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DOI:

Review

Real-Time Elastography in the diagnosis of prostate cancer:

a systematic review

Yang Zhang

1

*, Zheying Meng

1

*, Yanjun Xu

1

*, Qijie Lu

1

, Rui Hou

1

, Xiaojun Cai

1

, Lizhou Lin

2

, You Luo

3

, Fengxian Wei

4

, Yuanyi Zheng

1

, Bing Hu

1

* The authors shared the first authorship

1Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affliated Sixth People’s Hospital, Shanghai, 2Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 3Department of Urology, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, 4Department of General Surgery of the Second Hospital of Lanzhou University, Lanzhou, P.R. China

Received 24.02.2019 Accepted 11.06.2019 Med Ultrason

2019, Vol. 21, No 3, 327-335 Corresponding author: Prof Bing Hu

Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affliated Sixth People’s Hospital, 600th Yi Shan Road, Shanghai 200233, P.R. China E-mail: [email protected]

Introduction

In spite of the advances in prostate cancer (PCa) de- tection and treatment, PCa continues to be one of the

leading causes of cancer-related mortality in men [1], with approximately 180,000 new cases diagnosed and 26,000 cancer-related deaths projected in the United States in 2016 [2]. Hence, the diagnostic accuracy is es- sential to early intervention regarding tumor progression and metastasis, leading to increasing opportunity for sur- gery and satisfied prognosis.

Improvement has been achieved through different methods, ranging from digital rectal examination (DRE) to prostate-specific antigen (PSA) levels monitoring, computed tomography (CT) and the most widely-used ultrasonography. Magnetic resonance imaging (MRI), in particular, is an important modality in judging disease Abstract

Aim: To evaluate the diagnostic accuracy of real-time elastography as a method for detecting prostate cancer. Material and methods: Relevant studies applying real-time elastography as the diagnostic modality and biopsy as the reference stand- ard, published by March 1, 2018 were retrieved from PubMed, EMBASE, Web of Science and Cochrane Library databases.

Two independent reviewers inspected all these articles to confirm the matching of the inclusion criteria. One reviewer with methodological expertise extracted the data from the included studies. Sensitivity, specificity and diagnostic odds ratio (DOR) were used to obtain overall estimates. Randomized effect method, meta-regression and subgroup analysis were performed.

Results: Twenty-four studies out of 1156 identified articles met the inclusion criteria. Three groups were set: analysis by patient (Group 1), by core (Group 2), and by image (Group 3) and subgroups set in Group 1. The pooled estimate of real-time elastography sensitivity/ specificity/ DOR calculated with the identical P-value 0.00. Within subgroups “Asia” and

“PSA>=10 ng/ml”, the pooled sensitivity, specificity and DOR were 0.83, 0.65 (p=0.01, I2=73.40%; p=0.02, I2=69.5%), 0.80, 0.82 (p=0.66, I2=0.00%; p=0.58, I2=0.00%) and 20.2, 8.67 (p=0.09, I2=54.2%; p=0.20, I2=35.5%), respectively. In these three groups, the areas under the SROC curve were 0.7417, 0.9246, and 0.6213 independently. Conclusions: Real-time elastography is a promising, reliable modality for the non-invasive diagnosis of patients with prostate cancer. The diagnostic accuracy of real-time elastography correlates tightly to the presence of higher PSA level and may help avoid unnecessary biopsy. It seems to be a useful tool in systemic biopsy.

Keywords: real-time elastography; prostate cancer; diagnosis

DOI: 10.11152/mu-1965

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localization within prostate and an indicator in diagnosis along with the subsequent therapy [3]. As a non-invasive approach, trans-rectal ultrasound (TRUS) is a cost-effec- tive and readily available imaging modality (MRI is not popularized in opportunistic screening due to high cost).

Most prostate neoplasms (about 60%-80%) are hypo- echoic on grey-scale TRUS, whereas 30%-40% are iso- echoic, and approximately 1.5% are hyper-echoic [2].

The sensitivity and specificity of ultrasound for PCa diag- nosis vary considerably from 18% to 96% and from 46%

to 91% [1]. Considering the effectiveness and drawbacks of ultrasound, to develop a new protocol is necessary.

