- Open Access
Apparent diffusion coefficient measurements in the differentiation between benign and malignant lesions: a systematic review
© The Author(s) 2012
- Received: 7 December 2011
- Accepted: 13 April 2012
- Published: 7 June 2012
To systematically review the value of apparent diffusion coefficient (ADC) measurement in the differentiation between benign and malignant lesions.
A systematic search of the Medline/Pubmed and Embase databases revealed 109 relevant studies. Quality of these articles was assessed using the Quality Assessment of the Studies of Diagnostic Accuracy Included in Systematic Reviews (QUADAS) criteria. Reported ADC values of benign and malignant lesions were compared per organ.
The mean quality score of the reviewed articles was 50%. Comparison of ADC values showed marked variation among studies and between benign and malignant lesions in various organs. In several organs, such as breast, liver, and uterus, ADC values discriminated well between benign and malignant lesions. In other organs, such as the salivary glands, thyroid, and pancreas, ADCs were not significantly different between benign and malignant lesions.
The potential utility of ADC measurement for the characterisation of tumours differs per organ. Future well-designed studies are required before ADC measurements can be recommended for the differentiation of benign and malignant lesions. These future studies should use standardised acquisition protocols and provide complete reporting of study methods, to facilitate comparison of results and clinical implementation of ADC measurement for tumour characterisation.
- Apparent diffusion coefficient
- Diffusion-weighted imaging
Over the past two decades, magnetic resonance (MR) imaging (MRI) has proven to be a valuable diagnostic tool in oncology [1–4]. Rapid improvements in MRI techniques have resulted in MR images with excellent spatial resolution and soft tissue contrast, which contribute to the differentiation of suspected tumours. However, using conventional MRI sequences, difficulty in differentiating benign from malignant lesions may arise when malignant and benign lesions share certain morphologic and contrast-enhancement characteristics. In these cases, diffusion-weighted MR imaging (DWI) might be of value in tumour assessment, as it has the ability to provide tissue contrast based on molecular diffusion . Since the 1990s, DWI using single-shot echo-planar imaging (EPI) has been successfully applied in the field of neuroradiology. It is particularly valuable in the assessment of acute cerebral ischemia [6, 7]. Initially, DWI in other than intracranial sites did not yield sufficient image quality due to susceptibility artefacts and motion artefacts. More recently, technical advances in MRI, such as the development of parallel imaging, high gradient amplitudes, and multichannel coils, have enabled the performance of DWI in the body. These developments have initiated the investigation of applicability of DWI for tumour characterisation, both intra- and extracranially. Diffusion-weighted images can be assessed in two ways, qualitatively, by visual assessment of signal intensity, and quantitatively, by measurement of the apparent diffusion coefficient (ADC). The ADC value quantifies water proton motion, which in biological tissues is a combination of true water diffusion and capillary perfusion. The ADC value can theoretically be used to characterise tissues, as the degree of diffusion is correlated to cellular density and extracellular space volume [8, 9]. Malignant tumours are reported to have a high cellular density and low extracellular space volume, which is associated with impeded water proton diffusion and low ADC values. In contrast, various benign lesions are characterised by an increased amount of extracellular matrix with minimal increase of cellular density, which may result in higher ADCs [10, 11]. This hypothesis has been investigated for various types of lesions throughout the body. However, because of the large number of studies on this subject with sometimes conflicting results, the utility of ADC measurements in the characterisation of lesions remains unclear. The aim of this study was therefore to systematically review the current literature on the value of ADC measurement in the differentiation between benign and malignant lesions throughout the entire body.
Inclusion and exclusion criteria
Human, in vivo studies
Differentiation between benign and malignant lesions in any organ
ADC measurements used to differentiate benign from malignant lesions
It was possible to classify ADC measurements into a group of benign and a group of malignant lesions
Histological examination used as reference standard
Diffusion-weighted MRI with ADC measurements performed prior to any treatment
Absolute outcome measures (mean ADCs) can be obtained from article
Total sample size of at least 20 lesions
MR ≥ 1 Tesla
Therapeutic or prognostic studies
Reviews, meta-analyses, editorials, case reports
Studies that focus solely on ADC values of (pathologic) lymph nodes or vertebral fractures
Adjusted QUADASa tool for quality assessment
1. Was the spectrum of patients representative of the patients who will receive the test in practice?
Patients with lesions detected at conventional imaging (e.g., CT, US, or anatomical MRI). Conventional imaging could not assess whether those lesions were benign or malignant
2. Were selection criteria clearly described?
It was clear how patients were selected for inclusion
3. Is the reference standard likely to correctly classify the target condition?
Histological examination was used as a reference standard
4. Was the time period between histological assessment and DWI short enough to be reasonably sure that the target condition did not change between the two tests?
