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DOI: ./mco.
ORIGINAL ARTICLE
Contrast-enhanced ultrasound enables precision diagnosis
of preoperative muscle invasion in bladder cancer: a
prospective study
Qiyun Ou1,2,#Weibin Xie1,3,#Yunfang Yu1,4,5,#Bing Ou1Man Luo1
Yongjian Chen6Weiwei Pan1Yiming Lai1,3Zhuohang Li1,3
Jianqiu Kong1,3Zhuo Wu1Jingliang Ruan1Jingjing Han1
Tianxin Lin1,3,∗,## Baoming Luo1,∗,##
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Ultrasound in Medicine, Department of
Urology, Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, Guangdong, China
Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Shanwei, Guangdong, China
Faculty of Medicine, Macau University of Science and Technology, Taipa, Macao, China
Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
∗Correspondence
Tianxin Lin and Baoming Luo,
Guangdong Provincial Key Laboratory of
Malignant Tumor Epigenetics and Gene
Regulation, Department of Ultrasound in
Medicine, Department of Urology,
Department of Medical Oncology, Sun
Yat-sen Memorial Hospital, Sun Yat-sen
University, Guangzhou, Guangdong,
China.
Email: lintx@mail.sysu.edu.cn,
loubm@mail.sysu.edu.cn
Funding information
National Natural Science Foundation of
China, Grant/Award Numbers: ,
; Guangzhou Science and
Technology Project, Grant/Award
Numbers: AJ, AJ;
Natural Science Foundation of
Guangdong Province, Grant/Award
Numbers: B,
Abstract
Bladder cancer’s high mortality underscores the need for precise staging, espe-
cially to differentiate between nonmuscle invasive bladder cancer (NMIBC) and
muscle invasive bladder cancer (MIBC) types. This prospective study evaluated
the efficacy of contrast-enhanced ultrasound (CEUS) for preoperative staging,
focusing on its ability to distinguish NMIBC from MIBC. Conducted from April
to September , the study involved patients (median age: .
years; males, females), with NMIBC (.%) and MIBC (.%).
Each patient underwent CEUS followed by transurethral resection of bladder
tumor or radical cystectomy. CEUS demonstrated high diagnostic accuracy in
determining muscle invasion status (sensitivity .%, specificity .%, accu-
racy .%, area under the receiver operating characteristic curve [AUC] .).
Comparative analyses against MRI (AUC .) showed CEUS outperforming
in muscle invasion detection. Combining CEUS with MRI improved diagnos-
tic accuracy, particularly when MRI vesical imaging reporting and data system
score was points. The combined approach achieved an AUC of ., with
#Qiyun Ou, Weibin Xie, and Yunfang Yu contributed equally and should be considered co-first authors.
##Tianxin Lin and Baoming Luo contributed equally and should be considered co-corresponding authors.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
© The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.
MedComm. ;:e. wileyonlinelibrary.com/journal/mco 1of15
https://doi.org/./mco.
2of15 OU .
A; Guangdong Basic and
Applied Basic Research Foundation,
Grant/Award Number: A;
Sun Yat-sen Pilot Scientific Research
Fund, Grant/Award Number:
SYSQH-II--; Guangdong Yiyang
Healthcare Charity Foundation,
Grant/Award Number: CSM; Key
Areas Research and Development
Program of Guangdong, Grant/Award
Number: B; Guangdong
Provincial Clinical Research Center for
Urological Diseases, Grant/Award
Number: B
sensitivity, specificity, and accuracy of ., ., and .%, respectively. Thus,
CEUS emerges as a valuable diagnostic tool for preoperative staging of bladder
cancer, particularly in its role in assessing muscle invasion status and thereby
aiding in clinical decision-making and intervention outcomes.
KEYWORDS
bladder cancer, contrast-enhanced ultrasound, muscle invasion, precision diagnosis, prospec-
tive study
1 INTRODUCTION
Bladder cancer is the th most common cancer world-
wide, with approximately , new detected cases
and , deaths recorded in .Bladder cancer
staging is critical in determining therapeutic strategy.
Bladder cancer can be divided into nonmuscle invasive
bladder cancer (NMIBC) and muscle invasive bladder
cancer (MIBC), with the latter characterized by high
aggressiveness, complicated treatment, high propensity
to metastasis, and poor prognosis.In clinical practice,
radical cystectomy is performed on MIBC patients, and
transurethral resection of bladder tumor (TURBT) is per-
formed on NMIBC patients. Patients suspected to have
remaining MIBC after TURBT surgery require secondary
TURBT.
Cystoscopy biopsy determines the pathological classifi-
cation of the lesions, but it has limitations in diagnosing
muscular infiltration, especially in the case of large lesions.
The current recommendation is that patients with high-
grade bladder tumors (more aggressive tumors) or those
with abnormal urine cytology findings should undergo
random biopsies.This additional diagnostic step assists
healthcare providers in acquiring additional information
about the tumor, which is crucial for devising the most
suitable treatment strategy.
The magnetic resonance imaging (MRI)-based stan-
dardized vesical imaging reporting and data system
(VI-RADS) protocol is generally acknowledged as the
gold standard for predicting muscle invasion in bladder
cancer.However, its use has been limited by procedure-
related contraindications and the fact that it should be
avoided in patients with renal damage, especially in cases
of renal failure.
Ultrasound can be used to detect and stage bladder
cancers., Contrast-enhanced ultrasound (CEUS) identi-
fies the vascularity of tissues and organs. It can provide
more abundant and accurate diagnostic information than
conventional ultrasound and color Doppler ultrasound.
Moreover, it is characterized by the absence of radia-
tion exposure or previously known physically harmful
interactions with tissues, lack of risks in case of renal
insufficiency, lower incidence of adverse reactions, wide
accessibility, noninvasiveness, and affordability compared
with MRI.,, Continuous innovation of CEUS technol-
ogy, parametric micro-flow imaging (P-MFI), MFI, superb
microvascular imaging, time curve analysis, and other
related auxiliary functions have allowed to acquire more
information on diseases while greatly improving the diag-
nostic accuracy of this technique. However, the accuracy of
preoperative muscle invasion detection in bladder cancer
using CEUS remains unclear. The present study investi-
gated the value of CEUS in preoperative detection and
differentiation between NMIBC compared with MIBC in
diagnosed patients.