Real-time elastography (RTE) is a unique ultrasound (US) mode evaluating physical characteristics of tis- sue and firstly utilized for targeted prostate biopsies by König in 2005 [4]. The procedure relies on the detection of variance in tissue compliance by manual compression and relaxation and is used in conjunction with grey-scale ultrasound. Nowadays, flexible modalities are well de- veloped: vibration elastography, acoustic radiation force, and shear wave elastography (SWE). The two main types of elastography used in imaging today are compression/

strain and SWE. In the fields of breast, liver and prostate, a series of studies have been reported and meta-analyses were published [5-7].

The aim of the present study was to perform a meta- analysis of published papers to assess the overall accu- racy of RTE targeted biopsy in PCa detection based on data analysis: 1) Group 1-by patient, 2) Group 2-by core, and 3) Group 3-by image.

Material and methods Search strategy

The systematic review and meta-analysis were per- formed according to the Cochrane diagnostic accuracy reviews guidelines. Terms and Medical Subject Head- ings (MeSH) phrases used included: ‘Elasticity Imag- ing Techniques’ [Mesh], elastography AND ‘Prostatic Neoplasms’ [Mesh], prostate cancer. The search strategy was conducted to find relevant studies from the follow- ing databases: Medline (1966 to March 2018), Embase (1980 to March 2018), Cochrane Library (1999 to March 2018), Web of Science (1950 to March 2018).

Study selection

The inclusion criteria were as follows: 1) diagnos- tic clinical trials evaluating the accuracy of RTE in the detection of PCa; 2) study population: patients with el- evated serum PSA (>4 ng/mL), or abnormal DRE, or hy- po-echoic nodules on TRUS, or low-intensity lesions on T2-weighted images on MRI; 3) use of surgical specimen or TRUS-biopsy as the diagnostic reference standard;

4) English articles; and 5) outcome measurements were in consistency. The exclusion criteria were the follow- ing: 1) studies unavailable to construct tables for true- positive, false-positive, false-negative, and true-negative determinations; 2) overlap with the selected studies (ie, studies from the same study group, institution, and period of inclusion); 3) reviews, editorials, case reports, and cor- responding letters that did not report their own data; and 4) studies were not suitable for the reference standard.

Two independent reviewers inspected the retrieved studies to identify the conformation with inclusion cri- teria. Disagreement between two extracting authors was resolved by consensus involving a third party (one of the other members of the research team) after the stud- ies were scrutinized. Values of true positives (TPs), false positives (FPs), false negatives (FNs), and true nega- tives (TNs) were retrieved from literature. Additional data were extracted from the studies, including first author, publication year, country of origin of the study, study design, number of patients (cores/images), loca- tion of biopsy, reference standard for the diagnosis and imaging technique along with the machine used. One re- viewer with methodological competence independently extracted the data from the included studies. Any disa- greement was resolved by discussion and, if any clarifi- cation was necessary, the authors of these studies were contacted.

Statistical methods

Three groups were set in different aspects: Group 1-by patient, Group 2-by core, and Group 3-by image.

Because of significant heterogeneity in Group 1 (analysis by patient), subgroups were made subsequently.

Meta-analysis was performed for the diagnostic accu- racy of RTE by calculating pooled estimates of sensitiv- ity, specificity, and diagnostic odds ratio (DOR) in each group. Pooling results (included corresponding 95% con- fidence intervals [CIs]) were conducted by using the fixed effect model (Mantel-Haenszel method) when significant heterogeneity was not present; the random-effects model (Der Simonian-Laird method) was applied in which the weights were the inverse of variance of each single study.

The pooled results of sensitivity, specificity, DOR and symmetric receiver operator characteristic (SROC) curve were conducted by using Meta-Disc version 1.4 (Unit of Clinical Biostatistics, Ramony Cajal Hospital, Madrid Spain). The Cochrane Q test was used to detect the het- erogeneity among studies. When the p values were <0.10 it indicated the presence of heterogeneity. With regard to inconsistency (I2), the percentage of the variability attrib- utable to heterogeneity, >50% was considered significant.