Histological assessment was performed within 2 weeks after DWI
5. Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis?
All patients, or a random sample of patients, received histological examination
6. Did patients receive the same reference standard regardless of the index test result?
Patients received histological assessment regardless of ADC measured
7. Was the execution of the index test described in sufficient detail to permit replication of the test?
All of the following MRI parameters are described: field strength, coil type, sequence type, applied b-values, BH/RT/FB, and direction(s) of applied diffusion gradients
8. Was the execution of the reference test described in sufficient detail to permit replication?
Description of the following points: means of harvesting histological material (biopsy or surgery) given, interpreter of histological assessment mentioned
9. Were the index test results interpreted without knowledge of the results of the reference standard?
DWI was interpreted without knowledge of the histological assessment findings
10. Were the reference standard results interpreted without knowledge of the results of the index test?
Histological assessment was interpreted without knowledge of the DWI findings
11. Were the same clinical data available when test results were interpreted as would be available when the test is used in practice?
Clinical data were available to the interpreter(s) of the DWI
12. Were withdrawals from the study explained?
Withdrawals from the study after inclusion were explained
Reported ADC values of the reviewed studies are presented per organ or body region. The reported ADC values (mean ± standard deviation) of benign and malignant tumours in each organ will be discussed and compared and are represented graphically in the accompanying figures. We did not perform meta-analyses as the substantial variation in study characteristics and applied diffusion-weighted imaging parameters of the reviewed studies prevented meaningful pooling of the data. We aimed to give a broad overview of the literature on differentiation between benign and malignant tumours.
We identified 109 articles that described and compared mean ADC values for malignant and benign tumours in various body regions, of which 14 were intracranial and 95 extracranial. The included extracranial regions were salivary glands (6), thyroid (6), breast (24), lung (2), liver (14), gallbladder (1), pancreas (9), kidney (8), adrenal gland (4), uterus (8), ovaries (7), and soft tissue (6). Study design was prospective in 38 studies, retrospective in 39, and unreported in 32 out of 109 studies. Most studies (98 out of 109) used echo planar imaging (EPI) pulse sequences for diffusion-weighted imaging, and 64 out of 109 studies reported using diffusion gradients in three orthogonal directions (along the x, y, and z axes).
In the following section, a summary of the results will be presented per organ or body region. Due to the large number of studies reviewed, tables containing study characteristics could not be included in this paper but are provided in the Electronic Supplementary Material (ESM S1–S14).
The articles regarding intracranial DWI addressed the following issues: differential diagnosis between cerebral abscesses and necrotic or cystic malignant tumours and between typical (benign) and atypical (malignant) meningiomas. Differentiation of high- and low-grade malignant brain tumours has also been studied extensively but lies beyond the scope of this review and will not be discussed.
Six articles discussed the contribution of DWI to the differentiation between histologic grades of meningiomas (ESM Table S2) [21–26]. Quality scores ranged from 42 to 67%. DWI was performed on a 1.0 T MR system in one study, 1.5 T in four studies, and 3.0 T in one study , and all authors applied a high maximum b-value of 800–1,000 s/mm2. All except one of the studies showed lower ADC values in atypical and malignant meningiomas than in typical meningiomas, with P-values <0.05 in three out of six studies [21, 22, 26]. However, considerable overlap existed between the types of meningiomas. Mean ADC values of typical meningiomas ranged from 0.88 ± 0.08 to 1.17 ± 0.21 × 10−3 mm2/s, mean ADC values of atypical and malignant meningiomas ranged from 0.66 ± 0.13 to 0.923 ± 0.085 × 10−3 mm2/s (Fig. 3).