2RESULTS
2.1 Patient characteristics
A total of patients were evaluated for study eligibil-
ity (Figure ). The cohort had a median age of . years
(interquartile range [IQR] .–.), and consisted of
males (.%) and females (.%) patients with patho-
logically confirmed bladder cancer. Among these patients,
(.%) were diagnosed with NMIBC, while (.%)
had MIBC and were prospectively enrolled. In addition,
(.%) patients had a high pathology grade, while
(.%) had a low pathology grade. Further details
regarding the patients’ clinicopathological characteristics
are provided in Table .
OU . 3of15
Diagnostic performance of contrast-enhanced ultrasonography (n=171)
Patients excluded (n=8) for the following reason:
Received neoadjuvant chemotherapy before surgery
Patients selected for enroll (n=163)
Patients assessed for eligibility (n=179)
Patients excluded (n=8) for the following reasons:
Not received surgical treatment (n=7)
Diagnosed as polyps after surgery (n=1)
FIGURE 1 Study flow diagram.
2.2 CEUS characteristics associated
with muscle invasion and pathology grade
status
The univariate analysis of the bladder cancer muscle inva-
sion status in relation to clinicopathological characteristics
is shown in Table . The median tumor size in MIBC
( mm [IQR – mm]) was significantly larger than
that in NMIBC ( mm [IQR –]) (≥ mm [.%] vs.
[.%], p<.), and the area under the receiver oper-
ating characteristic curve (AUC) of the individual tests in
predicting muscle invasion status were . (Figure S).
The MIBC patients had significantly higher rates of tumor
sessile structures (. vs. .%, p<.), more irregular
tumor shapes (. vs. .%, p<.), more discontin-
uous changes in bladder base (. vs. .%, p<.),
and broader tumor bases (. vs. .%, p<.) than
the NMIBC patients, achieving AUCs of ., ., .,
and . in predicting muscle invasion status, respectively
(Figures S–S). Multivariable analysis showed that the
tumor size, tumor base structure status, tumor shape, blad-
der base continuity status, and tumor base width CEUS
characteristics were independent predictors of the bladder
cancer muscle invasion status (all p<.; Figure A).
Moreover, tumor size, tumor base structure status, tumor
shape, bladder base continuity status, tumor base width,
and tumor blood flow condition were closely associated
with the pathology grade status of bladder cancer (all
p<.; Figure B).
The tumor size of high-grade bladder cancer ( mm
[IQR –]) was relatively bigger than that of low-grade
bladder cancer ( mm [IQR –]) (≥ vs. < mm,
TABLE 1 Clinicopathologic characteristics of all patients.
Characteristic N=163
Gender (%)
Male (.)
Female (.)
Age, years, median (IQR) . (., .)
Gross hematuria (%)
No (.)
Yes ( .)
Number of urine red blood cell (median
(IQR)
(, )
Tumor size, median (IQR) (, )
Tumor size (%)
< mm (.)
≥ mm (.)
Tumor base structure status (%)
Pedunculated (.)
Sessile (.)
Tumor shape (%)
Papillary or cauliflower-like (.)
Irregularity (.)
Number of tumors (%)
(.)
(.)
≥(.)
Bladder base continuity status (%)
Good continuity (.)
Discontinuous change (.)
Tumor base width (%)
Narrow (.)
Broad (.)
Tumor blood flow situation (%)
Less (.)
Rich (.)
Bladder cancer muscle invasive status
NMIBC (.)
MIBC (.)
Bladder cancer pathology grade
Low (.)
High (.)
Abbreviations: IQR, interquartile range; MIBC, muscle invasive bladder
cancer; NMIBC, nonmuscle invasive bladder cancer.
p<.). Pedunculated lesions accounted for the major-
ity of the low-grade bladder cancers, among which their
proportion was much higher than that among the high-
grade bladder cancers (. vs. .%, p=.).
The high-grade bladder cancer patients had significantly
higher rates of irregular tumor shape (. vs. .%,
4of15 OU .
TABLE 2 Univariate analysis of the bladder cancer muscle invasion status in relation to clinicopathologic characteristics.
NMIBC group MIBC group
Characteristic N=133 N=30 pvalue
Gender (%) .b
Male (.) (.)
Female (.) (.)
Age, years, median (IQR) . (., .) . (., .) .a
Gross hematuria (%) .
No (.) (.)
Yes (.) (.)
Number of urine red blood cell, median (IQR) . (., .) . (., .) .a
Tumor size, median (IQR, cm) (, ) (, ) <.a
Tumor size (%)
< mm (.) (.) <.
≥ mm (.) (.)
Tumor base structure status (%) <.
Pedunculated (.) (.)
Sessile (.) (.)
Tumor shape (%) <.
Papillary or cauliflower-like (.) (.)
Irregularity (.) (.)
Number of tumors (%) .b
(.) (.)
(.) (.)
≥ (.) (.)
Bladder base continuity status (%) <.
Good continuity (.) (.)
Discontinuous change (.) (.)
Tumor base width (%) <.
Narrow (.) (.)
Broad (.) (.)
Tumor blood flow situation (%) .
Less (.) (.)
Rich (.) (.)
Abbreviations: IQR, interquartile range; MIBC, muscle invasive bladder cancer,
aWilcoxon rank-sum,
bfisher’s exact test; NMIBC, nonmuscle invasive bladder cancer.
p=.), more discontinuous changes in bladder base
(. vs. .%, p=.), a broader tumor base (. vs.
.%, p<.), and increased tumor blood flow (. vs.
.%, p=.) than the low-grade bladder cancer patients.
Multivariable analysis showed that CEUS characteris-
tics of tumor size, tumor base structure status, tumor
shape, bladder base continuity status, tumor base width,
and tumor blood flow condition CEUS characteristics
were independent predictors of bladder cancer pathology
grade status (all p<.). More details on univari-
ate and multivariate analyses are shown in Table and
Figure B.
