|Year : 2021 | Volume
| Issue : 4 | Page : 917-924
Magnetic resonance imaging for the study of mediastinal adenopathies in lung cancer: Comparison with standard tests
Tara Pereiro-Brea1, Anxo Martínez de Alegría2, Luis Valdés3, Antonio Golpe-Gómez4, José Martín Carreira-Villamor5, Alberto Ruano-Raviña6
1 Complejo Hospitalario Universitario de A Coruña, Departamento de Neumología, As Xubias, A Coruña, Madrid, Madrid, Spain
2 Complejo Hospitalario Universitario de Santiago de Compostela, Departamento de Radiología, A Choupana, Santiago de Compostela, Madrid, Madrid, Spain
3 Complejo Hospitalario Universitario de Santiago de Compostela, Departamento de Neumología, A Choupana, Santiago de Compostela; Grupo Interdisciplinar de Investigación en Neumología, Instituto Sanitario de Investigaciones en Santiago (IDIS), Santiago de Compostela, Madrid, Madrid, Spain
4 Complejo Hospitalario Universitario de Santiago de Compostela, Departamento de Neumología, A Choupana, Santiago de Compostela, Madrid, Madrid, Spain
5 Complejo Hospitalario Universitario de Santiago de Compostela, Departamento de Radiología, A Choupana, Santiago de Compostela, Madrid, Spain
6 Universidad de Santiago de Compostela, Departamento de Medicina Preventiva y Salud Pública, Santiago de Compostela; CIBER de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Madrid, Spain
|Date of Submission||30-Nov-2020|
|Date of Decision||20-May-2021|
|Date of Acceptance||16-Jun-2021|
|Date of Web Publication||14-Sep-2021|
University Hospital Complex, Pneumology Service, As Xubias, A Coruña 15006
Source of Support: None, Conflict of Interest: None
Background: Lung cancer is the second most common cancer in both men and women. Mediastinal lymph node involvement in these patients, determined by imaging tests, indicates prognosis and modifies therapeutic attitude.
Purpose: The aim of this study was to analyze the diagnostic capacity of magnetic resonance imaging (MRI) in the study of the mediastinum in comparison with conventional tests (computed tomography [CT] and positron-emission tomography [PET] or PET/CT scans), taking histology as the gold standard.
Materials and Methods: An observational study was conducted on 16 patients with suspicion of primary lung cancer (June 2016 through December 2018). We studied their demographic characteristics and used CT, PET, or PET/CT scans and MRI (diffusion-weighted imaging-MRI sequence) to examine mediastinal disease and compare MRIs diagnostic yield and percentage agreement to that of conventional tests.
Results: As compared to CT and PET scanning, MRI displayed a very low sensitivity and a specificity of 90 and 88%, respectively; positive predictive value was 0.67 (both) and negative predictive value (NPV) was 0.28 and 0.22, respectively. MRI showed a high degree of agreement in lymph node diagnosis when compared with histology (91.2%; P = 0.001): specificity in this case was high (E = 0.94), as was the NPV (NPV = 0.97).
Conclusions: The results of this study would appear to indicate that MRI could play a relevant role in mediastinal staging of lung cancer. More prospective, multicenter studies are, however, needed to be able to draw up firm recommendations about the role of MRI and its place in lung cancer staging.
Keywords: Adenopathies, computed tomography, lung cancer, magnetic resonance, positron-emission tomography, staging
|How to cite this article:|
Pereiro-Brea T, de Alegría AM, Valdés L, Golpe-Gómez A, Carreira-Villamor JM, Ruano-Raviña A. Magnetic resonance imaging for the study of mediastinal adenopathies in lung cancer: Comparison with standard tests. J Can Res Ther 2021;17:917-24
|How to cite this URL:|
Pereiro-Brea T, de Alegría AM, Valdés L, Golpe-Gómez A, Carreira-Villamor JM, Ruano-Raviña A. Magnetic resonance imaging for the study of mediastinal adenopathies in lung cancer: Comparison with standard tests. J Can Res Ther [serial online] 2021 [cited 2021 Oct 20];17:917-24. Available from: https://www.cancerjournal.net/text.asp?2021/17/4/917/325933
| > Introduction|| |
Cancer is the second leading cause of death worldwide, and lung cancer is the second most common cancer in men and women, after prostate and breast cancer (14% and 12%, respectively). Incidence of lung cancer has increased by 29% in recent years due to population aging and is responsible for 1.7 million deaths worldwide. Its development depends on continued exposure to known risk factors and individual genetic predisposition.,
Tumor, node, and metastasis (TNM) classification is currently considered the most appropriate tool for defining anatomic tumor extension, and guiding the management and prognosis of malignant tumor disease in each individual. In parallel with technological advances, the TNM classification has undergone successive updates, the most recent of which is the current 8th edition published in 2016 by the International Association for the Study of Lung Cancer (IASLC).
