• Users Online: 480
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2023  |  Volume : 14  |  Issue : 1  |  Page : 35-40

High D-Dimer level at first incident cancer-associated venous thromboembolism is a predictor for recurrence: A retrospective cohort study


1 Academic and Students Affairs Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Health Affairs, Ministry of National Guard; King Abdulaziz Medical City, Health Affairs, Ministry of National Guard; King Abdullah International Medical Research Centre, Health Affairs Ministry of National Guard, Riyadh, Saudi Arabia
2 Academic and Students Affairs Department, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Health Affairs, Ministry of National Guard; King Abdullah International Medical Research Centre, Health Affairs Ministry of National Guard, Riyadh, Saudi Arabia

Date of Submission30-Nov-2022
Date of Decision25-Dec-2022
Date of Acceptance13-Jan-2023
Date of Web Publication17-Feb-2023

Correspondence Address:
Prof. Fahad A S. Al-Eidan
College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Health Affairs, Ministry of National Guard, Riyadh
Saudi Arabia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_107_22

Rights and Permissions
  Abstract 

BACKGROUND: Cancer is considered a major risk factor of venous thromboembolism (VTE). Whether the D-dimer level at first incident cancer-associated VTE can predict recurrence is not fully elucidated.
AIM: The aim of this study was to assess the association between D-dimer level measured at first incident cancer-associated VTE and risk of recurrence.
METHODS: In this study, the electronic records of all patients with first incident cancer-associated VTE were retrospectively retrieved and followed up for a period of 36 months. The measured levels of D-dimer and clinical predictors for each patient prior intervention were collected. Univariate and multivariant Cox regressions were fitted to estimate the hazard ratio (HR) and 95% confidence interval (CI).
RESULTS: A total of 73 (34.3%) of 213 cancer-associated VTE patients had recurrent VTE. The crude recurrence rate was 11.4/100 person-years (95% CI, 9.2–14.2). The mean value of D-dimer was significantly higher seen in recurrent VTE patients than those without recurrence (14.8 ± 7.5 mg/L vs. 4.8 ± 5.7 mg/L, P < 0.001). The highest positive likelihood ratio using area under the receiver operating characteristic (ROC) curve occurred when a D-dimer threshold of 8.67 mg/L was chosen. At this threshold, the D-dimer was 92% sensitive and 80% specific in predicting recurrent VTE. The area under the ROC curve was 0.924 (95% CI 0.887–0.960, P < 0.001). Patients with a D-dimer ≥8.67 mg/L at first VTE in our study were 3.1-fold more likely to have a recurrence than those with lower D-dimer results.
CONCLUSION: A D-dimer ≥8.67 mg/L measured at the first incident cancer-associated VTE was associated with a 3.1-fold increased hazard of recurrence events. Our finding suggests that a low D-dimer level at the time of first cancer-associated VTE is suitable in the clinical practice to avoid extended-duration anticoagulation.

Keywords: Cancer, D-dimer, recurrence, venous thromboembolism


How to cite this article:
S. Al-Eidan FA, Alotaibi SA, Almajid HM, Alnahedh TA, Abdel Gadir AG. High D-Dimer level at first incident cancer-associated venous thromboembolism is a predictor for recurrence: A retrospective cohort study. J Appl Hematol 2023;14:35-40

How to cite this URL:
S. Al-Eidan FA, Alotaibi SA, Almajid HM, Alnahedh TA, Abdel Gadir AG. High D-Dimer level at first incident cancer-associated venous thromboembolism is a predictor for recurrence: A retrospective cohort study. J Appl Hematol [serial online] 2023 [cited 2023 Mar 20];14:35-40. Available from: https://www.jahjournal.org/text.asp?2023/14/1/35/369840