2.3 High overall CEUS diagnostic
performance in muscle invasion status
evaluation
The sensitivities, specificities, accuracies, positive predic-
tive values (PPVs), negative predictive values (NPVs), and
OU . 5of15
Characteristic
Tumor size
Tumor base structure status
Tumor shape
Bladder base continuity status
Tumor base width
OR (95% CI)
6.80 [ 2.45; 18.88]
65.50 [19.58; 219.14]
30.50 [11.01; 84.48]
141.20 [29.90; 666.73]
36.60 [12.29; 109.00]
0.01 0.1 1 10 100
Characteristic
Tumor size
Tumor base structure status
Tumor shape
Bladder base continuity status
Tumor base width
Tumor blood flow situation
OR (95% CI)
6.30 [2.46; 16.14]
27.90 [1.68; 462.25]
23.00 [1.38; 381.99]
30.00 [1.80; 500.72]
31.10 [1.88; 514.18]
4.40 [1.28; 15.14]
0.01 0.1 1 10 100
(A)
High pathology grade
Muscle invasiveNon-muscle invasive
Low pathology grade
(B)
FIGURE 2 Multivariate analysis of CEUS for the bladder cancer muscle invasion status and pathology grade status. CEUS,
contrast-enhanced ultrasound. Multivariate analysis of CEUS for the bladder cancer muscle invasion status; (B) multivariate analysis of CEUS
for the bladder cancer pathology grade status. CEUS, contrast-enhanced ultrasound.
AUCs of the individual tests in predicting muscle inva-
sion status are summarized in Figure A–F. The CEUS
demonstrated superior performance in muscle invasion
status diagnosis (.% [/] vs. .% [/] and inde-
pendent samples t-test, p<.; Figure A), as well
as high AUC (., % confidence interval (CI) .–
.; Figure B), sensitivity (.%), specificity (.%), and
accuracy (.%).
Subgroup analyses of CEUS diagnostic performance
in muscle invasion status evaluation are shown in
Figure A–F. The diagnostic performance of CEUS in
determining muscle invasion status in bladder cancer
patients is primarily influenced by the following sub-
groups: different machines may lead to AUC performance
heterogeneity, with scores of . (% CI .–.) for
Canon Aplio, . (% CI .–.) for Aloka Arietta
and Siemens ACUSON Sequoia, and . (% CI .–
.) for Mindray Resona S. Lesions in the anterior wall
(AUC: ., % CI .–.) and the triangle area (AUC:
., % CI .–.) were better diagnosed than those
located in the top, side, or posterior walls (AUC: ., %
CI .–.), indicating that lesions location may also
affect diagnostic accuracy.
The decision curve analysis (DCA) curve showed that
the net benefit of using CEUS was significantly higher than
that of using MRI if the threshold probability was between
and %. This suggests that using CEUS for predicting
patients’ muscle invasion status was more beneficial than
MRI (Figure C).
2.4 Comparative diagnostic
performance of CEUS and MRI in muscle
invasion detection in bladder cancer
MRI VI-RADS has been validated for the detection of
muscle invasion in bladder cancer. Bladder cancer lesions
classified as VI-RADS and above by MRI cannot exclude
the possibility of muscle infiltration. Diagnostic per-
formance comparison between CEUS and MRI for the
prediction of bladder cancer stage indicated that the
MRI performance in preoperative diagnosis of the mus-
cle invasion status was .% [/] versus .% [/]
(p=.; Figure D) for the detection of the presence
or absence of muscular infiltrates. MRI showed an AUC
of . (Figure E), and its overall diagnostic sensitiv-
ity, specificity, and accuracy were values ., ., and
.%, respectively. If MRI results are inconsistent with
pathological findings, using CEUS results instead yields
a combined diagnostic performance with a higher AUC
scoreof.(FigureF) compared with using MRI alone.
Based on our results, if MRI VI-RADS score of was con-
sidered to indicate muscle infiltration, there were cases
where the MRI results were inconsistent with the pathol-
6of15 OU .
TABLE 3 Univariate analysis of the bladder cancer pathology grade status in relation to clinicopathologic characteristics.
LPG group HPG group
Characteristic N=33 N=130 pvalue
Gender (%) .
Male (.) (.)
Female (.) (.)
Age, years, median (IQR) . (., .) . (., .) .a
Gross hematuria (%) .
No (.) (.)
Yes ( .) ( . )
Number of urine red blood cell, median (IQR) . (., .) . (., .) <.a
Tumor size, median (IQR) (, ) (, ) <.a
< mm (.) (.)
≥ mm (.) (.)
Tumor base structure status (%) .
Pedunculated (.) (.)
Sessile (.) (.)
Tumor shape (%) .
Papillary or cauliflower-like (.) (.)
Irregularity (.) (.)
Number of tumors (%) .b
(.) (.)
(.) (.)
≥(.) (.)
Bladder base continuity status (%) .
Good continuity (.) (.)
Discontinuous change (.) (.)
Tumor base width (%) <.
Narrow (.) (.)
Broad (.) (.)
Tumor blood flow situation (%) .
Less (.) (.)
Rich (.) (.)
Abbreviations: HPG, high pathology grade; IQR, interquartile range; LPG, low pathology grade,
aWilcoxon rank-sum,
bfisher’s exact test.
ogy results, while the CEUS outcomes were consistent with
the pathology results. Correspondingly, there were only
five cases misjudged by CEUS using pathology as a ref-
erence, while the MRI results were consistent with the
pathology results. An attempt was made to combine CEUS
with MRI, such that the CEUS results prevailed when the
MRI VI-RADS score was points. The combined results
showed a higher AUC score of . compared with MRI
alone, with an overall diagnostic sensitivity, specificity,
and accuracy values of ., ., and .%, respectively
(Figure ).