The “N” component refers to lymph node involvement (number of lymph nodes or stations affected), which worsens prognosis and modifies therapeutic attitude. The component is classified into different categories according to the degree of lymph node involvement (N0, N1, N2, N3, or Nx).
Mediastinal staging can be performed by means of a number of techniques including noninvasive imaging tests (computed tomography [CT] scan of the chest, positron-emission tomography [PET], or magnetic resonance [MR]); nonsurgically invasive procedures (conventional transbronchial needle aspiration, echobronchoscopy (endobronchial ultrasound-guided needle aspiration [EBUS]), echoendoscopy, transthoracic needle aspiration, or pleural nonsurgical techniques); and surgically invasive procedures (mediastinoscopy, thoracoscopy, or pleural or surgical pericardial exploration). In any of these cases, the benefit-risk relationship should be carefully assessed before deciding which lymph node staging technique or techniques should be used on the patient.
CT chest scanning is the most widely available and most commonly used noninvasive test for the evaluation of the mediastinum in lung cancer. It enables practitioners to carry out a good anatomic study and ascertain the site and number of suspicious nodules, their size, whether they exhibit signs of invasion, and their relationship with adjoining structures, by clearly defining the anatomic limits of the lymph node stations according to the IASLC lymph node map. Following a series of studies, a lymph node measuring ≥10 mm on its short axis diameter (cross section) in an axial CT cut has come to be regarded as pathological. Sensitivity (S), specificity (SP), positive and negative predictive values (PPVs and NPVs), and erroneous CT diagnoses (false positives and negatives) have however shown that this test has limitations and should therefore not be regarded as definitive.
PET screening is based on the biological activity of tumor cells, thus making it possible to ascertain the tumor metabolism, and whether there is mediastinal disease or evidence of distant metastasis. Nonetheless, it has limited anatomic resolution, and so by twinning it with CT in a “PET/CT scan,” both procedures can be combined in a single exploration to obtain better diagnostic yields and greater diagnostic accuracy than would be achieved individually., Uptake levels are measured by the maximum standardized uptake value (SUVmáx), though as yet no standardized values have been set: in some cases, agreement is reached to accept an SUVmax cut point of 2.5 above which a PET value would be considered pathological., For a prevalence of metastatic mediastinal disease of 28%, the S, SP, PPV, and NPV values for PET would be 80%, 88%, 75%, and 91%, respectively. The SP of a PET/CT scan would be higher but the S would be lower.
Magnetic resonance imaging (MRI) is an anatomic study technique which, thanks to a series of technical innovations, seems to be becoming increasingly relevant in the study of the chest. Indeed, it is even considered superior to CT in the study of mediastinal invasion, chest wall, diaphragm, and vertebral bodies. After a number of studies were undertaken by different groups, it was proposed that MRI could be a profitable, radiation-free alternative which did not require the use of contrast medium, entailed short study times (comparing diffusion-weighted imaging (DWI) sequences to PET/CT), and was relative accessible, in lymph node staging. In DWI, tissues are studied by reference to the apparent diffusion coefficient (ADC). To determine the value above which tissues are considered pathological, studies of the ADC of lymph nodes in lung cancer patients showed it to be significantly lower in metastatic than in benign lymph nodes. The optimal ADC value for differentiating between malignant and benign lymph nodes was deemed to be ≤1.0 × 10− 3 mm2/s, with a diagnostic accuracy of 96.7%, a sensitivity (S) of 100%, a specificity (SP) of 88.9%, a PPV of 95.4%, and an NPV of 100%. Available studies that analyze the role of MRI in mediastinal staging are few in number, heterogeneous in the use of sequences, and based on few patients.
