p53 status correlates with the risk of progression in stage T1 bladder cancer: a meta-analysis
Du et al. World Journal of Surgical Oncology
p53 status correlates with the risk of progression in stage T1 bladder cancer: a meta-analysis
Jun Du 0
Shu-hua Wang 0
Qing Yang 0
Qian-qian Chen 0
Xin Yao 0
0 Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy , Tianjin , People's Republic of China
Background: Published studies have yielded inconsistent results on the relationship between p53 status and the progression of stage T1 non-muscle invasive bladder cancer (NMIBC). Therefore, we performed a meta-analysis to evaluate the prognostic value of p53 in T1 NMIBC. Methods: We systematically searched for relevant literatures in MEDLINE, EMBASE, and Web of Science. Data were pooled together from individual studies, and meta-analysis was performed. Study quality was assessed using the Newcastle-Ottawa Scale. Pooled risk ratios (RRs) and 95 % CI were calculated to estimate the effect sizes. Moreover, subgroup analyses were carried out. Results: A total of 12 studies comprising 712 patients were subjected to the final analysis. p53 overexpression was significantly associated with higher progression rate of T1 NMIBC (RR 2.32, 95 % CI 1.59-3.38). Moderate heterogeneity was observed across the studies (I2 = 39 %, P < 0.0001). In a subgroup analysis stratified by stage, p53 overexpression was a predictor of progression in T1 grade 3 NMIBC (RR 2.71, 95 % CI 1.31-5.64). In addition, in a subgroup analysis stratified by intravesical therapy, p53 overexpression was a predictor of progression in T1 NMIBC received Bacillus Calmette-Guérin intravesical therapy (RR 3.35, 95 % CI 1.89-5.93). Furthermore, after excluding the study that possibly contributed to the heterogeneity by the sensitivity analysis, the association p53 overexpression was significantly correlated with progression of T1 NMIBC (RR 2.74, 95 % CI 2.05-3.65) without evidence of heterogeneity (I2 = 0 %, P < 0.0001). Conclusions: This meta-analysis suggested that p53 overexpression may be associated with progression of T1 NMIBC patients. Because of the heterogeneity and other limitations, further studies with rigid criteria and large populations are still warranted to confirm our findings.
p53; Non-muscle invasive bladder cancer; Stage T1; Progression; Meta-analysis
There are 386,000 new cases of bladder cancer
worldwide every year and caused 150,000 cancer-specific
]. Approximately 70 % of bladder cancer are
non-muscle invasive bladder cancers (NMIBCs) at the
time of presentation [
], and stage T1 disease showing
invasion of the lamina propria present 25 % of NMIBC
]. T1 NMIBC represent a clinical challenge because
they are inherently aggressive and have heterogeneous
outcomes. Up to 50 % of T1 NMIBC managed with
intravesical therapy progress to muscle invasive BC (MIBC)
within 5 years [
]. Progression rather than recurrence has
been associated with increased chance of metastasis and
death from systemic disease. The European Organisation
for Research and Treatment of Cancer (EORTC) has
proposed a scoring system for predicting progression of
NMIBC using a weighted variable system including grade
(WHO 1973), stage, CIS, multiplicity, size, and previous
recurrence rate [
]. Although the EORTC risk score
represents a major improvement, it does not fully capture
tumor heterogeneity of T1 NMIBC.
Another approach has been to identify biomarkers to
predict the probability of progression in T1 NMIBC [
Cell cycle modulators are often deregulated in bladder
cancer, including alterations in various proteins such as
p53, CCNB1, p16, and p27 [
]. p53 is frequently
mutated in patients with bladder cancer [
with the wild-type protein, mutant p53 proteins have a
prolonged half-life and are thus more likely to be
detected by immunohistochemical assays [
]. In bladder
cancer, because of the high concordance between p53
nuclear immunoreactivity and genomic mutations,
immunohistochemistry is a useful surrogate for examining
p53 mutation status [
]. The value of pretreatment
p53 status on the progression of T1 NMIBC has been
studied and discussed. As a result, several studies
reported that p53 overexpression is positively associated with
progression of T1 NMIBC [
]. However, some studies
failed to confirm the association between p53
overexpression and progression of T1 NMIBC [
Considering the inconsistent results of published
articles, we conducted a meta-analysis to determine the p53
status in predicting progression of T1 NMIBC.