2.5 Case studies: CEUS characteristics
and pathological features in bladder cancer
patients
Patient was determined to have NMIBC by CEUS. The
postoperative pathology confirmed nonmuscle invasive
status, gray-scale ultrasound showed good continuity of
muscular layer at the base of the lesion, while CEUS
revealed that the muscular layer at the lesion base was
intact and without interruption (Figure A–H and Video
S). In contrast, patient was diagnosed with MIBC by
OU . 7of15
83.3
92.9
50.0
83.3
100
13.6
100 100
71.4
61.9
100
83.3 83.3
75.0
57.1
72.2
92.5 92.5
100
86.7 90.0
97.4
90.9 86.5
96.1 99.0
85.7 86.7
100
66.7
100 100
90.8 92.5 87.5 85.2
93.3
67.2
91.9 90.0
0.88 0.93
0.75
0.85
0.95
0.56
0.96 0.93
PPVs NPVs AUCs
Sensitivity Specificity Accuracy
All patients
Canon Aplio i800
Aloka Arietta 850 and
Siemens ACUSON Sequoia
Mindray Resona 7S
Anterior wall
Top , side and posterior wall
T
riangle area
Multiple
All patients
Canon Aplio i800
Aloka Arietta 850 and
Siemens ACUSON Sequoia
Mindray Resona 7S
Anterior wall
T
op, side and posterior wall
Tr iangle area
Multiple
All patients
Canon Aplio i800
Aloka Arietta 850 and
Siemens ACUSON Sequoia
Mindray Resona 7S
Anterior wall
T
op, side and posterior wall
T
riangle area
Multiple
0
25
50
75
100
0
0.25
0.50
0.75
1
0
25
50
75
100
0
25
50
75
100
0
25
50
75
100
0
25
50
75
100
Value (%)
Value (%)
Value (%)Value (%)
Value (%)
Value
(A) (B) (C)
(E)(F)(D)
FIGURE 3 Diagnostic performance of CEUS for the muscle invasion status in bladder cancer. CEUS, contrast-enhanced ultrasound.
CEUS sensitivity for muscle invasion status in bladder cancer with different machines (such as Canon Aplio i, Aloka Arietta and
Siemens ACUSON Sequoia, Mindray Resona S) and lesion locations (such as anterior wall, top, side and posterior wall, triangle area,
multiple lesions); (B) CEUS specificity for muscle invasion status in bladder cancer with different machines (such as Canon Aplio i, Aloka
Arietta and Siemens ACUSON Sequoia, Mindray Resona S) and lesion locations (such as anterior wall, top, side and posterior wall,
triangle area, multiple lesions); (C) CEUS accuracy for muscle invasion status in bladder cancer with different machines (such as Canon
Aplio i, Aloka Arietta and Siemens ACUSON Sequoia, Mindray Resona S) and lesion locations (such as anterior wall, top, side and
posterior wall, triangle area, multiple lesions); (D) CEUS PPVs for muscle invasion status in bladder cancer with different machines (such as
Canon Aplio i, Aloka Arietta and Siemens ACUSON Sequoia, Mindray Resona S) and lesion locations (such as anterior wall, top, side
and posterior wall, triangle area, multiple lesions); (E) CEUS NPVs for muscle invasion status in bladder cancer with different machines (such
as Canon Aplio i, Aloka Arietta and Siemens ACUSON Sequoia, Mindray Resona S) and lesion locations (such as anterior wall, top,
side and posterior wall, triangle area, multiple lesions); (F) CEUS AUC for muscle invasion status in bladder cancer with different machines
(such as Canon Aplio i, Aloka Arietta and Siemens ACUSON Sequoia, Mindray Resona S) and lesion locations (such as anterior wall,
top, side and posterior wall, triangle area, multiple lesions). CEUS, contrast-enhanced ultrasound; PPVs, positive predictive values; NPVs,
negative predictive values; AUC, area under the receiver operating characteristics curve.
CEUS. The postoperative pathology confirmed the mus-
cle invasive status, and gray-scale ultrasound and CEUS
showed that the muscular layer at the base was inter-
rupted by the lesion (Figure A–H and Video S). Dynamic
observation with CEUS allowed the visualization of the
bladder wall divided into three different areas correspond-
ing to the enhanced mucosal layer and muscularis pro-
pria, nonenhanced muscular layer, and enhanced serosal
layer.
3DISCUSSION
This prospective study showed that bladder imaging using
CEUS is highly accurate in preoperative staging. CEUS
may achieve a more accurate diagnosis of muscular infil-
tration compared with MRI.
Neoadjuvant cisplatin-based combined chemotherapy
followed by total cystectomy is the main treatment for
MIBC., VI-RADS is a standardized system for acquiring
8of15 OU .
0.00
0.25
0.50
0.75
1.00
Percent weight
92.5%
(N=123)
7.5% (N=10)
83.3%
(N=25)
16.7%
(N=5)
No
Yes
0.0 0.2 0.4 0.6 0.8 1.0
−0.05 0.00 0.05 0.10 0.15 0.20 0.25
Net benefit
CEUS
MRI
All
None
High risk threshold
(A) (D)
(B) (E)
(C)(F)
CEUS predict muscle
invasion status
0.0 0.2 0.4 0.6 0.8 1.0
0.0 0.2 0.4 0.6 0.8 1.0
False positive rate
True positive rate
AUC = 0.68
Muscle invasiveNonmuscle invasive
p < 0.001
50.0%
(N=33)
50.0%
(N=33)
14.3%
(N=3)
85.7%
(N=18)
Muscle invasive
No
Yes
MRI predict muscle
invasion status
p < 0.001
0.00
0.25
0.50
0.75
1.00
Percent weight
Nonmuscle invasive
0.0 0.2 0.4 0.6 0.8 1.0
0.0 0.2 0.4 0.6 0.8 1.0
False positive rate
True positive rate
AUC = 0.88
0.0 0.2 0.4 0.6 0.8 1.0
0.0 0.2 0.4 0.6 0.8 1.0
False positive rate
True positive rate
AUC = 0.77
FIGURE 4 CEUS and MRI for detection of muscle invasion status in bladder cancer. CEUS, contrast-enhanced ultrasound, MRI,
magnetic resonance imaging. (A) Proportions of CEUS in patients with nonmuscle invasive versus muscle invasive bladder cancer; (B) CEUS
for bladder cancer muscle invasion status estimation; (C) decision curve analysis; (D) proportions of MRI in patients with nonmuscle invasive
versus those with muscle invasive cancer; (E) MRI results for bladder cancer muscle invasion status estimation; (F) CEUS prediction of
muscle invasion status for identification of MRI prediction error. CEUS, contrast-enhanced ultrasound; MRI, magnetic resonance imaging.