  Introduction Top


Venous thromboembolism (VTE), a term that describes both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious disease with an annual cumulative incidence of 1.7/1000 patients among people of Saudi ancestry.[1] VTE is a multifactorial disease and numerous traditional risk factors have been associated with its occurrence and recurrence and these include family history, previous DVT, advanced age, prolonged immobility, obesity, recent surgery/trauma/fracture, hospitalizations, hypercoagulable, and thrombophilic disorders as well as cancer.[2] However, the incidence rate is on a steady increase over the last two decades, especially in cancer patients who in addition suffer more complicated prognoses.[3],[4] Indeed, the connection between cancer and VTE has assumed more importance in recent years as the diagnosis of cancer increases the risk of VTE by 9-fold compared to individuals without cancer[5] and that cancer-associated VTE is linked to the frequent occurrence of VTE.[1],[3] However, it remains unclear if the reported high incidence rate of VTE is the result of increased disease prevalence or increased detection through improved diagnostic techniques.[3]

The reported incidence of VTE in cancer patients varies according to the patient population, follow-up, and the technique used in detecting and reporting thrombotic events.[6] Besides, cancer patients with VTE have a remarkable mortality risk compared to cancer patients without VTE[4] and the recurrence rate is high among these patients and increases further during the first 6 months following the first incidence detection of VTE.[7]

We took a special interest in finding a laboratory predictor of the recurrence of VTE in cancer patients following the first-time establishment of the diagnosis in these patients. A recent retrospective study among cancer-free VTE patients[8] found that low blood levels (≤1500 ng mL) of the laboratory thrombotic marker D-dimer, measured at first VTE diagnosis was associated with a low risk of recurrence, thereby avoiding prolonged anticoagulant therapy and its associated complications, especially bleeding. Increased D-dimer level after discontinuation of anticoagulation was also found to be independently associated with the recurrence events.[9],[10],[11],[12],[13]

D-dimer is generated as the result of the degradation of fibrin by the fibrinolytic enzyme plasmin, and accordingly, the measured blood level of D-dimer reflects the existence and extent of fibrin clot formation in vivo. The D-dimer test is commonly requested in clinical practice as a laboratory biomarker in the work-up of patients with suspicion of VTE[14],[15] and is routinely measured in these patients at the time of first incidence confirmation: We hypothesize that, in cancer patients, elevated plasma D-dimer level at the time of primary VTE diagnosis may predict individuals at risk of recurrence. Therefore, in the current study, we aimed to find out whether we can establish a significant correlation between the measured level of plasma D-dimer at the time of primary VTE confirmation and the risk of recurrent events.


  Methods Top


Study design and participants

This is a single-center retrospective cohort study of 213 patients, conducted in a tertiary care center, King Abdulaziz Medical City, Riyadh, Saudi Arabia, in the period between January 2016 and December 2020. All patients were diagnosed with primary cancer-associated VTE confirmed by color duplex sonography (in cases of proximal DVT) and spiral computed tomography (in case of PE). Their ages were ≥18 years, and all patients who received therapeutic anticoagulants were eligible during the study period. Exclusion criteria include pregnant, long-term anticoagulation, recent surgery or trauma, and more than one previous VTE. All included participants were followed up for a period of 36 months. The medical records of cancer cases with the first VTE event were electronically retrieved by trained personnel who reviewed the medical records of individual VTE cases and they recorded the information on recurrent events, clinical risk factors, and laboratory and imaging results on standardized data collection spreadsheets.

Statistical analysis

Data analysis was performed using the software of SPSS for Windows version 26 (IBM Corp. NY, USA). Quantitative variables were tested for normal distribution using the Kolmogorov–Smirnov test. Mann–Whitney U test (interquartile range) was used for the comparison of nonparametric data, and the student t-test was used for the comparison of parametric data. Chi-square or Fisher's exact test was used for the comparison of categorical data. All patients were followed from the date of completion of their anticoagulation treatment for the first VTE to the first occurring events of either recurrent VTE, death, or end of follow-up. Predictor factors impacting recurrent VTE were identified by conducting univariate and multivariate analysis with Cox proportional hazards regression models to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). The probability curve of recurrence was estimated according to Kaplan–Meier method.[16] The results were considered statistically significant at P < 0.05. The receiver operating characteristic (ROC) analysis was used for calculating the sensitivity and specificity of various cutoff points for the D-dimer.