We conducted and reported this meta-analysis following
the PRISMA statement. A MEDLINE, EMBASE, and
Web of Science search for studies investigating the
progression significance of p53 in T1 bladder cancer was
performed using the following keywords: [urinary
bladder neoplasms] OR [urinary AND bladder AND
neoplasms] OR [bladder AND cancer] OR [bladder cancer]
AND [T1] AND [p53] OR [TP53] AND [progression].
The final search was conducted on October 10, 2015.
Searches were limited to studies published in English.
The eligible publications were selected by two reviewers.
Inclusion and exclusion criteria
Studies were considered eligible if they met the following
inclusion criteria: (1) the study included proven
diagnosis of urothelial carcinoma; (2) the study considered
TURBT as a treatment modality; (3) the study assessed
the association between p53 and progression of patients
with T1 bladder cancer; (4) to detect p53 status in the
primary tumor tissues using immunohistochemistry
(IHC); and (5) the study provided the data that showed
number of events. Studies were excluded based on any
of the following criteria: (1) review articles,
commentaries, letters to the editor, or case reports or (2) laboratory
studies, such as studies on bladder cancer cell lines and
animal models; for overlapping studies, the most recent
or most complete study was used to avoid duplication of
According to the inclusion criteria listed above, data
were extracted independently by two reviewers for each
eligible study. We extracted data including (1) study
information including the name of first author, year of
publication, sample size, and time of research; (2) patient
characters including grade and intravesical therapy; (3)
p53 antibody clone and cutoff value of positivity of p53;
and (4) progression data (number of events).
Study quality assessment
Quality assessment of included studies was evaluated by
two independent reviewers (DJ and WSH) with the
Newcastle-Ottawa quality assessment scale (NOS) range
from 0 to 8 which is used in the evaluation of
nonrandomized studies. Studies with an NOS score ≥6 were
assigned as high-quality studies. Studies from conference
abstracts and with score of zero were defined as
lowquality studies. Discordant studies were evaluated by the
two reviewers together.
The main outcome measures for this meta-analysis were
rates of progression. The primary aim was to search the
effect of p53 status (positive or negative) detected by
IHC on progression rates. For dichotomous data, a
summary risk ratio (RR) and its 95 % CI were calculated. An
observed HR >1 implied progression for the study group
with positive p53, relative to the negative group.
Subgroup analyses were performed to examine if our pooled
estimate of the prognostic value was influenced by a test
of heterogeneity of the combined HRs, carried out using
the Chi-square test and I-squared statistic. A P > 0.10 for
the Chi-square test and an I2 value of <25 % was
considered to represent a low level of heterogeneity between
studies. I2 > 50 % indicated large heterogeneity among
studies, whereas I2 values between 25 and 50 % indicated
moderate heterogeneity [
]. Sensitivity analysis was also
performed by removing one study at a time to calculate
the overall homogeneity and effect size; the Galbraith
plot was also performed to examine the possible distinct
articles. Publication bias was estimated with a visual
inspection of funnel plots. All 95 % CIs were two-sided. The
meta-analysis was performed using Review Manager
(RevMan) software version 5.2 (RevMan 5.2; the Nordic
Cochrane Center, the Cochrane Collaboration,
Through electronic screening, 151 potentially relevant
articles consistent with our searching terms were
identified and 106 of them were eliminated after reading the
abstracts. Of the 45 article that were in full-text format,
24 were excluded because of not including progression
data; 9 were excluded since there were no specific result
about p53 status in T1 NMIBC. The flowchart of
selecting the procedure and the exclusive reason of studies is
summarized in Fig. 1. A total of 12 studies were included
in the meta-analysis (Table 1).
Quality assessment of the 12 studies included in the
metaanalysis was performed by using NOS. In this quality
assessment system, scores 0–3, 4–5, and 6–8 are accepted
as low, medium, and high quality, respectively. The
median score of the studies included in the meta-analysis was
found as 7.