and interpreting images to evaluate MIBC using multi-
parametric MRI. It was developed and jointly released
in by the Japanese Society of Abdominal Radiology,
European Association of Urology, and European Society of
Urogenital imaging. VI-RADS is a structured five-point
risk stratification system that categorizes the likelihood
of muscle invasion in bladder cancer patients, ranging
from least to most likely: VI-RADS (highly unlikely),
VI-RADS (unlikely), VI-RADS (equivocal), VI-RADS
(likely), and VI-RADS (very likely). A systematic
review, encompassing studies (n=), revealed that
MRI demonstrated ultimate sensitivity and specificity,
achieving . and ., respectively, in distinguishing
between NMIBC and MIBC. VI-RADS has attracted
OU . 9of15
29.9%
(N=20)
70.1%
(N=47)
23.8%
(N=5)
76.2%
(N=16)
Muscle invasive
(A)
No
Yes
p < 0.001
False positive rate
True positive rate
1.0 0.8 0.6 0.4 0.2 0.0
0.0 0.2 0.4 0.6 0.8 1.0
AUC = 0.73
(B)
0.00
0.25
0.50
0.75
1.00
Percent weight
Nonmuscle invasive
Muscle invasion status
FIGURE 5 Combining CEUS and MRI to predict muscle
invasion status, where CEUS results were used when MRI VI-RADS
score was points. CEUS, contrast-enhanced ultrasound, MRI,
magnetic resonance imaging, VI-RADS, vesical imaging reporting
and data system. The proportions of combining results of CEUS and
MRI in patients with nonmuscle invasive versus those with muscle
invasive; (B) combining results of CEUS and MRI for bladder cancer
muscle invasion status estimation. CEUS, contrast-enhanced
ultrasound; MRI, magnetic resonance imaging.
significant attention due to its ability to provide a
quantitative assessment of the risk of MIBC risk.
Compared with MRI, ultrasound offers several advan-
tages, including real-time dynamic observation, low inci-
dence of adverse reactions, wide accessibility, noninvasive-
ness, and cost effectiveness. It has been widely used in
various clinical fields, such as abdominal, urinary, repro-
ductive, and hepatobiliary system intervention, the latter
including liver or portal vein thrombosis biopsy, liver or
kidney ablation, cholangiography, and kidney or prostate
biopsy.,, Additionally, ultrasound also plays a signifi-
cant role in bladder cancer staging, allowing discrimina-
tion of different types and stages of bladder cancers.A
systematic review and meta-analysis of CEUS effectiveness
in bladder cancer indicated that it distinguishes T staging
and grading of bladder cancer with sensitivity, specificity,
anddiagnosticAUCof>.%.
The present prospective study found that the CEUS blad-
der imaging is highly accurate in preoperative staging,
particularly outperforming MRI in diagnosing muscular
infiltration, with an AUC of ., sensitivity of .%, speci-
ficity of .%, and overall accuracy of .%. The high level
of diagnostic performance of CEUS was validated in many
patient subgroups. According to visual observation and
radiologist’s experience, muscular layer infiltration can be
diagnosed when the continuity of the low-enhancement
muscular layer is interrupted. If the continuity of the mus-
cular layer is preserved, the lesion can be judged as not
infiltrating the muscular layer.
In addition, the diagnostic performance of CEUS in
bladder cancer stage prediction was compared with that
of MRI. Combined CEUS-based diagnosis, where ultra-
sound results were used to replace MRI results in cases of
discrepancies were found between MRI findings and post-
operative pathology findings, demonstrated higher AUC
(.) performance compared with that of MRI alone. This
suggests that CEUS can identify muscle invasion statuses
that was misdiagnosed by MRI before surgery.
DCA was used to compare the performance of different
models and determine the threshold probability at which
using the model is most beneficial. The DCA curve showed
that the net benefit of using CEUS was significantly higher
than that of using MRI if the threshold probability was
between and %. This demonstrated that the use of
CEUS to predict muscle invasion status was more bene-
ficial than MRI-based diagnosis. Moreover, CEUS can be
used for real-time dynamic observations that can reveal
the vascularity of tissues and organs and allow for con-
trast agent perfusion processes. These features can provide
more comprehensive and accurate diagnostic information
than conventional ultrasound and color Doppler ultra-
sound examinations. In addition, CEUS is characterized
by lower incidence of adverse reactions, wide accessi-
bility, noninvasiveness, and affordability compared with
MRI.,
It is also noteworthy that the present study results
showed that CEUS accuracy varies across different instru-
ments. The Aplio i offered exceptional diagnostic
performance as it showed the highest AUC. This may be
attributed to its auxiliary functions, such as P-MFI and
MFI, which effectively display the enhancement range and
10 of 15 OU .
FIGURE 6 Ultrasound characteristics and pathology status of nonmuscle invasive bladder cancer patients and pathology status. (A)
Gray-scale ultrasound; (B) color Doppler flow imaging; (C) contrast harmonic imaging +superb micro vascular imaging; (D) contrast
harmonic imaging in s just before the lesion began to strengthen; (E) contrast harmonic imaging in s almost before the lesion reached
the peak; (F) contrast harmonic imaging in s after contrast material was washed out; (G) contrast harmonic imaging +superb micro
vascular imaging +smart D; (H) pathology imaging. The yellow boxes highlight the lesions.
timing of lesions. P-MFI is a post-contrast processing imag-
ing function that utilizes time to encode the time sequence
of contrast agent perfusion. Therefore, P-MFI can reveal
whether a lesion is enhanced earlier than the bladder wall
and the overall enhancement lesion stage. This helps to
determine whether a lesion is benign or malignant and to
identify the lesion. Auxiliary examinations, such as superb
microvascular imaging, color superb microvascular imag-
ing, monochromatic superb microvascular imaging, and
Smart D, help in understanding the overall blood sup-
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FIGURE 7 Ultrasound characteristics of muscle invasive bladder cancer patients and pathology status. (A) gray-scale ultrasound; (B)
color doppler flow imaging; (C) contrast harmonic imaging +superb micro vascular imaging; (D) contrast harmonic imaging in s just after
the lesion begins to strengthen; (E) contrast harmonic imaging in s almost before the lesion reaches the peak; (F) contrast harmonic
imaging in s after contrast material has washed out; (G) contrast harmonic imaging +superb micro vascular imaging +smart D; (H)
pathology imaging. The yellow boxes highlight the lesions.
ply of a lesion, which contributes to staging and grading
it. It is remarkable that the use of equipment employing
different imaging technologies, data transmission systems,
image quality or functions, among other characteristics,
resulted in different diagnostic accuracies. Specifically, fac-
tors such as spatial resolution and frame rate are crucial for
diagnostic precision. The discrepancies in image quality
are particularly pronounced for lesions located in differ-
ent bladder locations. Using similar probe frequencies, the
distance between lesions and skin surface are considered
12 of 15 OU .
different, which affects the lateral resolution, resulting in
image quality variability, and diagnostic accuracy differ-
ences. Specifically, the energy of ultrasonic wave in the
transmission process decreases with the increase in the
propagation distance, which also decreases the image qual-
ity. Thus, choosing the right probe with a proper frequency
can help to improve diagnostic accuracy.