  Results Top


A total of 213 patients with cancer-associated VTE met our inclusion criteria and were included in the study population; 73 patients (34.3%) were identified as confirmed cases of recurrent cancer-associated VTE and 140 patients without recurrent VTE were considered the control group. The gross recurrence rate was 11.4/100 person-years (95% CI, 9.2–14.2). No significant differences were found between the cases and the control group in their age, sex, and body mass index, and the main demographic characteristics are presented in [Table 1].
Table 1: Demographic and baseline characteristics of the patients with cancer-associated venous thromboembolism

Click here to view


The mean value of D-dimer was significantly higher in the cases than in the control group (14.8 ± 7.5 mg/L vs. 4.8 ± 5.7 mg/L, P < 0.001). To assess the risk of recurrent VTE in relation to D-dimer levels, a ROC analysis was performed to determine the best cutoff points. The highest positive likelihood ratio using area under the ROC curve was noted when a D-dimer threshold of 8.67 mg/L was chosen. At this threshold, the D-dimer was 92% sensitive and 80% specific in predicting recurrent VTE [Figure 1]. The area under the ROC curve was 0.924 (95% CI 0.887–0.960, P < 0.001). The cumulative probability of recurrent VTE during 36-month follow-up based on the plasma level of D-dimer was estimated using Kaplan–Meier method, and accordingly, the probability of recurrent VTE was found to be higher among patients with D-dimer levels of ≥8.67 mg/L (P < 0.001 by the log-rank test) [Figure 2].
Figure 1: ROC curve for D-dimer predicting VTE recurrence. ROC = Receiver operating characteristic, VTE = Venous thromboembolism

Click here to view
Figure 2: Kaplan–Meier method estimates of the risk of recurrent cancer-associated VTE based on the plasma level of D-dimer. The probability of VTE recurrence was higher among patients with D-dimer levels of ≥8.67 mg/L than patients with lower D-dimer levels (P ≤ 0.001 by Log-rank test). VTE = Venous thromboembolism

Click here to view


Univariate and multivariate Cox regression analysis was used to create a model for predicting the risk associated with recurrent VTE using the significantly different independent covariant studied at the level of P < 0.05. Three covariates were found to be independent predictors associated with recurrent VTE, including D-dimer ≥8.67 mg/L measured at the first incident cancer-associated VTE (HR, 3.10; 95% CI, 1.86–5.27; P < 0.001), Eastern Cooperative Oncology Group performance status (HR, 1.44; 95% CI, 1.13–1.84; P = 0.003), and systemic infection (HR, 1.79; 95% CI, 1.04–3.07; P = 0.034). Patients with a D-dimer ≥8.67 mg/L at first VTE were 3.1-fold more likely to have a recurrence than those with lower D-dimer results [Table 2].
Table 2: Univariant and multivariant Cox regression for predictors associated with recurrent venous thromboembolism

Click here to view



  Discussion Top


In cancer patients, VTE events have an adverse impact on the clinical course of the disease as it worsens morbidity, mortality, increases health-care costs, and adds to the psychological burden of the patients, as reviewed elsewhere.[17] Therefore, optimizing therapeutic approaches by personalizing the primary prevention of cancer-associated VTE and secondary prevention of its recurrence remains an unmet but highly desirable medical goal.