Six studies addressed the issue of differentiating benign and malignant thyroid nodules with DWI and ADC measurement (ESM Table S4) [33–38]. Quality scores of these studies ranged from 25 to 75%. Applied maximum b-values were 300 , 500 , 800 , and 1,000 [35–37]. All authors measured ADC values in solid (components of) lesions. The six included studies showed a marked variance in ADC values of thyroid nodules. In five studies [33–37], ADC values of thyroid carcinoma were significantly lower than ADC values of benign thyroid nodules. In these studies, mean ADC values of benign nodules ranged from 1.15 ± 0.43 to 2.75 ± 0.60 × 10−3 mm2/s, mean ADC values of malignant lesions ranged from 0.30 ± 0.20 to 1.20 ± 0.25 × 10−3 mm2/s (Fig. 4). However, one study  found a remarkably high mean ADC value in 16 thyroid carcinomas (2.73 ± 0.65 × 10−3 mm2/s), which was significantly higher than the mean ADC of benign thyroid adenomas (1.93 ± 0.25 × 10−3 mm2/s).
Fourteen studies described ADC values of benign and malignant liver lesions (ESM Table S7) [65–78]. Quality scores ranged from 25 to 58%. All of these studies used single-shot EPI diffusion-weighted sequences. Seven studies applied maximum b-values of 400–600 s/mm2, while the other half of the studies applied maximum b-values of 800–1,000 s/mm2. Mean ADC values of benign hepatic lesions were higher than those of malignant lesions in all studies, of which 11 studies showed a statistically significant difference [65–70, 72–75, 78]. Mean ADC values of benign liver lesions ranged from 1.94 to 2.86 × 10−3 mm2/s, mean ADC values of malignant tumours ranged from 0.86 ± 0.11 to 1.52 ± 0.55 × 10−3 mm2/s (Fig. 6). In all but two of these studies, benign cysts were included in the group of benign lesions.
We identified only one article in which the differentiation of benign and malignant gallbladder lesions with ADC measurement is described (ESM Table S8). Sugita et al.  retrospectively studied ADC values of 14 benign and 15 malignant gallbladder lesions, with b-values of 0 and 1,000 s/mm2. Quality score of this study was 50%. Mean ADC of benign lesions was 1.92 ± 0.21 × 10−3 mm2/s, mean ADC of malignant lesions was 1.28 ± 0.41 × 10−3 mm2/s; the difference was statistically significant (P < 0.01) (Fig. 6).
ADC values of kidney tumours were described in six retrospective studies and two prospective studies (ESM Table S10) [89–96]. Quality scores of these studies ranged from 42 to 67%. Applied maximum b-values ranged from 400 to 1,000 s/mm2. All studies included benign renal cysts and seven out of eight studies showed significant differences between benign and malignant renal lesions. Lowest mean ADC values of benign lesions were reported for angiomyolipomas (1.40 to 1.81 × 10−3 mm2/s), and highest mean ADC values of benign lesions were reported for simple cysts (2.50 to 3.82 × 10−3 mm2/s). Mean ADC values of malignant renal lesions (mainly renal cell carcinomas) ranged from 1.05 to 2.49 × 10−3 mm2/s (Fig. 7).
We found four studies that described ADC values of adrenal gland lesions (ESM Table S11). These studies had quality scores of 33–50% and applied high maximum b-values of 800–1,000 s/mm2. Sandrasegaran et al.  and Song et al.  evaluated benign pheochromocytomas and adenomas, which were reported to have significantly higher ADC values than malignant (metastatic) adrenal lesions (1.07 to 1.35 × 10−3 mm2/s versus 0.88 to 0.92 × 10−3 mm2/s, respectively). However, a larger study by Miller et al.  did not show a significant difference between benign and malignant adrenal gland lesions. Tsushima et al.  could only confirm a significant difference between adenomas and malignant pheochromocytomas, but not between adrenal adenomas and metastases (Fig. 7).