Threshold effect was tested with ROC space and Spearman correlation coefficient [8]. The representation

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of atypical ‘‘shoulder arm’’ pattern in a ROC space and a strong positive correlation between the log of sensitiv- ity and log of 1-specificity would suggest presence of threshold effect.

In our study the pooled DORs were obtained calculat- ing the weighted average using the Der-Simonian Laird random effect model. The DORs combined sensitiv- ity and specificity into one measurement of diagnostic performance. The value of a DOR equals to 1 meant the method had no ability to discriminate, while the higher DOR indicated better ability of the test to differentiate subjects with and without the disease of interest. The SROC curve was constructed by using the Moses-Shap- iro-Littenberg method to summarize the difference from each study. In addition, the area under the curve (AUC) was calculated, the value ranging from 0.5 to 1.0. When the value closed to 0.5 indicated a poor test while a value of 1.0 indicated a perfect one.

As for a meta-analysis of diagnostic trials, publica- tion bias can be examined by using Deek’s funnel plot.

It was conducted by a regression of diagnostic log odds ratio against 1/sqrt (effective sample size [ESS]), weight- ing by effective sample size, with P<0.10 indicating sig- nificant asymmetry [9]. Stata (version 12.0) was used for publication bias analysis.

Before performing the statistical analysis, the qual- ity of eligible studies was evaluated with the Quality As- sessment of Diagnostic Studies (QUADAS) in Rev-Man (version 5.30). The items of QUADAS were quantified by “yes”, “no”, or “unclear” with 14 questions [10].

Results

Eligible studies and quality assessment

We searched 1156 records and 482 duplicates were removed. After screening titles and abstracts, we identi- fied 104 articles for full-text review. Of these articles, 15 were excluded for type of review articles, 19 for sympo- siums, 27 for insufficient data, and 19 for different ref- erence standard. Finally, 24 potentially relevant studies were identified as eligible studies [11-34] (fig 1). The quality assessed according to the QUADAS criteria is reported in figure 2.

Study characteristics

The studies were published between 2002 and 2018, with seven studies performed in Asia. The main charac- teristics are reported in Table I. Three groups are set in different dimensions: pooled analysis by patient in 16 studies [12,16,17,19,23-34], by core in 9 studies [11-19]

and by image in 3 studies [20-22]. In these studies, 2094 patients, 12145 cores and 2182 images were analyzed respectively. Twenty-three studies had a prospective de-

Fig 2. The quality of the eligible studies as assessed accord- ing to the Quality Assessment of Diagnostic Accuracy Studies criteria

Fig 1. Flowchart of the literature search and selection.

Fig 3. Deek’s plot in the test of publication bias (p=0.38). Sym- metrical funnel obtained indicated no significant publication bias was introduced in our study.

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Table I. Baseline characteristics of studies included in the meta-analysis. Three groups are set in different dimensions: pooled analysis by patient, by core, and by images. In these studies, 2094 patients, 12145 cores and 2182 images were analyzed respectively. StudyMethodThresholdGolden standardDesignNumber of patients/ cor