In the present retrospective study, we aimed to evaluate the association between plasma D-dimer level measured before the commencement of anticoagulation at the time of the first event of cancer-associated VTE and the risk of recurrence. Our results showed that the incidence of recurrence rate among the study cohort, at 36-month follow-up, was 11.4/100 person-years (95% CI, 9.2–14.2). D-dimer level of ≥8.67 mg/L at the first occurrence of cancer-associated VTE was found to be a predictor of patients at high risk for developing recurrent VTE after the cessation of anticoagulation. Besides, plasma D-dimer levels ≥8.67 mg/L in patients with first cancer-associated VTE were associated with a 3.1-fold increased hazard of recurrence events compared to patients with plasma D-dimer levels <8.67 mg/L, which was found to be independent covariate variable.

A recent Norwegian study examined the association between D-dimer, measured at the time of confirming first VTE, and the risk of recurrent VTE.[8] Their hypothesis was that low D-dimer level at the time of confirming the first VTE event could identify individuals at low risk of recurrence. However, VTE patients with active cancer were excluded from the analysis. The study concluded that a low D-dimer (≤1.5 mg/L) measured at the time confirming the first VTE was associated with low recurrence risk and this led the researchers to recommend avoiding prolonged anticoagulant treatment.[8] A similar observation has been raised earlier in two published studies.[12],[18] In the first study, a patient-level meta-analysis, elevated D-dimer level was associated with a 2.59-fold increased risk of recurrence compared to patients with normal D-dimer.[12] In the second, which is a case–control study of 626 patients and 361 controls, patients with elevated D-dimer levels (>500 ng/ml) measured after completion of anticoagulation duration, a 2.3-fold increased risk of recurrence was found compared to patients with normal levels.[18]

We believe that the development of VTE in cancer patients needs to be studied as a special disease situation in view of the fact that the development of VTE in these cancer patients other than worsening the prognosis in these patients,[19],[20],[21] cancer is known to be a prothrombotic (hypercoagulable) state. Many studies have described prothrombotic blood changes in cancer patients. The cell-surface glycoprotein tissue factor, which is the main trigger of the coagulation system in vivo, is overexpressed in both cancer cells as well as in the circulating procoagulant extracellular vesicles (EVs) shed by cancer cells.[22] There are also increased blood levels of inflammatory cytokines (e.g., tumor necrosis factor and interferon-gamma), platelets, leukocytes, clotting factor VIII, and laboratory markers of coagulation activation (thrombin-antithrombin complex and prothrombin fragments 1 + 2). Thus, in cancer patients, these factors, alone or in combination, interact to shift the hemostatic balance toward a procoagulant direction. The resulting excess thrombin and fibrin-forming activity would enhance the development of cancer-associated VTE.[19],[20],[21]

In this respect, of the numerous global diagnostic techniques used in the assessment of hypercoagulability, the measurement of the blood levels of D-dimer has outperformed all other tests and was repeatedly been relied on to reflect the presence and extent of an intravascular clot[9],[10],[11],[12],[13],[23],[24] D-dimer is the most well-characterized of soluble cross-linked fibrin degradation product release from fibrin polymers when broken down by the fibrinolytic enzyme plasmin during thrombus formation.[20],[25] In routine hospital practice, the D-dimer has nowadays established itself as the routine diagnostic test of VTE.[24] Although low D-dimer levels can be detected in the plasma specimens of healthy individuals, patients with VTE often display a significant elevation of plasma D-dimer levels.[26],[27],[28],[29] Moreover, D-dimer levels can be used to rule out VTE, however, its specificity is low as D-dimer levels can be increased in certain clinical conditions (with no evidence of the assistance of VTE), including cancer, infections, and major surgery.[30],[31]

The strong point of our study is that it added further important use of the D-dimer test besides its routine use in the diagnosis of VTE and that magnitude of its measured level at the first incident of cancer-associated VTE can predict the risk of recurrence and thereby help in the clinician's decision to engage in long-term anticoagulation.