The mediastinal staging gold standard is the histology result in the form of cytology or biopsy, with invasive nonsurgical tests, invasive surgical tests, or pleural nonsurgical techniques being used for the purpose.
Nowadays, CT and PET or PET/CT scans are the standardized studies for the study of the mediastinum but whose limitations mean that histological mediastinal study may often be required to arrive at diagnostic certainty.,,, On the other hand, MRI is available, an imaging test less used to date for the study of the thorax and mediastinum, which seems to have sufficient capacity to distinguish metastatic from nonmetastatic lesions and with interesting qualities in its favor (radiation and contrast free, accessible, relatively cheap, etc.,).,,
Accordingly, this study sought: first, to evaluate the diagnostic yield of MRI in mediastinal staging in lung cancer patients through the DWI-MRI (diffusion) sequence; and second, to compare this technique's sensitivity and specificity against those of CT, PET, or PET/CT scans, using lymph node histology as the gold standard.
| > Materials and Methods|| |
The patients included were drawn from the Lung Cancer Rapid Diagnosis Unit (Pneumology Department) of a tertiary health facility equipped with the full range of pneumological techniques. The patients were consecutively recruited when mediastinal lymphadenopathy was detected by CT, PET or PET/CT from June 2016 through December 2018. All were over 18 years of age and had been referred to the Unit due to suspicion of primary lung cancer, with presence of mediastinal adenophaties that were apparently pathological on the grounds of size (≥1 cm on short axis) and/or metabolism (SUVmax >2.5; independently of size). Patients who had distant extrathoracic metastasis were excluded, since mediastinal staging was not required in their study protocol. An initial clinical evaluation was made and different diagnostic imaging tests were performed with a view to mediastinal staging due to presence of neoplasm, in accordance with routine clinical practice. The imaging examinations available were: CT and/or fluorodeoxiglucose (18-FDG)-PET or 18FDG-PET/CT screening, aimed at characterization of the adenophaties; and finally, the relevant surgical or nonsurgical invasive approach to such adenophaties which would confirm or rule out any metastatic involvement. All patients selected underwent MRI and CT, PET, or PET/CT scans, as well as the corresponding histology study. The tests were performed according to the order of the usual practice for the mediastinal study: 1st CT, 2nd PET or PET/CT, 3rd MRI, and 4th histological techniques. The CT scan and MRI were analyzed by the same and only experienced radiologist participating in the study. The PET or PET/CT was analyzed by an experienced nuclear medicine physician, who was blinded to the results of the previous CT. And finally, the histological results were evaluated by two experienced pathologists who knew patient's clinical data (age, sex, smoking rate, and suspected diagnosis), but they were blinded for radiological tests. All stations were histologically studied fact that we considered as an advantage of the study. Given that each patient might present with lymph node stations of a malignant or benign aspect, for study purposes, all lymph node stations of an apparently pathological nature were individually taken into account in the imaging of all patients. For the histology study, the most frequently used tests were EBUS (cytology specimen) and invasive surgical procedures (mediastinoscopy or thoracoscopy) (specimen: Biopsy).
All MRI sequences were performed on a Philips 1.5T scanner without the administration of gadolinium. DWI sequences were performed in all cases. We excluded from de study any patient aged under age 18 years, those who failed to sign the informed consent form, or those who presented with contraindications for the performance of MRI. The study was officially approved by the Research Ethics Committee from our hospital. All patients gave their informed consent to undergo MRI and participate in the study. The remaining tests formed part of the routine mediastinal staging study.
Patients' demographic characteristics (age, sex, and smoking habit) were studied. With respect to the imaging tests analyzed, we calculated lymph node size on the basis of the CT scans, determined uptake according to SUVmax as per the PET or PET/CT scans, and in the MRI study, obtained the ADC for each lymph node in the DWI-MRI sequence from the Philips IntelliSpace Portal. N was established according to the lymph node characteristics for each of the tests performed, using the TNM classification 8th edition. The following lymph nodes were considered suspect of malignancy: those measuring ≥1 cm on their short axis diameter in the CT scan; those having a SUVmax >2.5 in the PET scan; and those with an ADC value of ≤1.0 × 10− 3 mm2/s on MRI. For the different S, SP, PPV, and NPV values and diagnostic accuracy, the histology result was taken as the gold standard. Analyses were conducted by subgroup, taking patients' smoking habits into account.