Seven articles retrieved in our search studied ADC values in ovarian tumours (ESM Table S13) [103, 109–114]. Quality scores ranged from 50 to 67%. Applied maximum b-value was 1,000 s/mm2 in four studies, and 500–800 s/mm2 in three studies. In two studies, ADC values were measured in regions of interest placed in the cystic components of ovarian lesions [110, 112], two studies measured ADC values of solid components [109, 113] and three studies measured ADC values of both cystic and solid components [103, 111, 114]. Mean ADC values of cystic components of benign ovarian lesions ranged from 1.24 ± 0.46 to 2.32 ± 0.56 × 10−3 mm2/s, mean ADC values of cystic components of malignant lesions ranged from 1.64 ± 0.48 to 2.34 ± 0.47 × 10−3 mm2/s (Fig. 8). Only one study  found a significant difference between mean ADC values of cystic components of benign (1.33 ± 0.82 × 10−3 mm2/s) and malignant tumours (2.28 ± 0.32 × 10−3 mm2/s). The ADC values of solid components of benign ovarian lesions (range 1.15 ± 0.55 to 1.47 ± 0.42 × 10−3 mm2/s) and malignant ovarian lesions (range 1.14 ± 0.28 to 1.41 ± 0.34 × 10−3 mm2/s) were not significantly different [109, 114].
Six articles have been published in which the application of diffusion-weighted imaging and ADC measurement to the characterisation of soft-tissue tumours is discussed (ESM Table S14) [115–120]. Quality scores of these articles ranged from 33 to 67%. One article focused on the differentiation between chronic expanding hematomas (CEH) and malignant soft-tissue tumours and observed significantly (P < 0.01) higher mean ADC values in CEH (1.55 ± 0.121 × 10−3 mm2/s) than in malignant tumours (0.92 ± 0.139 × 10−3 mm2/s) . Five authors studied ADC values in various benign and malignant tumours [115–117, 119, 120]. Mean ADC values of benign soft-tissue tumours (range of mean ADC values 1.36 ± 0.48 to 1.80 × 10−3 mm2/s) overlapped with those of malignant soft-tissue tumours (range of mean ADC values 0.88 ± 0.20 to 1.70 × 10−3 mm2/s). Only one study found a significant difference between benign desmoid tumours and malignant soft-tissue tumours (Fig. 8) .
Since its development in the early 1990s, the application of diffusion-weighted imaging has expanded from intracranial to extracranial disease and from detection of brain ischemia to assessment of tumour masses. Its potential additional value in oncological imaging lies in the fact that it provides functional tissue information, which can be combined with anatomical MR images to improve the specificity of lesion characterisation. Besides the qualitative assessment of signal intensity in DWI, images can be assessed quantitatively by the measurement of ADC values. We performed a systematic review of the recent literature in order to obtain an insight into the value of DWI and ADC measurement in differentiating benign from malignant tumour masses.
Additional value of ADC measurement in tumour characterisation
In DWI, tissue contrast is obtained through differences in free water motion between various tissue types and between normal and pathological tissues. The functional information provided by DWI and ADC measurement may be of value in tumour characterisation, complementary to the anatomical information obtained with conventional MRI sequences. Because of its high contrast-to-noise ratio, lesions with restricted diffusion are usually easily recognised on diffusion-weighted images . A drawback of DWI is the relatively low spatial resolution of the images, compared with conventional T1- or T2-weighted MR images. Small lesions (i.e., below spatial resolution) may not be visible on DWI and ADC maps , and partial volume averaging is more likely to occur. Several of the reviewed studies excluded small lesions for this reason. Similarly, lesions with a degree of diffusivity equal to the surrounding normal tissue may not be easily distinguished on DWI images and ADC maps. Thus, not all lesions are suitable for ADC measurement.