es/ images

Age, mean / median years PSA, ng/ml

Machine used Group 1: By patients Cochlin 2002Colour patternBlue areaNeedle biopsyProspective10064.012.0Power Vision 6000, Toshiba Pallwein 2007Colour patternBlue areaNeedle biopsyProspective23062.3NSEUB-8500, Hitachi Kamoi 2008Colour patternBlue areaNeedle biopsyProspective10768.411.4EUB-6500, Hitachi Pallwein 2008Colour patternBlue areaNeedle biopsyProspective49261.96.8EUB-8500, Hitachi Ferrari 2009Colour patternBlue areaNeedle biopsyProspective8461.3NSEUB-8500, Hitachi Aigner 2010Colour patternBlue areaNeedle biopsyProspective9457.43.2EUB-8500, Hitachi Giurgiu 2010Colour patternBlue areaNeedle biopsyProspective6568.0NSEUB-8500, Hitachi Kapoor 2011Colour patternBlue areaNeedle biopsyProspective5062.112.6Acuson S 2000, Siemens Zhang 2012Colour patternBlue areaNeedle biopsyProspective14869.5NSHI VISION 900 Taverna 2013Colour patternBlue areaNeedle biopsyProspective10264.55.9EUB-8500, Hitachi Nygard 2014Colour patternBlue areaNeedle biopsyProspective12764.29.2Hitachi Preirus Zhang 2014Colour patternBlue areaNeedle biopsyProspective4266.6NSHI VISION 900 Boehm 2015SWEMaximum SWE valueNeedle biopsyProspective9567.06.7Supersonic Imagine Aixplorer Correas 2015SWEMaximum SWE valueNeedle biopsyProspective18465.17.4Supersonic Imagine Aixplorer Gadalla 2015Colour patternBlue areaNeedle biopsyProspective5063.143.2EUB-7500, Hitachi Nygard 2016Colour patternBlue areaNeedle biopsyProspective12464.09.1Hitachi Preirus Ultrasound Group 2: By cores Cochlin 2002Colour patternBlue areaNeedle biopsyProspective62264.012.0Power Vision 6000, Toshiba Nelson 2007Colour patternBlue areaNeedle biopsyProspective81864.011.2Hi-Vision 8500 Pallwein 2008Colour patternBlue areaNeedle biopsyProspective295261.96.8EUB-8500, Hitachi Ferrari 2009Colour patternBlue areaNeedle biopsyProspective89461.3NSEUB-8500, Hitachi Brock 2012Colour patternBlue areaNeedle biopsyProspective106864.18.7EUB-7500 Hitachi Barr 2012SWEMaximum SWE valueNeedle biopsyProspective5164.25.1Supersonic Imagine Aixplorer Ahmad 2013SWEMaximum SWE valueNeedle biopsyProspective62669.0NSSupersonic Imagine Aixplorer Correas 2015SWEMaximum SWE valueNeedle biopsyProspective104065.17.4Supersonic Imagine Aixplorer Schiffmann 2016Colour patternBlue areaNeedle biopsyRetrospective404766.07.7EUB 6500, Hitachi / HI VISION Preirus Group 3: By images Tsutsumi 2007Colour patternBlue areaSurgery specimenProspective35264.011.0EUB-8500, Hitachi Miyagawa 2009Colour patternBlue areaSurgery specimenProspective153867.08.4EUB-8500, Hitachi Tsutsumi 2010Colour patternBlue areaSurgery specimenProspective29265.013.3EUB-8500, Hitachi

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sign and fifteen studies clearly stated that the pathologists were blinded to the results of RTE.

Publication bias and influence analysis

Deek’s funnel plot (fig 3) showed that p=0.38 (p>0.10), indicating symmetrical funnel was obtained. It is also observed that the regression line is close to right 90° vertical to the DOR line. Therefore, no significant publication bias was introduced in our study.

Studies were analyzed after excluding each study in turn and no significant changes are observed in newly pooled sensitivity and specificity, which indicated a good stability of enrolled studies along with credible results generated below.

Pooled analysis by patient (Group 1)

Significant heterogeneity was found in diagnostic OR (DOR=5.06, Cochrane-Q=139.52, df=15, p=0.00, I2=89.2%). The pooled sensitivity, specificity, positive LR and negative LR and its responding p-value were 0.76 (p=0.00), 0.62 (p=0.00), 2.00 (p=0.00), and 0.41 (p=0.00). Spearman correlation coefficient was 0.032 (p=0.91), which means no threshold effect existed. Meta- regression was performed, and “region” resulted in het- erogeneity across the studies. The diagnostic value in

“Asia” was 6.91 times higher than in “non-Asia” coun- tries (Table II, RDOR=6.91, p=0.03).

Subgroups were set for “region”, along with “PSA level”, “age”, “method”, “volume” and “localization (‘peripheral zone’ or ‘whole organ’)” of targeted le- sions. No significant heterogeneity was found by DOR in the subgroup “Asia” (Table III, DOR=20.2, Cochrane- Q=6.54, df=3, p=0.09, I2=54.2%) and “PSA>=10ng/ml”

(DOR=8.67, Cochrane-Q=4.65, df=3, p=0.20, I2=35.5%).