All the variables were recorded in a database and analyzed using the SPSS computer software program version 22.0 SPSS inc, 2013. Chicago University, United States. A descriptive analysis was performed, with the categorical variables expressed as absolute and relative frequencies, and the continuous variables as means, medians, and ranges. Sensitivity, specificity, and the positive and NPVs were calculated according to the usual formulae. Inter-rater agreement was assessed using weighted kappa analysis. Results were deemed significant at P < 0.05.
| > Results|| |
A total of 16 patients (all male, median age 73.5 years) attending the Lung Cancer Rapid Diagnosis Unit were studied by MRI. In terms of smoking habit, 10 patients (62.5%) were ex-smokers, six patients (37.5%) were active smokers, and no patients were never smokers. All patients underwent CT scans of the chest (100%) and PET (75%) or PET/CT scans (25%) to complete the evaluation of tumor extension by imaging tests, as well as invasive or noninvasive histological mediastinal staging. In these 16 patients, a total of 35 lymph node stations were completely studied by MRI and at least one histological technique. Unbiopsied adenophaties were not included in the study, due to the fact that results could not be compared against the gold standard. A breakdown of patients' characteristics is shown in [Table 1].
|Table 1: Description of the sample of patients with neoplasm, comparing the imaging techniques used|
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The results obtained by routine mediastinal staging techniques were compared against those yielded by MRI, with essentially two goals in mind: first, to ascertain whether each test diagnosed each of the 35 lymph node stations as benign or malignant; and second, to ascertain what degree of mediastinal disease (N), they established as per the TMN classification 8th edition (N0, N1, N2, or N3).
Analyzing the patients as a whole and using each lymph node as a study unit, MRI was observed to be slightly insensitive yet highly specific when compared to the imaging tests routinely used in mediastinal staging, i.e. in comparison with CT and PET, sensitivity was 0.08 and 0.07, respectively, and specificity was 0.90 and 0.88, respectively. The PPVs were considerably high (0.67 in both cases) and the NPVs were low (0.28 and 0.22, respectively). Percentage agreement between MRI and CT, PET, or PET/CT was low, both for diagnosis of individual lymph node stations and for degree of mediastinal disease (statistically significant). In contrast, comparison of MRI with histology (gold standard) showed a high, statistically significant (P = 0.001) percentage agreement for distinguishing between benign and malignant lymph nodes (91.2%). Sensitivity and specificity in this case were also high, with values of 0.5 and 0.94, respectively. The NPV was 0.97 [Table 2]. Real images are attached to show the comparison between the standard tests, the MRI and the histological study [Figure 1] and [Figure 2].
|Table 2: Magnetic resonance imaging validity parameters versus other imaging tests and histology (gold standard), using lymph nodes as the study unit|
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|Figure 1: Computed tomography, positron-emission tomography and magnetic resonance imaging images of real patient. Patient A. Male with a lung mass in the right upper lobe. In computed tomography the lymphadenopathies stood out: 2R (10.7 mm), 4L (14.4 mm), 7 (13.7 mm) and 11R (10.2 mm). Positron-emission tomography mediastinal uptakes were: 4L (maximum standardized uptake value 4.6), 7 (maximum standardized uptake value 4.8) and 11R (maximum standardized uptake value 3.7). Both, computed tomography and positron-emission tomography, made suspect N3. Magnetic resonance imaging showed the following mediastinal apparent diffusion coefficient values: 4L (2.12 × 10–3 mm2/s), 7 (2 × 10–3 mm2/s) and 11R (1.98 × 10–3 mm2/s) that indicated lymphadenopathy benign in appearance (N0). EBUS histology of 4L and 7 did not show alterations suspicious of malignancy (N0)|
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|Figure 2: Computed tomography, positron-emission tomography, and magnetic resonance imaging images of real patient. Patient B. Male with a lung mass in the left upper lobe. In computed tomography the adenophaties stood out: 5 (12 mm) and 11L (10 mm), being for this reason suspicious of N2. Positron-emission tomography mediastinal uptakes were: 4L (maximum standardized uptake value 6.5), 5 (maximum standardized uptake value 12.3) and 11L (maximum standardized uptake value 20). Suspicion of N2 remained with this test. The magnetic resonance imaging showed mediastinal apparent diffusion coefficient values of: 4L (0.85 × 10–3 mm2/s), 5 (1.85 × 10–3 mm2/s) and 11L (1.87 × 10–3 mm2/s) that oriented, like computed tomography and positron-emission tomography, to N2. Histological 4L study confirmed invasion by adenocarcinoma but 11L study did not show alterations in 11L|