  Conclusion Top


The prime finding of the current study of plasma D-dimer levels ≥8.67 mg/L in patients with first cancer-associated VTE being associated with a 3.1-fold increased hazard of recurrence events compared to patients with plasma D-dimer levels <8.67 mg/L would indicate that in the patients who suffer a recurrence of DVT continue to suffer a state of heightened hemostatic activation (or hypercoagulability) that eventually results in the recurrence of DVT event. These findings should answer the question raised in a recent publication: Which patients are at high risk of recurrent VTE.[17] It is our hope that the findings of the current study would also raise the awareness of clinicians to pay special attention to the magnitude of plasma D-dimer level elevation at the time of confirmed first VTE in patients with cancer. This could be a guide to stratification of the risk of recurrence among these patients into high-or low-risk patients and therefore will enlighten decisions on the short- and or long-term anticoagulation treatment in these patients. However, the reliability of plasma D-dimer level measured at the time of first confirmed VTE, as a predictor for recurrence in patients with cancer needs to be further investigated in an additional prospective observational study and confirmed in clinical randomized studies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
AlEidan FA, AlManea RK, AlMoneef AT, Shalash NA, AlRajhi NA, AlMousa SF, et al. Incidence and predictors of recurrence and mortality following first venous thromboembolism among the Saudi population: Single-center cohort study. Int J Gen Med 2022;15:7559-68.  Back to cited text no. 1
    
2.
Baylis RA, Smith NL, Klarin D, Fukaya E. Epidemiology and genetics of venous thromboembolism and chronic venous disease. Circ Res 2021;128:1988-2002.  Back to cited text no. 2
    
3.
Kraaijpoel N, Di Nisio M, Mulder FI, van Es N, Beyer-Westendorf J, Carrier M, et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: Results from the Hokusai VTE Cancer Study. Thromb Haemost 2018;118:1439-49.  Back to cited text no. 3
    
4.
Ay C, Pabinger I, Cohen AT. Cancer-associated venous thromboembolism: Burden, mechanisms, and management. Thromb Haemost 2017;117:219-30.  Back to cited text no. 4
    
5.
Mulder FI, Horváth-Puhó E, van Es N, van Laarhoven HW, Pedersen L, Moik F, et al. Venous thromboembolism in cancer patients: A population-based cohort study. Blood 2021;137:1959-69.  Back to cited text no. 5
    
6.
Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-associated venous thrombosis. Blood. Semin Thromb Hemost 2013;122:1712-23.  Back to cited text no. 6
    
7.
Pabinger I, van Es N, Heinze G, Posch F, Riedl J, Reitter EM, et al. A clinical prediction model for cancer-associated venous thromboembolism: A development and validation study in two independent prospective cohorts. Lancet Haematol 2018;5:e289-98.  Back to cited text no. 7
    
8.
Bjøri E, Johnsen HS, Hansen JB, Braekkan SK. D-dimer at venous thrombosis diagnosis is associated with risk of recurrence. J Thromb Haemost 2017;15:917-24.  Back to cited text no. 8
    
9.
Righini M, Perrier A, De Moerloose P, Bounameaux H. D-Dimer for venous thromboembolism diagnosis: 20 years later. J Thromb Haemost 2008;6:1059-71.  Back to cited text no. 9
    
10.
Baglin T, Palmer CR, Luddington R, Baglin C. Unprovoked recurrent venous thrombosis: Prediction by D-dimer and clinical risk factors. J Thromb Haemost 2008;6:577-82.  Back to cited text no. 10
    
11.
Bruinstroop E, Klok FA, Van De Ree MA, Oosterwijk FL, Huisman MV. Elevated D-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: A meta-analysis. J Thromb Haemost 2009;7:611-8.  Back to cited text no. 11
    
12.
Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S, et al. Patient-level meta-analysis: Effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010;153:523-31.  Back to cited text no. 12
    
13.
Eichinger S, Minar E, Bialonczyk C, Hirschl M, Quehenberger P, Schneider B, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA 2003;290:1071-4.  Back to cited text no. 13
    
14.
Lloyd AJ, Dewilde S, Noble S, Reimer E, Lee AY. What impact does venous thromboembolism and bleeding have on cancer patients' quality of life? Value Health 2018;21:449-55.  Back to cited text no. 14
    