Besides, this prospective study’s results indicate that
lesions in the anterior wall (AUC: ., % CI .–.)
and the triangle area (AUC: ., % CI .–.) are
diagnosed with higher accuracy compared with lesions
located in the top, side, or posterior walls (AUC: ., %
CI .–.). This variation in diagnostic accuracy can
be attributed to several factors. Lesions in the top region
are often affected by lateral wall echo drop-out and inter-
ference from bowel gas, which can obscure the image.
Sidewall lesions are primarily impacted by echo drop-
out, leading to decreased visibility. Posterior lesions face
challenges due to their greater distance from the probe,
resulting in reduced lateral resolution. Conversely, lesions
in the anterior wall and triangle area benefit from their
closer proximity to the probe and superior lateral reso-
lution, making them more clearly visible and easier to
diagnose.
Despite its promising results, the present study had sev-
eral limitations. First, the diagnosis of sessile structures,
irregular tumor shapes, broader tumor bases, and tumor
blood flow was based on subjective evaluation, which
could introduce variability. Future studies should incor-
porate quantitative metrics and standardized evaluation
criteria to mitigate this bias. Additionally, potential con-
founding variables such as patient age and prior treatment
history were not controlled for in the present study. Future
research should account for these variables to isolate the
effect of CEUS on diagnostic accuracy.
Second, due to differences in hardware conditions such
as imaging technology and spatial resolution, diagnostic
accuracy may vary between different devices. Therefore,
future research should aim to use the same machine to
acquire ultrasound contrast images and make diagnoses
for patients in order to control potential confounding
variables and thereby increase the reliability of assessing
diagnostic accuracy.
Third, transabdominal CEUS’s effectiveness in deep
position examinations was limited due to decreased lateral
resolution at greater depths, particularly for masses on the
posterior bladder wall. In addition, the evaluation of the
top bladder wall was hindered by lateral wall echo drop-
out and bowel gas interference, while the lateral bladder
wall assessment was mainly affected by lateral echo loss.
This limitation may explain why the AUC for diagnosing
lesions on the top, side, and posterior wall was ., sig-
nificantly lower than that for lesions on the anterior wall
and in the bladder triangle area. To overcome this limi-
tation, combining transabdominal CEUS with transrectal
or transvaginal CEUS could be considered in the future to
further improve the diagnostic accuracy of bladder cancer
staging.
Furthermore, metabolic profiling holds significant
scientific value in predicting cancer immunotherapy
effectiveness. Developing a radiomics model can predict
the risk of metastasis in cancer patients. Integrating
artificial intelligence (AI) technology to explore the
relationship between CEUS’s key imaging features and
metabolic signatures or immunotherapy effectiveness may
enable AI-based prediction of the efficacy and prognosis
of immunotherapy for bladder cancer based on CEUS
imaging. In addition, AI technology holds the potential
to establish predictive models using big data to overcome
diagnostic inconsistencies among radiologists of varying
expertise levels, thereby providing greater stability in diag-
nostic models. Therefore, future research could focus on
developing predictive models that utilize AI technology to
integrate multiomics data from CEUS and MRI for precise
diagnosis of bladder cancer, potentially even predicting
the efficacy of bladder cancer immunotherapy.
Finally, since the present study was based on a sin-
gle center, the sample size needs to be expanded in the
future and the effectiveness of combined diagnosis should
be validated in multicenter studies. To enhance CEUS’s
diagnostic accuracy and generalizability in assessing mus-
cle invasion in bladder cancer, future research should
incorporate larger multicenter studies involving various
radiologists to confirm the present study findings.
In conclusion, the present study demonstrated the clin-
ical value of CEUS in the evaluation of muscle invasion
status in bladder cancer patients prior to TURBT or rad-
ical cystectomy, which has the potential to aid in clinical
decision-making and improve intervention outcomes in
clinical practice.
4 MATERIALS AND METHODS
4.1 Study design and participants
This prospective study was conducted between April
and September , recruiting patients from Sun Yat-sen
Memorial Hospital, Sun Yat-sen University (Guangzhou,
China). The study adhered to both the principles outlined
in the Declaration of Helsinki and the guidelines of the
Standards for Reporting of Diagnostic Accuracy (STARD)
checklist for the accurate reporting of diagnostic accuracy
studies. The study was approved by the Ethics Committee
of Sun Yat-sen Memorial Hospital, Sun Yat-sen University
(SYSEC-KY-KS--), and written informed consent
OU . 13 of 15
was obtained from all participants. The study is registered
with ClinicalTrials.gov (No. NCT).
The inclusion criteria were as follows: (a) age of ≥
years; (b) histologically or cytologically confirmed pri-
mary bladder cancer diagnosis. The exclusion criteria were
as follows: (a) participants who were confirmed to have
no carcinoma of the bladder by postoperative pathology;
(b) patients who underwent therapy, bladder surgery, or
received chemotherapy, radiotherapy or immunotherapy
treatment; (c) participants diagnosed with tumor recur-
rence or metastasis; (d) individuals with thickening of the
bladder wall due to obstruction and trabeculated bladder
(even with diverticula, such as benign prostatic hyper-
plasia); and (e) those who were allergic to ultrasound
contrast agents or could not tolerate CEUS examination,
such as patients with recent myocardial infarction, angina
pectoris, cardiac insufficiency, severe cardiac arrhythmia,
right/left cardiac shunt, severe pulmonary hypertension,
uncontrolled systemic hypertension, acute respiratory dis-
tress syndrome, or chronic obstructive pulmonary disease.