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A subgroup analysis by tobacco use was performed, with a breakdown by ex-smokers (10 patients, 24 lymph node stations) and active smokers (six patients, 11 lymph node stations). The results for ex-smoker patients were similar to those for all patients as a whole: S =0.06, SP = 0.83, PPV = 0.50, and NPV = 0.23 in comparison with the CT scan, and S = 0.56, SP = 0.80, PPV = 0.50, and NPV = 0.18 in comparison with the PET or PET/CT scans. The degrees of agreement were low and nonsignificant for CT and PET or PET/CT scans. With respect to histology, MRI in contrast proved to be highly sensitive and specific (S = 1 and SP = 0.96), showed a high NPV and a relatively good level of agreement for the premises studied (differentiating between benign and malignant lymph nodes, percentage agreement 64.5% (P = 0.001); and classification of N, percentage agreement 65.1% (P < 0.0001)) [Table 3]. In the group of active-smoker patients, MRI yielded no statistically significant results in terms of percentage agreement with respect to the tests against which it was compared [Table 4].
|Table 3: Magnetic resonance imaging validity parameters versus other imaging tests and histology (gold standard) in ex-smoker patients, using lymph nodes as the study unit|
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|Table 4: Magnetic resonance imaging validity parameters versus other imaging tests and histology (gold standard) in active smokers, using lymph nodes as the study unit|
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In the concordance analysis for mediastinal staging (N), using patients as the common denominator, the degree of agreement between CT scanning and MRI was low (kappa 0.216; P = 0.010), and this was also the case for PET scanning (kappa 0.018; P = 0.778). Concordance in terms of diagnosis of N was higher between MRI and the gold standard (histology), with a kappa value of 0.33 (P = 0.043) [Table 5]. Furthermore, the analysis of concordance between conventional tests for mediastinal staging (CT and PET or PET/CT scans) and the gold standard showed a low degree of agreement and non-significant results, both as between CT scanning and histology (kappa 0.129; P = 0.091), and as between PET or PET/CT scanning and histology (kappa 0.088; P = 0.115) [Table 5].
|Table 5: Comparison of the mediastinal staging results of the different techniques, using patients as the study unit|
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| > Discussion|| |
This is the first study in Spain to compare the diagnostic yield of MRI in the mediastinal staging of lung cancer with that of conventional tests. When compared with the gold standard (histology), MRI shows a high degree of agreement, both as regards diagnosis (benign versus malignant) and as regards N classification in staging, which would seem to indicate that it could be a test with diagnostic utility for the study of the mediastinum, particularly in the case of lung cancer patients.
Mediastinal staging is an essential item of information when it comes to treatment of lung cancer. Indeed, it so important that small differences in staging can determine very different therapeutic options; and this is why the diagnostic accuracy of routinely used tests continues to be studied over the years, so as to be able to offer the patients affected the most accurate diagnosis and propose changes in their position in the diagnostic cascade, should these be required.
Currently, the use of CT and PET or PET/CT scans for the study of the mediastinum is standardized but both tests have limitations. On the one hand, CT screening has a limited capacity for the diagnosis of lymph node metastasis. One study of 7368 patients reported that its sensitivity and specificity were 55% and 81%, respectively. It had an NPV of 83% and a PPV of 58%. In up to 15% of cases, the diagnosis proved to be erroneous once the histology study of the lymph node had been obtained. This leads us to think that, though it is a test with an important role in mediastinal staging, it is nonetheless limited and imperfect, and should therefore be complemented by other studies. On the other hand, there is the PET or PET/CT scan, a metabolic-type test shown to have a sensitivity and specificity superior to that of CT. Yet, even though it has a high sensitivity and NPV, its specificity and PPV are not that high, thus making it a test with a false positive rate of as much as 25%. This implies that, despite having these imaging studies, the histological mediastinal study may often be required in order to be able to arrive at diagnostic certainty.