Meta-analysis of the correlation between p53
overexpression with progression of T1 NMIBC resulted in P < 0.0001
and I2 = 39 %, suggesting that there was moderate
heterogeneity and that the subgroup analysis should be carried
out. Hence, we carried out subgroup analysis according to
stage, intravesical therapy, antibody clone, cutoff value of
positivity of p53, and ethnicity. However, none of these
factors was found to be significantly correlated to
heterogeneity using subgroup analysis among the studies.
p53 overexpression and progression of T1 NMIBC
There were 12 studies with a total of 712 patients included
in final analysis to assess the effect of p53 overexpression
on progression of T1 NMIBC. As shown in Fig. 2,
the pooled RR was 2.32 (95 % CI 1.59–3.38) by
random-effects model for the existence of a moderate
heterogeneity (I2 = 39 %, P < 0.0001), which suggested p53
overexpression was associated with progression of T1
NMIBC. Subgroup analysis according to grade,
intravesical therapy, antibody clone, cutoff value of positivity of
p53, and ethnicity was also performed (Table 2). The
results suggested that all of the relevant stratified factors
did not have a significant correlation with heterogeneity
(P ranging from 0.18 to 0.63) and did not alter the
significant prognostic impact of p53 overexpression.
p53 overexpression and progression of T1G3 NMIBC
There were 3 studies that included a total of 141 pure
T1 grade 3 (T1G3) NMIBC patients; the RR was 2.71
(95 % CI 1.31–5.64) by random-effects model for the
existence of no heterogeneity (I2 = 0 %, P = 0.007), which
suggested p53 overexpression was associated with
progression of T1G3 NMIBC (Table 2).
p53 overexpression and progression of T1 NMIBC
treated with BCG There were 4 studies that included a
total of 286 pure T1 NMIBC patients treated with
Bacillus Calmette-Guérin (BCG) intravesical therapy; the RR
was 2.71 (95 % CI 1.31–5.64) by random-effects model for
the existence of no heterogeneity (I2 = 0 %, P < 0.0001),
which suggested p53 overexpression was associated with
progression of T1 NMIBC patients treated with BCG
intravesical therapy (Table 2).
Records identified through database searching (n=297)
Records after duplicates removed (n=146)
Records screened (n=151)
Records excluded (n=106)
Full-text articles assessed for eligibility (n=45)
Full-text articles excluded, with reasons (n=33)
Studies included in meta-analysis (n=12)
Publication bias assessment and sensitivity analysis
Investigation of bias by a funnel plot showed no
evidence of significant publication bias among the studies
with respect to the effect of p53 status on progression of
T1 NMIBC (Fig. 3).
Sensitivity analysis was conducted to assess the
influence of individual study on the pooled effect. One study
by Vatne et al. was identified in the Galbraith plot as the
outliers (Fig. 4). When we removed the study by Vatne
et al., the initial heterogeneity (I2 = 39 %, P < 0.0001) was
reduced to none (I2 = 0 %, P = 0.63) in evaluating the
association of p53 overexpression and progression of T1
NMIBC patients (Table 3).
T1 NMIBC are potentially more lethal because
approximately 40 % of tumors managed conservatively progress
to MIBC or develop distant metastasis within 5 years
]. Molecular markers are promising for accurately
predicting the progression of T1 NMIBC patients. p53 plays
an important role in the regulation of cell cycle and
apoptosis. To date, the majority of available clinical
reports have involved small sample sizes and given
conflicting results, therefore unable to determine the value of p53
status in predicting progression of T1 NMIBC. Thus, we
conducted a meta-analysis of 12 studies to systematically
evaluate the association between p53 status and
progression of T1 NMIBC.
To the best of our knowledge, this is the first
metaanalysis to evaluate the relationship between p53 status
and the progression of T1 NMIBC. In the overall pooled
analysis of the association of p53 status with progression
of T1 NMIBC, the results suggested that p53
overexpression associated with progression of T1 NMIBC.
In the test of heterogeneity, there was a moderate
heterogeneity (I2 = 39 %) in the analysis of the association
of p53 status with progression of T1 NMIBC. Although
the data were aggregated using the random-effects
models, heterogeneity among the studies continued to
be a potential problem to influence the reliability of
pooled results. Hence, we carried out subgroup analysis
according to grade, intravesical therapy, antibody clone,
cutoff value of positivity of p53, and ethnicity. However,
none of these factors was found to be significantly
correlated to heterogeneity using a subgroup analysis.
However, there is no heterogeneity in T1G3 NMIBC
(I2 = 0 %); it suggested that p53 overexpression was
associated with incremental progression of T1G3 NMIBC.
T1G3 NMIBC is one subtype of NMIBC, with the highest
progression risk [
]. Because T1G3 NMIBC can present
clinical characteristics of invasive tumors and clinical T1
tumors contain a variable proportion of understaged pT2
tumors, long-term rates of cancer-specific mortality reach
up to 34 % [
]. Expert recommendations on the optimal
treatment strategy for patients with T1G3 NMIBC range
from conservative intravesical therapy to early radical
]. Underestimation of the potential for
progression in T1G3 NMIBC could lead to unpreventable
morbidity and mortality; however, patients treated with
early radical cystectomy faced increased perioperative
mortality and decreased quality-of-life. Therefore, T1G3
NMIBC patients with p53 overexpression may probably
obtain better benefit from early radical cystectomy.