The pooled sensitivity in two subgroups were 0.83, 0.65 (p=0.01, I2=73.40%; p=0.02, I2=69.5%), and specificity 0.80, 0.82 (p=0.66, I2=0.00%; p=0.58, I2=0.00%) inde- pendently, as shown in figure 4 and 5.

The SROC curve was obtained. The AUC was 0.7417 (fig 6 - line a).

Pooled analysis by core (Group 2)

Nine researches were enrolled in this part and there was a heterogeneity. Meta-regression and subgroup- setting were not performed as there were not enough studies in this part. The pooled sensitivity, specificity,

positive LR, negative LR, DOR and their responding p values were 0.51 (p=0.00), 0.88 (p=0.00), 4.30 (p=0.00), 0.41 (p=0.00), and 11.76 (p=0.00). The SROC curve was drawn. The AUC was 0.9246 (fig 6-line b).

Pooled analysis by image (Group 3)

A heterogeneity was found. The pooled sensitivity, specificity, positive LR, negative LR, DOR and their re- sponding values were 0.77 (p=0.00), 0.36 (p=0.00), 1.22 (p=0.00), 0.52 (p=0.00), and 2.38 (p=0.00). The AUC was 0.6213 (fig 6-line c).

Discussions

Screening, detection and diagnosis of prostate cancer are currently on the basis of DRE, PSA levels, CT, MRI and greyscale ultrasound. However, limitations to these approaches in clinical practice are clear. Digital examina- tion depends mainly on the experience of the physician subjectively and, occult lesions or minor ones cannot be detected effectively; PSA levels can be influenced by in- fections, hyperplasia, drugs in-taken and so on, following a poor specificity and low predictive value; CT virtually Fig 4. Forest plot of subgroup (Asia) of meta-analysis in sen- sitivity, specificity and DOR for the diagnostic value of RTE in differentiation of prostate cancer. The pooled specificity was 0.80 (p=0.66, I2=0.00%).

Table II. Results of meta-regression in Group 1 (by patient).

“Region” lead to significant heterogeneity. The diagnostic val- ue in “Asia” was 6.91 times higher than “non-Asia” countries (RDOR=6.91, p=0.03).

Var Coeff. Std. Err p-value RDOR [95%CI]

Cte 1.090 0.4026 0.0179 — — — —

S 0.155 0.2457 0.5393 — — — —

Region 1.933 0.7864 0.0288 6.91 (1.26; 37.79)

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Table III. Results of subgroup analysis in Group 1 (by patient). No significant heterogeneity was found by DOR in the subgroup “Asia” (DOR=20.2, Cochrane-Q=6.54, df=3, p=0.09, I2=54.2%) and “PSA>=10 ng/ml” (DOR=8.67, Cochrane-Q=4.65, df=3, p=0.20, I2=35.5%). SensitivitySpecificityPositive LRNegative LRDOR No. of studiesPooled estimates, %/ (95% CI)

p

I-square (%)

Pooled estimates, % / (95% CI)

p

I-square (%)

Pooled estimates, % / (95% CI)

p

I-square (%)

Pooled estimates, % / (95% CI)

p

I-square (%)

Pooled estimates, % / (95% CI)

p

I-square (%)

Region Asia4

0.83 (0.76;0.89)

0.0173.40

0.80 (0.74;0.85)

0.580.00

4.01 (3.03;5.30)

0.530.00

0.20 (0.08;0.47)

0.0173.20

20.23 (7.78;52.64)

0.0954.20 Non- Asia12

0.74 (0.71;0.77)

0.0090.10

0.58 (0.55;0.61)

0.0092.30

1.62 (1.19;2.20)

0.0092.10

0.51 (0.32;0.81)

0.0091.30

3.30 (1.49;7.30)

0.0090.10 PSA ≥10 ng/ml4

0.65 (0.57;0.74)

0.0269.50

0.82 (0.75;0.87)

0.660.00

3.61 (2.56;5.09)

0.373.90

0.42 (0.27;0.66)

0.0757.80

8.67 (4.15;18.10)

