◽  
Immunoglobulin Variable Region

Abstract Although the presence or absence of somatic mutations in the immunoglobulin variable region (IgVH) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses, the assay is technically complex and unavailable to most laboratories. CD38 expression has been suggested as a surrogate marker for the 2 subtypes. IgVHmutations and CD38 expression in 145 patients with B-CLL with a long follow-up were compared. The 2 assays gave discordant results in 41 patients (28.3%). Multivariate analysis demonstrated that Binet stage,IgVH mutations and CD38 were independent prognostic indicators. Median survival time in patients whose cells had unmutated IgVH genes and expressed CD38 was 8 years; in those with mutated IgVHgenes not expressing CD38, it was 26 years. For those with discordant results, median survival time was 15 years. Thus, although CD38 expression does not identify the same 2 subsets as IgVHmutations in CLL, it is an independent risk factor that can be used with IgVH mutations and clinical stage to select patients with B-CLL with the worst prognoses. Using cryopreserved cells taken at intervals during the course of the disease, however, changes of CD38 expression over time were demonstrated in 10 of 41 patients. Causes of the variation of CD38 expression require further study. Additional prospective studies are required for comparing CD38 expression with other prognostic factors and for taking sequential measurements during the course of the disease.

Distribution of histopathologic types of primary pulmonary neoplasia in dogs and outcome of affected dogs: 340 cases (2010–2019)

2022 ◽  
pp. 1-10
Author(s):  
Jourdan B. McPhetridge ◽  
Valery F. Scharf ◽  
Penny J. Regier ◽  
Darby Toth ◽  
Max Lorange ◽  
...  
Keyword(s):  
Adjuvant Chemotherapy ◽  
Neuroendocrine Tumor ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Clinical Stage ◽  
Histiocytic Sarcoma ◽  
Tumor Type ◽  
Pulmonary Carcinoma ◽  
Pulmonary Neoplasia

Abstract OBJECTIVE To provide updated information on the distribution of histopathologic types of primary pulmonary neoplasia in dogs and evaluate the effect of postoperative adjuvant chemotherapy in dogs with pulmonary carcinoma. ANIMALS 340 dogs. PROCEDURES Medical records of dogs that underwent lung lobectomy for removal of a primary pulmonary mass were reviewed, and histopathologic type of lesions was determined. The canine lung carcinoma stage classification system was used to determine clinical stage for dogs with pulmonary carcinoma. RESULTS Pulmonary carcinoma was the most frequently encountered tumor type (296/340 [87.1%]), followed by sarcoma (26 [7.6%]), adenoma (11 [3.2%]), and pulmonary neuroendocrine tumor (5 [1.5%]); there was also 1 plasmacytoma and 1 carcinosarcoma. Twenty (5.9%) sarcomas were classified as primary pulmonary histiocytic sarcoma. There was a significant difference in median survival time between dogs with pulmonary carcinomas (399 days), dogs with histiocytic sarcomas (300 days), and dogs with neuroendocrine tumors (498 days). When dogs with pulmonary carcinomas were grouped on the basis of clinical stage, there were no significant differences in median survival time between dogs that did and did not receive adjuvant chemotherapy. CLINICAL RELEVANCE Results indicated that pulmonary carcinoma is the most common cause of primary pulmonary neoplasia in dogs; however, nonepithelial tumors can occur. Survival times were significantly different between dogs with pulmonary carcinoma, histiocytic sarcoma, and neuroendocrine tumor, emphasizing the importance of recognizing the relative incidence of these various histologic diagnoses. The therapeutic effect of adjuvant chemotherapy in dogs with pulmonary carcinoma remains unclear and warrants further investigation.

Isolated Chromosome 20q Deletions in Patients with Non-Myeloid Disorders

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1442-1442
Author(s):  
Dean Andrea ◽  
Melissa Hayden ◽  
Kathleen W. Rao ◽  
Yuri D. Fedoriw ◽  
Bahjat Qaquish ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Clinical Evidence ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Red Blood Cell Transfusion ◽  
Bone Marrow Biopsies ◽  
Chromosome 20 ◽  
Dose Modifications