In addition, we did not observe heterogeneity in
patients treated with BCG intravesical therapy (I2 = 0 %); it
suggested that p53 overexpression was associated with
elevated progression of T1 NMIBC received by BCG
intravesical therapy. Several investigators have evaluated
the prognostic value of nuclear p53 immunoreactivity
before BCG intravesical therapy. A correlation between
pretreatment p53 overexpression and disease progression
after BCG therapy was found in several studies [
Other authors found no such correlation [
Nevertheless, it was found that BCG treatment was less likely to
be successful in patients with mutated p53 by using yeast
functional assay [
]. To date, whether p53 tumor status
is an independent predictive factor of BCG response in T1
NMIBC still remains a debate. The present meta-analysis
suggested that T1 NMIBC patients with p53
overexpression have increased progression risk after BCG intravesical
therapy; early radical cystectomy could be considered in
It should be noted that our meta-analysis has several
limitations. First, this meta-analysis was limited by the
presence of heterogeneity across the studies. The
heterogeneity possibly caused by the differences in the
characteristics of the patients, IHC technique, cutoff values,
and follow-up time. Second, to reduce the bias from
different detection methods, we only included the studies
measuring p53 expression by IHC. IHC has been widely
used to detect molecular markers, because the method
is simple, fast, and reliable [
]. However, the differences
of the clones of antibody, concentration, and cutoff
value used in different studies might also cause potential
bias. Especially, the cutoff used to define p53
overexpression is probably of prime importance. In the present
meta-analysis, most of the studies chose a cutoff value of
20 %; p53 overexpression was a predictor of progression
in T1 NMIBC, and there is low heterogeneity among
these studies (I2 = 9 %, P < 0.0001). It suggested that a
cutoff value of 20 % may be a proper cutoff of p53.
Furthermore, the interpretation of immunohistochemical
results may vary among different centers. It is, therefore,
necessary to define a standard evaluation system to
promote the application of p53 detected by IHC in clinical
practice. Third, the meta-analysis may have been
influenced by publication bias, as we limited the literature
search to studies performed in English. Finally, most of
the included studies were observational trials, which
contained more potential confounders and provided the
lower level of evidence compared with randomized
controlled studies. Therefore, the results should be
The present study is the first meta-analysis to
quantitatively assess the association between p53 status and
progression of T1 NMIBC. The results showed that p53
overexpression might be a useful predictive biomarker
for evaluating progression in T1 NMIBC patients,
especially in T1G3 NMIBC and patients treated by BCG
intravesical therapy. However, to strengthen our findings,
further larger prospective studies with better standardized
methods are needed to make a comprehensive conclusion
on the prognostic role of p53 overexpression in T1
This article does not contain any studies with human
participants performed by any of the authors.
NMIBC: non-muscle invasive bladder cancer; T1G3: T1 grade 3.
The authors declare that they have no competing interests.
JD carried out the manuscript drafting, acquisition of data, and statistical
analysis. S-hW carried out the acquisition of data and statistical analysis. QY
carried out acquisition of data, analysis, and statistical analysis. Q-qC carried
out the acquisition of data. XY carried out the study design and the final
approval of the version to be published. All authors read and approved the
This study was funded by the National Natural Science Foundation of China
(grant number 81502218).
Grant supported by the National Natural Science Foundation of China, No.
1. Ferlay J , Shin HR , Bray F , Forman D , Mathers C , Parkin DM . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008 . Int J Cancer . 2010 ; 127 ( 12 ): 2893 - 917 .
2. Nepple KG , O'Donnell MA. The optimal management of T1 high-grade bladder cancer . Can Urol Assoc J . 2009 ; 3 ( 6 Suppl 4 ): S188 - 92 .
3. Nieder AM , Brausi M , Lamm D , O'Donnell M , Tomita K , Woo H , Jewett MA . Management of stage T1 tumors of the bladder: International Consensus Panel . Urology. 2005 ; 66 ( 6 Suppl 1 ): 108 - 25 .