The primary outcome was to evaluate the diagnostic per-
formance of CEUS to determine muscle invasion status
in bladder cancer and compare it with surgery-based
pathological results. All bladder cancer patients received
CEUS followed by standard TURBT or radical cystectomy
regardless of whether they have undergone a previous
cystoscopy procedure. Treatment decisions depended pri-
marily on computed tomography/MRI and cystoscopy
results, although CEUS outcomes may also have been
considered.
4.2 CEUS protocol and image analysis
CEUS examinations were performed using four machines
at the time of the examination (Aplio i, Canon Medi-
cal Systems Co., Ltd; ACUSON Sequoia, Siemens Medical
Solutions; ALOKA ARIETTA , Hitachi; Resona S,
Mindray Bio-Medical Electronics Co., Ltd.). The iCX
(Aplio i), C (ACUSON Sequoia), C- (ALOKA ARI-
ETTA ), and SC-U (Resona S) probes were utilized.
CEUS images were captured and analyzed by two expe-
rienced radiologists to determine the degree of tumor
infiltration. Specifically, the initial CEUS examinations
and image analysis were first performed by a radiolo-
gist with more than years of experience and were then
reassessed under the guidance of a senior radiologist with
more than years of experience by reviewing the video.
Both radiologists were blinded to the patients’ clinical and
histologic information and to one another’s results. The
mechanical index was maintained between . and ..
The patients were asked to drink an appropriate amount
of water to fill their bladder (optimal volume: ± mL)
before the CEUS examination. Poor bladder filling can
affect tumor appearance, while overfilling can easily lead
to the missed diagnosis of small lesions and interfere with
muscular infiltration valuation. A CEUS SonoVue dose of
. mL was used for most patients. All doses were admin-
istered as intravenous bolus injections, followed by rinsing
with . mL of normal saline. Most patients needed only
one injection. Up to three injections could be given if
there were multiple lesions or if additional imaging was
required. The observations and stored videos were a min-
imum of min each. The results were analyzed on a
per-patient basis. Patients enrolled in the analysis with a
single or multiple lesions were classified as follows: (a)
they were positive if they had at least one lesion show-
ing muscle infiltration as detected with CEUS, and (b)
they were negative if they had only one lesion without
muscle invasion, or if they had multiple lesions but no
muscle invasion as detected with CEUS. In CEUS exami-
nations, the bladder wall muscle was scrutinized for any
interruptions to assess whether the tumor had invaded
the muscular layer. None of the patients developed an
allergy, had their tests interrupted, or died during the
trial.
4.3 MR protocol and image analysis
MR images, including the individual TW, DWI, and DCE
MRI categories, were analyzed and scored by two experi-
enced radiologists according to the VI-RADS protocol to
determine the degree of tumor infiltration. Both radiolo-
gists, each with over years of experience, were blinded
to the patients’ clinical and histologic information and one
another’s results. They independently scored the images
and then compared their results. If there were discrep-
ancies between their scores, they reached a consensus
through discussion.
4.4 Histological analyses
All tissue specimens were fixed in % neutral-buffered
formalin, embedded in paraffin, and stained with
hematoxylin-eosin. Specimens were examined by two
expert uropathologists to assess the grade and stage
of the tumors. Malignant tumors were classified and
graded according to the World Health Organization
classification. Tumor stages were defined according
to the American Joint Committee on Cancer/Union
for International Cancer Control TNM system. All
histopathologic measurements were performed by a
pathologist with more than years of experience who was
blinded to the participants’ clinical and CEUS data.
14 of 15 OU .
4.5 Statistical analysis
Differences between categorical variables from different
groups were statistically assessed using the χ test. If any
expected frequency was less than , the fisher’s exact
test was applied. Differences between continuous vari-
ables between two groups were statistically assessed by
the independent samples t-test or Wilcoxon rank sum test.
The results were compared with those of postoperative
pathological staging, and the coincidence rate, sensitivity,
specificity, and positive and NPVs of CEUS were calcu-
lated. The predictive accuracy of CEUS signatures was
assessed using receiver operating characteristic analysis by
R package pROC. AUC was used to evaluate sensitivity
and specificity. DCA was utilized to evaluate the predic-
tive values of CEUS by R package rmda. DCA is a statistical
method that assesses the net benefit of a model by compar-
ing it with other available options, allowing to determine
the model’s clinical usefulness. The DCA results were pre-
sented as a curve that plots the net benefit of using a
model against the threshold probability of the outcome.
Accuracy, sensitivity, specificity, PPVs, and NPVs were cal-
culated using the caret and epiR packages in R. For all
analyses, two-sided pvalues <. were considered sta-
tistically significant. Statistical analyses were performed
using R software (version ..).
AUTHOR CONTRIBUTIONS
Conceptualization, data curation, formal analysis, funding
acquisition, methodology, resources, software, validation,
visualization, writing—original draft, and writing—review
and editing: Qiyun Ou. Conceptualization, data curation,
project administration, funding acquisition, resources, vali-
dation, visualization, writing—original draft, and writing—
review and editing:WeibinXie.Conceptualization, for-
mal analysis, funding acquisition, methodology, software,
visualization, writing—original draft, and writing—review
and editing: Yunfang Yu. Resources, validation, and
project administration:BingOu.Data curation and inves-
tigation:ManLuo.Methodology, software, and visu-
alization: Yongjian Chen. Data curation and investi-
gation:WeiweiPan.Resources and validation:Yim-
ing Lai. Resources: Zhuohang Li. Investigation: Jianqiu
Kong. Validation:ZhuoWu.Validation: Jingliang Ruan.
Resources: Jingjing Han. Conceptualization, funding acqui-
sition, project administration, resources, and writing—
review and editing: Tianxin Lin. Conceptualization, funding
acquisition, project administration, resources, and writing—
review and editing: Baoming Luo. All authors have read and
approved the final manuscript.
ACKNOWLEDGMENTS
Qiyun Ou, Weibin Xie, Yunfang Yu, Tianxin Lin, and
Baoming Luo had full access to all the data in the study
and take responsibility for the integrity of the data and the
accuracy of the data analysis. This study was supported by
the National Natural Science Foundation of China (grant
number and ), the Guangzhou Sci-
ence and Technology Project (grant number AJ
and AJ), the Natural Science Foundation of
Guangdong Province (grant number B and
A), the Guangdong Basic and Applied Basic
Research Foundation (grant number A), the
Sun Yat-sen Pilot Scientific Research Fund (grant number
SYSQH-II--), the Guangdong Yiyang Healthcare
Charity Foundation (grant number CSM), the Key
Areas Research and Development Program of Guang-
dong (grant number B), and the Guangdong
Provincial Clinical Research Center for Urological Dis-
eases (grant number B).