Abstract Abstract 1442 Background: Deletions of the long arm of chromosome 20 have conventionally been associated with myeloid neoplasms. The frequency of chromosome 20q deletion (del(20q)) is 1–10% in myeloid diseases and associated with good prognosis in patients with myelodysplastic syndromes (MDS) and poor response to treatment in patients with acute myeloid leukemia (Greenberg 1997; Campel 1994). Previously chromosome 20q deletions were thought to be pathognomonic for myelodysplastic syndrome. Due to the observation that del(20q) may be present in non-malignant clones in patients with non-myeloid cancers, the 2008 WHO Classification (Swerdlow ed.) stated that MDS could not be diagnosed solely on the basis of isolated del(20q). The significance of isolated del(20q) in non-myeloid disorders have yet to be defined. When this chromosomal abnormality is found incidentally in marrows of patients for non-myeloid cancers, some oncologist may consider altering plans for cytotoxic chemotherapy out of concern for developing MDS. The aim of this study was to determine if isolated del(20q) in non-myeloid disorders implies an impending myeloid disease and if treatment should be altered for such patients. Methods: We conducted a retrospective, single institution cohort study among patients who between January 2005 and July 2012 were found to have 20q deletions without other chromosomal alterations per conventional cytogenetics and non-myeloid disorders per clinical history or bone marrow biopsies. Patients with isolated 20q deletion were identified from the clinical cytogenetic laboratory database and results were reviewed per cytogeneticist for accuracy. Pathology reviewed initial and subsequent bone marrow biopsies for histopathologic or immunophenotypic evidence of a myeloid disease. If a subsequent bone marrow exam was not available, the patient's complete blood counts were reviewed to determine if they developed clinical evidence of a myeloid disorder. We defined clinical suspicion for MDS as the development of transfusion dependence (≥1 unit red blood cell transfusion every 8 weeks over 4 months), any grade = 2 anemia with either grade = 2 thrombocytopenia or grade = 2 neutropenia not related to chemotherapy or immunotherapy, or any grade = 3 cytopenia without known etiology. For patients undergoing chemotherapy, MDS was suspected if there was evidence of poor bone marrow reserve as manifest by dose modifications or delays for hematologic toxicity. Results: Thirty nine patients with isolated del(20q) were identified in the cytogenetic database from January 2005 to July 2012. Twelve out of thirty nine (31%) patients were found to have non-myeloid disorders. Three patients with multiple myeloma (25%), two patients with chronic lymphocytic leukemia (17%), two patients with autoimmune disorders (17%) and five others with breast cancer, diffuse large B cell lymphoma, monoclonal gammopathy of undetermined significance, Crohn's disease and melanoma. There were an equal number of men and woman with median age of 60 years (range 30–83 years) at the time of isolated del(20q) detection. Six patients were found to have del(20q) at the initial presentation of their disease and six developed del(20q) after undergoing treatment. Nine patients were treated with standard first line systemic therapies. Six of the nine patients were treated with chemotherapy and four of them did not have to undergo any dose modifications due to myelosuppression. In the patients with chronic lymphocytic leukemia, FCR (Fludarabine,Cyclophosphamide and Rituximab) was dose modified and later discontinued due to persistent neutropenia and thrombocytopenia. After a median follow up of twenty two months (range 2 – 64 months) no patients developed evidence of a myeloid disorder by bone marrow pathology or clinical evidence. Conclusion: Isolated deletion of the long arm of chromosome 20 in patients with non-myeloid disorders does not result in bone marrow failure or myeloid disease, therefore physicians should not alter their treatment plans. Further patient follow up is necessary to provide more insight on the prognosis and treatment of non-myeloid disorders with isolated chromosome 20q deletion. Disclosures: No relevant conflicts of interest to declare.