4. van Rhijn BW , Burger M , Lotan Y , Solsona E , Stief CG , Sylvester RJ , Witjes JA , Zlotta AR . Recurrence and progression of disease in nonmuscle-invasive bladder cancer: from epidemiology to treatment strategy . Eur Urol . 2009 ; 56 ( 3 ): 430 - 42 .
5. Babjuk M , Burger M , Zigeuner R , Shariat SF , van Rhijn BW , Comperat E , Sylvester RJ , Kaasinen E , Bohle A , Palou Redorta J. EAU guidelines on nonmuscle-invasive urothelial carcinoma of the bladder: update 2013 . Eur Urol . 2013 ; 64 ( 4 ): 639 - 53 .
6. Patschan O , Sjodahl G , Chebil G , Lovgren K , Lauss M , Gudjonsson S , Kollberg P , Eriksson P , Aine M , Mansson W. A molecular pathologic framework for risk stratification of stage T1 urothelial carcinoma . Eur Urol . 2015 ; 68 ( 5 ): 824 - 32 .
7. da Silva GN , Evangelista AF , Magalhaes DA , Macedo C , Bufalo MC , Sakamoto-Hojo ET , Passos GA , Salvadori DM . Expression of genes related to apoptosis, cell cycle and signaling pathways are independent of TP53 status in urinary bladder cancer cells . Mol Biol Rep . 2011 ; 38 ( 6 ): 4159 - 70 .
8. Sarkis AS , Dalbagni G , Cordon-Cardo C , Zhang ZF , Sheinfeld J , Fair WR , Herr HW , Reuter VE . Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression . J Natl Cancer Inst . 1993 ; 85 ( 1 ): 53 - 9 .
9. Esrig D , Spruck 3rd CH , Nichols PW , Chaiwun B , Steven K , Groshen S , Chen SC , Skinner DG , Jones PA , Cote RJ . p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer . Am J Pathol . 1993 ; 143 ( 5 ): 1389 - 97 .
10. Finlay CA , Hinds PW , Tan TH , Eliyahu D , Oren M , Levine AJ . Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life . Mol Cell Biol . 1988 ; 8 ( 2 ): 531 - 9 .
11. Cordon-Cardo C , Dalbagni G , Saez GT , Oliva MR , Zhang ZF , Rosai J , Reuter VE , Pellicer A. p53 mutations in human bladder cancer: genotypic versus phenotypic patterns . Int J Cancer . 1994 ; 56 ( 3 ): 347 - 53 .
12. Saint F , Le Frere Belda MA , Quintela R , Hoznek A , Patard JJ , Bellot J , Popov Z , Zafrani ES , Abbou CC , Chopin DK . Pretreatment p53 nuclear overexpression as a prognostic marker in superficial bladder cancer treated with Bacillus Calmette-Guérin (BCG) . Eur Urol . 2004 ; 45 ( 4 ): 475 - 82 .
13. Llopis J , Alcaraz A , Ribal MJ , Solé M , Ventura PJ , Barranco MA , Rodriguez A , Corral JM , Carretero P. p53 expression predicts progression and poor survival in T1 bladder tumours . Eur Urol . 2000 ; 37 ( 6 ): 644 - 53 .
14. Dalbagni G , Parekh DJ , Ben-Porat L , Potenzoni M , Herr HW , Reuter VE . Prospective evaluation of p53 as a prognostic marker in T1 transitional cell carcinoma of the bladder . BJU Int . 2007 ; 99 ( 2 ): 281 - 5 .
15. Gil P , Allepuz C , Blas M , Borque A , del Agua C , Plaza L , Rioja LA . Significance of protein p53 overexpression in the clinical course of high-risk superficial bladder cancer . Urol Int . 2003 ; 70 ( 3 ): 172 - 7 .
16. Higgins JP , Thompson SG , Deeks JJ , Altman DG . Measuring inconsistency in meta-analyses . BMJ . 2003 ; 327 ( 7414 ): 557 - 60 .
17. Soloway MS . It is time to abandon the “superficial” in bladder cancer . Eur Urol . 2007 ; 52 ( 6 ): 1564 - 5 .
18. Kulkarni GS , Hakenberg OW , Gschwend JE , Thalmann G , Kassouf W , Kamat A , Zlotta A . An updated critical analysis of the treatment strategy for newly diagnosed high-grade T1 (previously T1G3) bladder cancer . Eur Urol . 2010 ; 57 ( 1 ): 60 - 70 .