CONFLICT OF INTEREST STATEMENT
All authors declare no conflicts of interest.
DATA AVAILABILITY STATEMENT
The datasets generated or analyzed during the study are
not publicly available but are available from the corre-
sponding author on reasonable request.
ETHICS STATEMENT
The study was approved by the Ethics Committee of
Sun Yat-sen Memorial Hospital, Sun Yat-sen University
(SYSEC-KY-KS--), and written informed consent
was obtained from all participants in the study. The study
is registered with ClinicalTrials.gov (NO. NCT).
ORCID
Yunfang Yu https://orcid.org/---
Tianxin Lin https://orcid.org/---X
Baoming Luo https://orcid.org/---
REFERENCES
. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics :
Globocan estimates of incidence and mortality worldwide for
cancers in countries. CA Cancer J Clin. ;():-
.
. Flaig TW, Spiess PE, Agarwal N, et al. Bladder cancer, version
., NCCN clinical practice guidelines in oncology. JNatl
Compr Canc Netw. ;():-.
. Babjuk M, Burger M, Capoun O, et al. European Association of
Urology Guidelines on non-muscle-invasive bladder cancer (Ta,
T, and carcinoma in situ). Eur Urol. ;():-.
OU . 15 of 15
. Lai AL, Law YM. VI-RADS in bladder cancer: overview, pearls
and pitfalls. Eur J Radiol. ;:.
. Saita A, Lughezzani G, Buffi NM, et al. Assessing the feasibil-
ity and accuracy of high-resolution microultrasound imaging for
bladder cancer detection and staging. Eur Urol. ;():-
.
. Gupta VG, Kumar S, Singh SK, Lal A, Kakkar N. Con-
trast enhanced ultrasound in urothelial carcinoma of urinary
bladder: an underutilized staging and grading modality. Cent
European J Urol. ;():-.
. Dietrich CF, Nolsøe CP, Barr RG, et al. Guidelines and good
clinical practice recommendations for contrast enhanced ultra-
sound (CEUS) in the liver—update - WFUMB in coop-
eration with EFSUMB, AFSUMB, AIUM, and FLAUS. Aktu-
alisierte Leitlinien und Empfehlungen für die gute klinische
Praxis für CEUS der Leber. Ultraschall Med. ;():-
.
. Jakobsen JA, Oyen R, Thomsen HS, Morcos SK, Members of
Contrast Media Safety Committee of European Society of Uro-
genital Radiology (ESUR). Safety of ultrasound contrast agents.
Eur Radiol. ;():-.
. Beckmann S, Simanowski JH. Update in contrast-enhanced
ultrasound. Visc Med. ;():-.
. Panebianco V, Narumi Y, Altun E, et al. Multiparametric mag-
netic resonance imaging for bladder cancer: development of
VI-RADS (vesical imaging-reporting and data system). Eur Urol.
;():-.
. Ruiz de Porras V, Pardo JC, Etxaniz O, Font A. Neoadjuvant
therapy for muscle-invasive bladder cancer: current clinical sce-
nario, future perspectives, and unsolved questions. Crit Rev
Oncol Hematol. ;:.
. Cornelissen SWE, Veenboer PW, Wessels FJ, Meijer RP. Diag-
nostic accuracy of multiparametric MRI for local staging of
bladder cancer: a systematic review and meta-analysis. Urology.
;:-.
. Pecoraro M, Takeuchi M, Vargas HA, et al. Overview of VI-
RADS in bladder cancer. AJR Am J Roentgenol. ;():-
.
. Dietrich CF, Nolsøe CP, Barr RG, et al. Guidelines and good
clinical practice recommendations for contrast-enhanced ultra-
sound (CEUS) in the liver-update WFUMB in cooperation
with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultrasound Med
Biol. ;():-.
. Wang F, Zhang Q, Yan K, et al. D-CEUS/MRI-CEUS fusion
imaging vs D-CEUS after locoregional therapies for hepatocel-
lular carcinoma: a multicenter prospective study of therapeutic
response evaluation. Eur Radiol..
. Zhou Y, Ding J, Qin Z, et al. Combination of CT/MRI LI-RADS
with CEUS can improve the diagnostic performance for HCCs.
Eur J Radiol. ;:.
. Bicchetti M, Simone G, Giannarini G, et al. A novel pathway to
detect muscle-invasive bladder cancer based on integrated clini-
cal features and VI-RADS score on MRI: results of a prospective
multicenter study. Radiol Med. ;():-.
. Li C, Gu Z, Ni P, et al. The value of contrast-enhanced ultra-
sound and magnetic resonance imaging in the diagnosis of
bladder cancer. J Cancer Res Ther. ;():-.
. Ou Q, Lu Z, Cai G, et al. Unraveling the influence of metabolic
signatures on immune dynamics for predicting immunother-
apy response and survival in cancer. MedComm—Future Med.
;:e.
. Zhao J, Jiang O, Chen X, et al. Development and validation
of a prediction model for metastasis in colorectal cancer based
on LncRNA CRNDE and radiomics. MedComm-Future Med.
;:e.
. Bossuyt PM, Reitsma JB, Bruns DE, et al. STARD : an
updated list of essential items for reporting diagnostic accuracy
studies. Radiology. ;():-.
. Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE.
The WHO classification of tumours of the urinary system
and male genital organs-part B: prostate and bladder tumours.
Eur Urol. ;():-.
. Paner GP, Stadler WM, Hansel DE, Montironi R, Lin DW,
Amin MB. Updates in the eighth edition of the tumor-node-
metastasis staging classification for urologic cancers. Eur Urol.
;():-.
. Zhao L, Leng Y, Hu Y, et al. Understanding decision curve
analysis in clinical prediction model research. Postgrad Med J.
;():-.
SUPPORTING INFORMATION
Additional supporting information can be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Ou Q, Xie W, Yu Y, et al.
Contrast-enhanced ultrasound enables precision
diagnosis of preoperative muscle invasion in
bladder cancer: a prospective study. MedComm.
;:e. https://doi.org/./mco.