This study sought to analyze the diagnostic power of MRI in a group of lung cancer patients with similar characteristics, who underwent CT, PET, or PET/CT scans and a histological mediastinal study. MRI displayed a high specificity, thus appearing to be a test with a marked capacity for ruling out mediastinal disease. The NPVs were high in comparison with the PPVs, which were lower. These points to the fact that, being a specific yet relatively insensitive test, it would be useful in patients with high suspicion of mediastinal disease but would not have the same benefit in the case of screening studies, since many affected patients might not be diagnosed. The low PPV, whose value may be influenced by the high prevalence of mediastinal disease in this risk population, indicates that there may be many false positives. Comparing its results with histology shows that MRI tends to identify N0 well, whereas both CT and PET and PET/CT scans tend to overestimate the degree of mediastinal disease (N1, N2, or N3).
In sum, this could be seen as a test that could complement but not replace existing tests. It should, however, be stressed that the percentage agreement obtained between MRI and the gold standard, both for the sample overall and for the subgroup of ex-smokers, is significantly higher than that obtained with other imaging tests.
The results of this study do not indicate that MRI might have a place in the study of mediastinal disease in lung cancer, though it is not clear exactly where this test would fit within the staging process nor are there studies that express a firm opinion on this point. Like CT and PET or PET/CT scans, MRI seems to have weaknesses that would bar it from being used as the sole imaging test, as a substitute for known tests, or in lieu of the histology study. At all events, the high percentage agreement with the gold standard suggests that its role in mediastinal staging could be of value in combination with routine tests. Our study used a specific resonance sequence, the diffusion sequence, which seems to be the most suitable for the study of the mediastinum according to various studies, though there are also other sequences that could serve the purpose. The absence of MRI protocols for this use, coupled with the scant knowledge of each sequence's potential in this respect, hinders progress in this type of study.
MRI has certain advantages that should be highlighted: (1) there is no exposure to radiation; (2) certain sequences do not require the use of contrast medium; (3) its cost is lower; (4) the sequences are of shorter duration than in PET/CT scanning; (5) fasting is not required; and (6) it is more easily accessible than PET/CT scans, for example, for hospitals with fewer resources., By way of disadvantages, it should be pointed out: first, that it can suffer interference from respiratory movements or heartbeat, interferences which can, in turn, give rise to study artifacts; and second, that it cannot be used on claustrophobic patients or on patients with certain tattoos or metallic material in their bodies (some types of pacemaker, prosthesis, etc.,).
This study's main limitation lies in its small sample size, as well as the absence of women and never-smoker patients in the sample. While the majority of patients underwent a PET scan as a metabolic study test, a change of equipment at our hospital meant that the last patients to be included were examined by PET/CT scanning. This turn of events might have influenced the results, due to the fact that a PET/CT scan has a higher diagnostic yield than do its components performed separately. No patients underwent both studies, and no comparisons by subgroup were made subsequently. The CT and MRI images were analyzed by a single radiologist, something that would likely serve to avoid interobserver errors but could nevertheless amount to a limitation if that same radiologist had knowledge of the results of the previous tests. Furthermore, the PET and PET/CT scans were analyzed separately by a different radiologist. The temporal difference between the tests performed was not taken into account and only one MRI sequence was studied. As a result, the results could not be extrapolated to the other sequences, and indeed there was no specific protocol for performing this technique.
A recently published systematic review covered 23 studies, including a meta-analysis whose stated aim was to evaluate the diagnostic capacity of MRI in mediastinal staging as compared to CT and PET or PET/CT scans. It concluded that MRI was a test with a high diagnostic power, superior or at least comparable, but in no case inferior, to conventional tests. These data are similar to those of our study which evaluated MRI's applicability in routine clinical practice and likewise concluded that it could be considered at least comparable to standard techniques. Although previous studies do not establish firm recommendations as to what point in staging to include an MRI study,, they highlight the relevant role to be played by MRI in the study of the mediastinum and propose the possibility of using it in this process as a complementary technique, to replace some other imaging test or even the histology study itself.,,
| > Conclusions|| |
Although our results would seem to be similar to those of other studies in the literature, they do not suffice to establish firm recommendations. To this end, it would thus be ideal to have prospective, multicenter studies that confirmed MR's role in lung cancer staging.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]