19. Daneshmand S. Determining the role of cystectomy for high-grade T1 urothelial carcinoma . Urol Clin North Am . 2013 ; 40 ( 2 ): 233 - 47 .
20. Caliskan M , Turkeri LN , Mansuroglu B , Toktas G , Aksoy B , Unluer E , Akdas A . Nuclear accumulation of mutant p53 protein: a possible predictor of failure of intravesical therapy in bladder cancer . Br J Urol . 1997 ; 79 ( 3 ): 373 - 7 .
21. Park J , Song C , Shin E , Hong JH , Kim C-S , Ahn H. Do molecular biomarkers have prognostic value in primary T1G3 bladder cancer treated with bacillus Calmette-Guerin intravesical therapy? Urol Oncol-Semin Orig Investig . 2013 ; 31 ( 6 ): 849 - 56 .
22. Peyromaure M , Sun WB , Sebe P , Verpillat P , Toublanc M , Dauge MC , Boccon-Gibod L , Ravery V . Prognostic value of p53 overexpression in T1G3 bladder tumors treated with bacillus Calmette-Guerin therapy . Urology . 2002 ; 59 ( 3 ): 409 - 13 .
23. Pages F , Flam TA , Vieillefond A , Molinie V , Abeille X , Lazar V , Bressac-de Paillerets B , Mosseri V , Zerbib M , Fridman WH. p53 status does not predict initial clinical response to bacillus Calmette-Guerin intravesical therapy in T1 bladder tumors . J Urol . 1998 ; 159 ( 3 ): 1079 - 84 .
24. Lacombe L , Dalbagni G , Zhang ZF , Cordon-Cardo C , Fair WR , Herr HW , Reuter VE . Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus CalmetteGuerin therapy: correlation to clinical outcome . J Clin Oncol . 1996 ; 14 ( 10 ): 2646 - 52 .
25. Lebret T , Becette V , Barbagelatta M , Herve JM , Gaudez F , Barre P , Lugagne PM , Botto H . Correlation between p53 over expression and response to bacillus Calmette-Guerin therapy in a high risk select population of patients with T1G3 bladder cancer . J Urol . 1998 ; 159 ( 3 ): 788 - 91 .
26. Zlotta AR , Noel JC , Fayt I , Drowart A , Van Vooren JP , Huygen K , Simon J , Schulman CC . Correlation and prognostic significance of p53, p21WAF1/ CIP1 and Ki-67 expression in patients with superficial bladder tumors treated with bacillus Calmette-Guerin intravesical therapy . J Urol . 1999 ; 161 ( 3 ): 792 - 8 .
27. Pfister C , Flaman JM , Dunet F , Grise P , Frebourg T. p53 mutations in bladder tumors inactivate the transactivation of the p21 and Bax genes, and have a predictive value for the clinical outcome after bacillus Calmette-Guerin therapy . J Urol . 1999 ; 162 ( 1 ): 69 - 73 .
28. Lee KE , Lee HJ , Kim YH , Yu HJ , Yang HK , Kim WH , Lee KU , Choe KJ , Kim JP . Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer . Jpn J Clin Oncol . 2003 ; 33 ( 4 ): 173 - 9 .
29. Lopez-Beltran A , Luque RJ , Alvarez-Kindelan J , Quintero A , Merlo F , Carrasco JC , Requena MJ , Montironi R . Prognostic factors in stage T1 grade 3 bladder cancer survival: the role of G1-S modulators (p53, p21Waf1, p27kip1, Cyclin D1, and Cyclin D3) and proliferation index (ki67-MIB1) . Eur Urol . 2004 ; 45 ( 5 ): 606 - 12 .
30. Shariat SF , Weizer AZ , Green A , Laucirica R , Frolov A , Wheeler TM , Lerner SP . Prognostic value of p55 nuclear accumulation and histopathologic features in T1 transitional cell carcinoma of the urinary bladder . Urology . 2000 ; 56 ( 5 ): 735 - 40 .
31. Toktaş G , Türkeri LN , Ünlüer E , Atuǧ F , Murat C , Özveren B , Çalişkan M , Akdaş A . Prognostic significance of p53 protein accumulation in stage pT1 transitional cell carcinoma of the bladder . Int Urol Nephrol . 1999 ; 31 ( 4 ): 437 - 41 .
32. Vatne V , Maartmann-Moe H , Hoestmark J. The prognostic value of p53 in superficially infiltrating transitional cell carcinoma . Scand J Urol Nephrol . 1995 ; 29 ( 4 ): 491 - 5 .