CXCR4 Invalidation Limits the MLL-ENL Induced Leucemogenesis in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4089-4089
Author(s):  
Yanyan Zhang ◽  
Hadjer Abdelouahab ◽  
Aline Betems ◽  
Monika Wittner ◽  
William Vainchenker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Survival Time ◽  
Median Survival ◽  
Median Survival Time ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Abstract 4089 The receptor CXCR4 and its ligand SDF-1 play major physiological roles especially on hematopoietic stem cells homing and retention. Many studies have implicated CXCR4 in the invasion by tumor cells of organs that produce SDF-1. In acute myeloid leukemia, the physiological role of CXCR4 is not fully understood. We used retrovirus to express MLL-ENL oncogene in CXCR4+/+ and CXCR4−/− hematopoietic primitive cells (Lin- isolated from fetal liver) and showed that CXCR4 is dispensable for generation of immortalized colonies in vitro. To determine CXCR4 function in vivo, CXCR4+/+ and CXCR4−/− transformed cells were transplanted into lethally irradiated mice. Whatever their phenotype, the recipient developed a myelo-monocytique leukemia characterized by their expression of Gr-1 and Mac-1. As expected, all recipients of MLL-ENL transduced CXCR4+/+ cells were moribund within 35 to 80 days post transplant (median survival time: 50 days). Strikingly, recipients of MLL-ENL transduced CXCR4−/− cells showed significantly increased lifespan, with a median survival time of 90 days. The cellularity of the peripheral blood of recipients of MLL-ENL transduced cells displayed considerable increases over time although this increase was much lower in CXCR4−/− than in CXCR4+/+ chimera. Bone marrow of MLL-ENL transduced CXCR4−/− chimera had moderately decreased numbers of mononuclear cells. There were important numbers of leukemic CD45.2+/Gr1+/Mac1+/c-kit+ cells in spleen from MLL-ENL CXCR4+/+ chimera which suggested that CXCR4 is important for leukemic progenitors cells retention in the bone marrow and especially in the spleen. The homing capacity of transduced CXCR4+/+ cells is comparable to the CXCR4−/− cells. Finally, more DNA damages were found in the BM cells of MLL-ENL CXCR4−/− chimera. All these results were confirmed by treating of MLL-ENL CXCR4+/+ chimera with CXCR4 inhibitor (TN140). These results demonstrated that in absence of CXCR4, the cells transduced by oncogene MLL-ENL are capable of generating leukemia in the recipients. However, mice transplanted with MLL-ENL transduced CXCR4−/− FL cells developed acute myeloid leukemia with reduced aggressiveness and organ infiltration, which is associated with induced differentiation and DNA instability. These results indicated that the MLL-ENL progenitors are dependent on CXCR4 for their maintenance in the BM and spleen suggesting that CXCR4 inhibitors might have potential therapeutic applications. Disclosures: No relevant conflicts of interest to declare.

CD13 Expression in B-Cell Chronic Lymphocytic Leukemia is Associated with the Pattern of Bone Marrow Infiltration

1992 ◽  
Vol 6 (3) ◽  
pp. 209-218 ◽  
Author(s):  
Antonio Pinto ◽  
Vittorina Zagonel ◽  
Antonino Carbone ◽  
Diego Serraino ◽  
Giuseppe Marotta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Bone Marrow Infiltration ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Clinical staging of chronic lymphocytic leukemia

Blood ◽  
1975 ◽  
Vol 46 (2) ◽  
pp. 219-234 ◽  
Author(s):  
KR Rai ◽  
A Sawitsky ◽  
EP Cronkite ◽  
AD Chanana ◽  
RN Levy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Median Survival ◽  
Prognostic Significance ◽  
Stage Iv ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Stage Ii ◽  
Stage Iii ◽  
Clinical Staging ◽  
Survival Times

A method of clinical staging of chronic lymphocytic leukemia (CLL) has been proposed which is based on the concept that CLL is a disease of progressive accumulation of nonfunctioning lymphocytes: stage O, bone marrow and blood lymphocytosis only; stage 1, lymphocytosis with enlarged nodes; stage II, lymphocytosis with enlarged spleen or liver or both; stage III, lymphocytosis with anemia; and stage IV:lymphocytosis with thrombocytopenia. Analysis of 125 patients. in the present series showed the following median survival times (in months) from diagnosis: stage 0, is greater than 150; stage I 101; stage II, 71; stage III, 19; stage IV, 19, The median survival for the entire series was 71 mo. The prognostic significance of the stage remained even after adjustment was made for age and sex. However, both sex and age were shown to be poor predictors of survival after adjustment for stage. The method of staging proved to be a reliable predictor of survival whether used at diagnosis or during the course of the disease. The proposed staging system was an equally accurate indicator for survival when applied to two other previously published studies of large series of patients.