15.
Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003;349:1227-35.  Back to cited text no. 15
    
16.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Amer Stat Assoc 1958;53:457-81.  Back to cited text no. 16
    
17.
Áinle FN, Kevane B. Which patients are at high risk of recurrent venous thromboembolism (deep vein thrombosis and pulmonary embolism)? Blood Adv 2020;4:5595-606.  Back to cited text no. 17
    
18.
van Hylckama Vlieg A, Baglin CA, Luddington R, MacDonald S, Rosendaal FR, Baglin TP. The risk of a first and a recurrent venous thrombosis associated with an elevated D-dimer level and an elevated thrombin potential: Results of the THE-VTE study. J Thromb Haemost 2015;13:1642-52.  Back to cited text no. 18
    
19.
ten Cate H, Falanga A. Overview of the postulated mechanisms linking cancer and thrombosis. Pathophysiol Haemost Thromb 2008;36:122-30.  Back to cited text no. 19
    
20.
Zwicker JI, Furie BC, Furie B. Cancer-associated thrombosis. Crit Rev Oncol Hematol 2007;62:126-36.  Back to cited text no. 20
    
21.
Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol 2009;22:49-60.  Back to cited text no. 21
    
22.
Hisada Y, Mackman N. Cancer-associated pathways and biomarkers of venous thrombosis. Blood 2017;130:1499-506.  Back to cited text no. 22
    
23.
Hron G, Kollars M, Binder BR, Eichinger S, Kyrle PA. Identification of patients at low risk for recurrent venous thromboembolism by measuring thrombin generation. JAMA 2006;296:397-402.  Back to cited text no. 23
    
24.
Lippi G, Cervellin G, Franchini M, Favaloro EJ. Biochemical markers for the diagnosis of venous thromboembolism: The past, present and future. J Thromb Thrombolysis 2010;30:459-71.  Back to cited text no. 24
    
25.
Rowe CA, Bolitho JS, Jane A, Bundesen PG, Rylatt DB, Eisenberg PR, et al. Rapid detection of D-dimer using a fiber optic biosensor. Thromb Haemost 1998;79:94-8.  Back to cited text no. 25
    
26.
Kearon C, Ginsberg JS, Douketis J, Crowther M, Brill-Edwards P, Weitz JI, et al. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and D-dimer testing. Ann Intern Med 2001;135:108-11.  Back to cited text no. 26
    
27.
Escoffre-Barbe M, Oger E, Leroyer C, Grimaux M, Le Moigne E, Nonent M, et al. Evaluation of a new rapid D-dimer assay for clinically suspected deep venous thrombosis (Liatest D-dimer). Am J Clin Pathol 1998;109:748-53.  Back to cited text no. 27
    
28.
Wilde JT, Kitchen S, Kinsey S, Greaves M, Preston FE. Plasma D-dimer levels and their relationship to serum fibrinogen/fibrin degradation products in hypercoagulable states. Br J Haematol 1989;71:65-70.  Back to cited text no. 28
    
29.
Flores J, Lancha C, Pérez Rodríguez E, García Avello A, Bollo E, García Frade LJ. Efficacy of D-dimer and total fibrin degradation products evaluation in suspected pulmonary embolism. Respiration 1995;62:258-62.  Back to cited text no. 29
    
30.
Kovacs MJ, MacKinnon KM, Anderson D, O'Rourke K, Keeney M, Kearon C, et al. A comparison of three rapid D-dimer methods for the diagnosis of venous thromboembolism. Br J Haematol 2001;115:140-4.  Back to cited text no. 30
    
31.
Adam SS, Key NS, Greenberg CS. D-dimer antigen: Current concepts and future prospects. Blood 2009;113:2878-87.  Back to cited text no. 31
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed382    
    Printed8    
    Emailed0    
    PDF Downloaded30    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]