The lowest mean ADC value of extracerebral benign lesions (0.86 × 10−3 mm2/s) was reported for Warthin tumours of the parotid glands, while benign renal cysts showed the highest mean ADC value (3.82 × 10−3 mm2/s). The lowest and highest mean ADC values reported for malignant lesions were 0.30 × 10−3 mm2/s in thyroid carcinomas and 2.70 × 10−3 mm2/s in malignant pancreatic lesions, respectively. The observed wide variation in ADC values within benign and malignant tumours can be partly explained by the wide variety of histological subtypes of proliferative tumours. In most malignant tumours, diffusion is restricted due to increased cellular density and decreased extracellular matrix volume, which impede free motion of water molecules [10, 121, 122]. However, some malignant tumours show increased diffusion due to an increase in intratumoural water content, which is the case in intratumoural edema and in cystic tumour components. The degree of serous or mucinous content and intratumoural hemorrhage also influences the signal intensity and ADC value through their effect on restriction of free proton diffusion and magnetic susceptibility of the tumour tissue. Furthermore, loss of cell membrane integrity in necrotic tumours may result in increased diffusion [10, 121, 122]. This was also demonstrated in the studies that compared ADC values of cerebral necrotic/cystic tumours and cerebral abscesses, in which high mean ADC values of necrotic tumours (ranging from 2.58 ± 0.60 to 2.84 ± 0.30 × 10−3 mm2/s) were reported [13–20]. In cerebral abscesses restricted diffusion was observed, with mean ADC values ranging from 0.42 ± 0.15 to 0.91 ± 0.65 × 10−3 mm2/s [13–20]. It is postulated that the restricted diffusion in abscesses is attributable to high viscosity of pus resulting from high protein and different types of viable or dead cells, along with necrotic tissue and bacteria . Mean ADC values in other benign or malignant cystic lesions in the body were comparable to the high values in malignant cerebral cystic tumours (1.45 to 2.96 × 10−3 mm2/s) [13–20]. For example, the following ranges of mean ADC values were described in various cystic lesions: 2.35 ± 0.08 to 2.65 ± 0.30 × 10−3 mm2/s in benign cystic breast lesions [43, 56], 1.902 to 3.63 × 10−3 mm2/s in simple liver cysts [66, 68–71, 75, 76, 78], 1.33 ± 0.82 to 2.32 ± 0.56 × 10−3 mm2/s in cystic components of benign ovarian tumours  and 2.34 ± 0.47 × 10−3 mm2/s in cystic components of malignant ovarian tumours .
We observed significant differences in reported ADC values between benign and malignant tumours in the following tissues: brain abscesses vs. cystic brain tumours, meningiomas, breast, liver, and uterus. However, many studies showed considerable overlap between ADC values of benign and malignant tumours. The presence of overlap complicates potential prospective usage of these quantitative measurements, which calls for the use of “artificial” cut-off values.
In some organs, such as the salivary glands, thyroid, lungs, pancreas, and soft tissue, the reported data on the value of ADC measurements showed contradictory results. ADC measurement in these organs is unlikely to contribute to the differentiation between benign and malignant lesions. In the pancreas, ADC measurements fail to differentiate cysts. Furthermore, it is generally accepted that we need both high b-value DWI and ADC mapping for the diagnosis of solid pancreatic lesions. Likewise, we have observed widely varying reported ADC values of benign and malignant ovarian lesions. In cystic ovarian lesions, conventional MR imaging is often not conclusive and differentiation by ADC measurement would be useful. However, the reviewed studies that compare ADC values in cystic components of benign and malignant ovarian tumours showed contradictory results. Moreover, ADC values of solid components of benign and malignant cystic ovarian lesions were not significantly different [103, 109–114]. In several breast and liver studies, simple benign cysts were enrolled, which are well recognised on conventional (T1- and T2-weighted) imaging and usually do not cause diagnostic dilemmas. Including these cysts may overestimate the ability of ADC measurements to discriminate benign from malignant lesions. Another limitation of many studies included in this review was that benign lesions in particular were frequently confirmed by other imaging modalities and follow-up, without histological assessment. This is a common procedure in daily practice but may cause bias in the comparison of ADC values of benign and malignant tumours.
Technical aspects of DWI and ADC measurement
Quality of diffusion-weighted images and ADC measurements may vary when different MR imaging parameters and MR systems are used. The most important limitations of DWI are the low SNR and susceptibility to artefacts . Strategies to optimise image quality often incorporate the use of parallel imaging techniques, fat-suppression techniques, and signal averaging. Additional factors that can influence measured ADC values are use of breath-hold, respiratory triggering, or free-breathing acquisition and direction of diffusion gradients. Diffusion-weighting gradients are commonly applied in three orthogonal directions, which is desirable particularly in tissues with anisotropic orientation such as brain and kidney, in which ADC values may differ among the x, y, and z directions .