Efficacy of SMIP-016, a novel CD37-directed biologic therapy, in human NHL tumor xenograft models

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2565-2565
Author(s):  
D. S. Barone ◽  
C. Nilsson ◽  
J. Ledbetter ◽  
M. Hayden-Ledbetter ◽  
K. Mohler
Keyword(s):  
Survival Time ◽  
Median Survival ◽  
Nude Mice ◽  
Median Survival Time ◽  
Single Agent ◽  
Human Tumor ◽  
Lymphocytic Leukemia ◽  
Tumor Xenograft ◽  
Human Tumor Xenograft ◽  
Xenograft Models

2565 Background: Small Modular Immuno-Pharmaceuticals (SMIP) biopharmaceuticals belong to a novel proprietary biologic compound class that retain Fc mediated effector functions and are smaller than monoclonal antibodies. SMIP-016 is a SMIP product candidate that binds to CD37 on human B cells and has potent ADCC and apoptotic activity in vitro. CD-37 is known to be over-expressed in non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). We have evaluated the activity of SMIP-016 in established human tumor xenograft models in nude mice. Methods: Nude mice were injected subcutaneously with either Ramos or Daudi tumor cells. At approximately 7 days post tumor inoculation the mice were randomized to groups with roughly equivalent mean tumor volumes (>200mm3) and were treated with SMIP-016 or rituximab as a comparator. Groups were evaluated for median survival time (MST), tumor volume and percentage of tumor-free animals. Results: In nude mice bearing Daudi tumors, SMIP-016 treated mice showed a significant improvement in MST compared to control mice (p < 0.0001). Nude mice bearing Ramos tumors treated with SMIP-016 also demonstrated a significant enhancement in their median survival time (MST) in comparison to control mice (p < 0.0001). In addition, mice receiving SMIP-016 administered in combination with rituximab in this model demonstrated improvements in survival time over either single agent therapy alone. Conclusions: SMIP-016 is effective in treating established tumors in these human tumor xenograft models. Addition of SMIP-016 to rituximab therapy resulted in enhanced survival times compared to animals treated with rituximab alone. [Table: see text]

Safety and Efficacy Of Abbreviated Induction With Only 4 Cycles Of Fludarabine (F), Cyclophosphamide (C) and Rituximab (R) In Physically Fit Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Early Complete Remission (CR) With Undetectable Minimal Residual Disease (MDR)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2886-2886
Author(s):  
Carolina Pavlovsky ◽  
Astrid Pavlovsky ◽  
Isolda Fernandez ◽  
Adriana Galeano ◽  
Francisco Lastiri ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Residual Disease ◽  
Clinical Stage ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Blue Laser ◽  
Minimal Residual

Abstract Background Chemoimmunotherapy with 6 cycles of FCR is considered standard therapy for physically fit patients (pts) with Chronic Lymphocytic Leukemia (CLL). Many pts are unable to complete planned treatment, due to treatment related complications. Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher S et al. Leukemia, 2009). Achieving a negative MRD is therefore a mayor endpoint in treatment. Patients and methods From 4/2003, 39 physically fit pts with CLL who had IWCLL-NCI criteria for initiating treatment started therapy with FCR in our institution. Eleven pts had previously received chlorambucil/prednisone and 28 were not previously treated. Median age at start of therapy was 63 years (34-80), Binet´s clinical stage were A/B: 22 pts (56%) and C: 17 (44%). The CD38 expression was positive (>7% of cells) in 23 (59%) and negative in16 (41%) of the pts. After 4 courses of FCR response was assessed in peripheral blood (PB) or bone marrow (BM) using three colour flow Cytometry. Negative MRD was defined as < 0,1% of light chain restricted CD5+CD19+ B cells in PB and BM as assesed collecting 100000 CD19 cells in a three colour cytometer (FacsScalibur- blue laser ). All these patients stopped therapy after evaluation due to early CR with eradication of MRD. Results All patients had negative MRD in peripheral blood, 35 were also evaluated in bone marrow, 29 showed CR and 6 nodular partial remission (NPR). Neutropenia and infectious events grade 3-4 were observed in 24% and 7% of all the courses respectively. No pts died of toxicity. After a median follow-up of 81 months (4.6-120), progression free survival (PFS) and overall survival (OS) at 72 months was 51% and 75% respectively. Five pts died of progressive disease and 3 of a secondary neoplasm. Conclusion Stopping therapy in patients who achieve negative MRD after 4 cycles of FCR is safe and induces durable remission with a PFS and OS of 51% and 75% at 72 months exposing them to less chemotherapy. Large randomized trials are necessary to confirm this data. Disclosures: Pavlovsky: Novartis: Speakers Bureau; BMS: Speakers Bureau.

Sign in / Sign up

Export Citation Format

Share Document