0.2035.50 <10 ng/ml7

0.77 (0.73;0.80)

0.0092.80

0.59 (0.55;0.62)

0.0093.90

1.40 (0.88;2.22)

0.0095.30

0.51 (0.21;1.24)

0.0095.30

2.75 (0.72;10.53)

0.0094.50 Age ≥65 years6

0.85 (0.80;0.89)

0.0075.80

0.66 (0.61;0.71)

0.0085.50

2.48 (1.63;3.78)

0.0086.70

0.25 (0.14;0.45)

0.0073.70

10.61 (4.88;23.07)

0.0168.40 <65 years10

0.71 (0.67;0.75)

0.0089.80

0.60 (0.57;0.63)

0.0093.70

1.76 (1.17;2.63)

0.0093.40

0.56 (0.33;0.93)

0.0091.80

3.29 (1.28;8.49)

0.0091.50 Method Colour gradient14

0.73 (0.70;0.76)

0.0087.80

0.63 (0.60;0.66)

0.0092.20

2.04 (1.44;2.89)

0.0092.40

0.46 (0.30;0.71)

0.0090.60

4.63 (2.13;10.06)

0.0090.00 SWE2

0.91 (0.85;0.96)

0.540.00

0.54 (0.46;0.62)

0.0091.70

1.83 (0.97;3.43)

0.0093.00

0.19 (0.07;0.53)

0.1162.00

9.67 (1.95;48.00)

0.0378.70 Volume ≥60 ml 3

0.66 (0.58;0.73)

0.0177.40

0.33 (0.25;0.42)

0.0091.50

1.17 (0.60;2.30)

0.0091.10

0.89 (0.26;3.00)

0.0092.00

1.37 (0.19;9.81)

0.0092.50 < 60 ml7

0.82 (0.78;0.85)

0.0090.60

0.63 (0.60;0.67)

0.0092.90

2.13 (1.43;3.16)

0.0092.80

0.30 (0.12;0.73)

0.0094.80

7.02 (2.65;18.56)

0.0088.00 Localization Peri- pheral zone

9

0.75 (0.71;0.80)

0.0087.50

0.61 (0.57;0.65)

0.0092.60

2.14 (1.35;3.40)

0.0092.80

0.38 (0.21;0.69)

0.0088.00

5.96 (1.95;18.23)

0.0090.60 Whole organ7

0.76 (0.71;0.80)

0.0090.70

0.63 (0.59;0.66)

0.0091.90

1.86 (1.22;2.83)

0.0091.80

0.46 (0.23;0.91)

0.0093.50

4.09 (1.54;10.81)

0.0089.00

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plays no role in the detection of PCa and is not recom- mended for diagnostic purposes as soft tissues resolution is low and margins of the gland are poorly defined [1].

Conventional MRI is of value in predicting the patho- logical stage and extra-capsular extension. Prostate MRI used before first prostate biopsy, could identify men who might safely avoid an unnecessary biopsy. However, it is less cost-effective in active surveillance. The use of TRUS has limited diagnostic accuracy, for benign lesions such as prostatitis, infarction, and benign prostate hyper- trophy, may be hypo-echoic, resulting to varying sensi- tivity and specificity.

Within the stages including the occurrence and pro- gression of neoplasms, cancerous lesions became harder and less elastic, following the changes histologically:

increased cellular density, rising micro-vascularity, a loss of glandular tissue architecture [35], and increased collagen deposition in the stroma [36]. Real-time elas- tography is applied in detecting abnormal lesions by im- ages accessing of tissue elasticity or stiffness, involving many fields like thyroid, liver, kidney, breast, pancreas and prostate [37-43]. As a modality of great importance, however, the sensitivity and specificity are variously re- ported. Our study was designed to analyze pooled data and evaluate the diagnostic value of RTE in the detection of prostate cancer.

Though meta-analyses have been performed before [6,7,43], updates based on new and large-scale data is still necessary, with setting of subgroups and deeper explora- tion. As an invasive procedure, TRUS-guided biopsy may cause infections and hematuria. Over the past decade, there has been a trend to obtain larger numbers of biopsy specimens, with most clinicians taking 8 to 12 biopsy cores and most current studies recommending a 12-core biopsy scheme [44]. According to our study, real-time elastography will decrease the rate of unnecessarily per- formed cores with lower health care costs and side effects.