Another important factor in DWI is the maximum b-value. When low b-values are applied, the ADC values tend to be higher due to the contribution of perfusion. This was shown by several studies that applied low b-values to ADC measurement of breast lesions [42, 52, 56]. On the other hand, among the reviewed studies on ADC values of liver lesions, the ADC values did not clearly differ between high and low b-values. In malignant tumours, a higher percentage of microvessels is present than in benign tissue . Accordingly, perfusion may artificially increase the ADC in malignant lesions and complicate differentiation. Therefore, if ADC measurement is performed to differentiate tissues by their water diffusion characteristics exclusively, applying high maximum b-values may be preferable. However, signal-to-noise ratios decrease as the b-value increases, thus limiting the maximum b-value. Another way of minimising contribution of perfusion to the ADC value is to select minimum b-values higher than 0 s/mm2 (e.g., 100 s/mm2), which was done in several reviewed studies [19, 41, 69]. Optimal b-values should be chosen for each organ, however, no consensus or guidelines are available for that purpose. In the reviewed articles, various methods of ADC measurement have been used. ADC measurement is performed by placing regions of interest (ROI) in the lesion on the acquired ADC maps. Variations occurred in applied size and shape of the ROI, use of T1/T2 MR images for guidance of ROI placement on ADC map, and averaging of multiple ROIs. As the ROI placement is usually performed manually, training is required to optimise the reproducibility (minimise interobserver variation) of ADC measurement. Furthermore, in case of lesions with both solid and cystic components, a consensus on localisation of ROI (in solid or cystic part of lesion) should be established.
Selection of eligible articles and assessment of study quality was performed by one author only, which could be considered a limitation. However, in a study by Whiting et al., reproducibility of the QUADAS instrument has been reported to be good . Three reviewers independently rated the quality of 30 studies using QUADAS. The proportion of agreements between each reviewer and the final consensus rating was assessed. This was done for all QUADAS items combined and for each individual item. Over all items, the agreements between each of the reviewers and the final consensus rating were 91, 90, and 85%. The results for individual QUADAS items ranged from 50 to 100% with a median value of 90% .
As this study aimed to evaluate the potential of ADC measurements to differentiate between benign and malignant lesions in the body, we included a large number of studies on ADC measurement in a variety of organs. Consequently, heterogeneity in study methods and applied MRI parameters was observed, which precluded the performance of statistical meta-analysis.
Towards standardisation of ADC measurement and reporting
Checklist for reporting diffusion-weighted imaging (DWI) technique in studies on apparent diffusion coefficient (ADC) measurement in tumour characterisation (recommended minimum requirements)
Field strength (T)
Coil type (i.e., built-in body coil/surface coils)
Pulse sequence [e.g., single-shot spin-echo/single-shot double spin-echo/multi-shot spin-echo, echo planar imaging (EPI)/non-EPI, etc.]
Repetition time, echo time (ms)
Directions of diffusion-weighting gradients
Fat saturation technique (e.g., fat saturation, inversion recovery, water selection only, etc.)
Number of excitations
Parallel acquisition factor
Echo train length
Respiratory motion correction technique (i.e., breath-hold/respiratory gating/none)
Cardiac motion correction technique (i.e., ECG triggering/finger pulse triggering/none)
Voxel size (mm3)
Acquisition of DWI data before or after intravenous contrast administration
Method of ADC calculation
Applied model for ADC calculation (e.g., monoexponential, biexponential, etc.)
b-values that were used to calculate the ADC
Method of ADC measurement
Description of which portion of the tumour was measured (e.g., whole tumour, only enhancing and/or solid portions, etc.)
Description of ROI margins (i.e., distance from tumour periphery)
ROI shape and size (fixed or variable)
Single or multiple slice ROI measurement
Verification of ROI position on diffusion-weighted images that were used to calculate the ADC map
Reported ADC values among studies and between benign and malignant lesions differ considerably. In several tumours, such as brain abscesses vs. cystic brain tumours, meningiomas, and breast, liver, and uterine tumours, ADC measurement may be of value to discriminate benignancy from malignancy. However, in other organs, such as the salivary glands, thyroid, lungs, pancreas, and soft tissue, the ADC value does not appear to contribute to tumour characterisation.
One of the challenges that must be faced to enable widespread adoption of ADC measurement in clinical practice is standardisation of study methods and reporting. The development of organ-specific guidelines for DWI acquisition and ADC measurement and checklists for reporting of results may facilitate comparison of study results and contribute to the implementation of ADC measurement for tumour characterisation in the clinical setting.
This work was supported by the ZonMW Programme for Health Care Efficiency Research (grant number 80-82310-98-08012). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
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