Subgroups were set in Group 1 by considering region, PSA levels, age, prostate volume, method and tumor lo- calization based on the results of meta-regression and clinical perspectives. Total serum PSA, prostate volume and age have been found to be clinically significant pre- dictors of positive biopsy findings [45]. Within the sub- group of PSA level >=10 ng/ml and region of Asia, the pooled sensitivity was 0.65, 0.83 and specificity 0.82, 0.80. No significant heterogeneity was found in specific- ity (p=0.66, I2=0.00%; p=0.58, I2=0.00%). This indicat- ed that patients in Asia counties and/or with higher PSA may be more likely to be precisely diagnosed by RTE.

The values of RTE climbed as the PSA level increased, meaning the progression of tumor, and that RTE is a reli- able indicator in the detection of abnormal lesions. As to

Fig 6. The summary receiver operating characteristics (SROC) curve for the diagnostic value of RTE in differentiation of prostate cancer. Line a (red), b (green) and c (blue) referred to the analysis by patient, by core and by image. The AUC was 0.7417, 0.9246, 0.6213 literally.

Fig 5. Forest plot of subgroup (PSA>=10 ng/ml) of meta-anal- ysis in sensitivity, specificity and DOR for the diagnostic value of RTE in differentiation of prostate cancer. The pooled speci- ficity was 0.82 (p=0.58, I2=0.00%).

the data in Asian areas, the diagnostic odds ratio is six times higher than that in non-Asian countries, but with a I-square (54.2%) which indicated the inconsistency

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within this group. Not many relevant studies (only 4) that conform with our standards were well performed in Asia, and this is the principal reason leading to the high DOR in this subgroup. More studies and following updates are still required.

To our knowledge, this is the first meta-analysis in- troducing analysis of RTE with three dimensions: by pa- tient, by core and by image respectively, along with both reference standard of TRUS-guided biopsy and radical- prostatectomy biopsy. According to the results of our study, the diagnostic accuracy of RTE quantified by AUC is 0.9246 for the diagnosis of prostate cancer in the group

“analysis by core”. Our meta-analysis indicated that RTE can be used with a high diagnostic accuracy to detect ma- lignant prostate lesions.

There are several limitations to our study. First, only three studies were included in the analysis by image.

Second, though high sensitivity, specificity and DOR are obtained with fine consistency in subgroup “Asia” and

“PSA>=10 ng/ml”, the small number of studies as a fac- tor cannot be neglected which will give rise to higher es- timates. Third, as data on Gleason score were not well described in research the analysis was not performed un- fortunately. Fourth, RTE is a modality dependent on phy- sicians’ performance. Though colour-gradient scale was applied in ultrasound system, the judgment of the right images and localization is still influenced by the pres- sure given by doctors and their experience. Reproducible results cannot be obtained satisfactorily. Modalities like SWE which uses acoustic radiation force and are less de- pendent on performers need to be popularized. In addition, in this paper, the publication bias cannot be excluded, even though the analysis of the Deek’s plot indicated small risk.

In conclusion, in our study, RTE achieved an exciting efficiency in PCa detection, with the analysis of sensi- tivity, specificity and diagnostic odds ratio. Furthermore, it showed quite correspondence with the PSA elevation, indicating its value as a potential marker. Due to the ob- tained results and to their non-invasive characteristics, RTE is a promising modality for the early characteriza- tion in patients with prostate cancer and may reduce the unnecessary biopsies in the future, along with digital rec- tal examination, serum indicator, greyscale US and MRI.

Large-scale trials are warranted to further explore the di- agnostic value of RTE in the diagnosis of prostate cancer and other fields.

Acknowledgement: This study was supported by the Shanghai Key Discipline of Medical Imaging (No:

2017ZZ02005), Clinical Science and Technology Inno- vation Project (grant nos. SHDC22015001) and the Nat- ural Science Foundation of China (grant nos. 81271597, 81401421 and 81372732).

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