- Email: [email protected]
1239 ELEVATED URINE LEVELS OF RANTES AND HIGH EXPRESSION LEVELS OF THE RANTES RECEPTOR (CCR5) IN BLADDER CANCER
e496
THE JOURNAL OF UROLOGY姞
Vol. 185, No. 4S, Supplement, Monday, May 16, 2011
1238
1239
IMMUNOCYTOLOGY IS A STRONG PREDICTOR OF BLADDER CANCER PRESENCE IN PATIENTS WITH ASYMPTOMATIC HEMATURIA
ELEVATED URINE LEVELS OF RANTES AND HIGH EXPRESSION LEVELS OF THE RANTES RECEPTOR (CCR5) IN BLADDER CANCER
Eugene Cha*, New York, NY; Lenuta-Ancuta Tirsar, Furth, Germany; Shahrokh Shariat, Douglas Scherr, New York, NY; Christian Schwentner, Joerg Hennenlotter, Arnulf Stenzl, Tuebingen, Germany; Christine Mian, Bolzano, Italy; Paul Christos, Madhu Mazumdar, New York, NY; Michele Lodde, Armin Pycha, Bolzano, Italy; Bernd Schmitz-Drager, Furth, Germany
Hiroshi Tsuruta*, Yohei Horikawa, Shintaro Narita, Takamitsu Inoue, Takashi Obara, Kazuyuki Numakura, Shinya Maita, Shigeru Sato, Norihiko Tsuchiya, Tomonori Habuchi, Akita, Japan
Model 3
Model 2
Model 1
Base Model
INTRODUCTION AND OBJECTIVES: The ImmunoCyt immunocytology assay detects cellular biomarkers for bladder cancer (BCa) in exfoliated urothelial cells. The role of ImmunoCyt for BCa detection remains controversial. Therefore, we assessed the performance of ImmunoCyt for detecting BCa in a large multi-institutional cohort of patients undergoing initial evaluation for asymptomatic hematuria. METHODS: Data from 1,182 consecutive subjects without a history of BCa undergoing evaluation for hematuria were collected at three centers. Clinical risk factors including age, gender, smoking status, and degree of hematuria were recorded. All subjects underwent standard workup (i.e., voided cytology, upper tract imaging, and cystoscopy) and immunocytology. Factors associated with the presence of BCa were evaluated by univariate and multivariable logistic regression analyses. Internal validation was performed using 200 bootstrap samples. RESULTS: Overall, 245 subjects (20.7%) had BCa. The sensitivity/specificity/negative predictive value for ImmunoCyt and cytology were 82.4%/86.6%/95.0% and 46.5%/94.9%/87.2%, respectively. ImmunoCyt (OR 18.3, p⬍0.001), cytology (OR 2.9, p⬍0.001), age (OR 1.03, p⬍0.001), smoking status (OR 3.7, p⬍0.001), and degree of hematuria (OR 1.6, p⫽0.01) were associated with BCa in a multivariable analysis. The base model (age, gender, smoking status, degree of hematuria) predicted BCa with an accuracy of 74.1%. Addition of cytology to the base model (Model 1) improved predictive accuracy (PA) to 83.5% (p⬍0.001), while addition of ImmunoCyt to the base model (Model 2) improved PA to 90.1% (p⬍0.001). Addition of ImmunoCyt to the model with cytology significantly improved PA further (⫹7.6%, p⬍0.001), but addition of cytology to the model with ImmunoCyt did not (⫹1.0%, p⫽0.057). ImmunoCyt performed equally well in patients with microscopic and gross hematuria (OR 30 vs 27), in contrast to cytology (OR 18 vs 12). CONCLUSIONS: ImmunoCyt is a strong, independent predictor of BCa presence in patients with hematuria; it outperforms cytology. Addition of ImmunoCyt into the clinical decision-making process may help with patient counseling, improve referral patterns (via increased awareness and prioritization), and possibly spare patients at extremely low risk of BCa from unnecessary hematuria workups.
OR p Value OR p Value 1.04 ⬍0.001 1.03 ⬍0.001
OR p Value 1.03 ⬍0.001
OR p Value 1.03 ⬍0.001
Gender
1.22
1.00
0.97
Smoker
3.17 ⬍0.001 3.72 ⬍0.001
3.38 ⬍0.001
Hematuria (gross vs micro)
1.90 ⬍0.001 1.71
1.71
0.007
1.63
Cytology
-
-
-
-
2.92 ⬍0.001
ImmunoCyt
-
-
Predictive Accuracy
74.1%
1.10
0.66
0.002
14.71 ⬍0.001 -
83.5%
0.99
0.89
3.66 ⬍0.001
0.014
27.71 ⬍0.001 18.26 ⬍0.001 90.1%
91.1%
OR, odds ratio. Model 1, base model ⫹ cytology; model 2, base model ⫹ ImmunoCyt; model 3, base model ⫹ ImmunoCyt ⫹ cytology.
Source of Funding: None
Source of Funding: None
1240
Predictors Age
0.31
INTRODUCTION AND OBJECTIVES: It has been suggested that expression of the inflammatory chemokine CCL5 (RANTES; regulated upon activation, normal T-cell expressed and secreted) by tumor cells is associated with tumor progression in several types of cancer. The aim of this study was to determine if RANTES and CCR5, its main receptor, are produced locally in patients with bladder cancer, whether urine RANTES level is a tumor marker, and whether there is a correlation between tumor progression and the expression levels of RANTES or CCR5. METHODS: Urine RANTES level was measured using a sandwich enzyme-linked immunosorbent assay in 84 patients with bladder cancer and 35 healthy control subjects, and CCR5 expression was determined using immunohistochemical staining in paraffin-embedded sections of primary tumors from 39 patients with bladder cancer. Tumors were classified according to CCR5 protein expression levels in both cytoplasm and nucleus. The correlation between clinicopathological variables such as tumor stage/grade and urine RANTES or CCR5 expression level was assessed. RESULTS: The mean urinary RANTES level in patients with bladder cancer was significantly higher than that in healthy control subjects (patients, 63.1 ⫾ 12.7 pg/mL; control subjects, 22.4 ⫾ 3.8 pg/mL; P⬍0.001, Mann-Whitney U test). The AUC-ROC was 0.696 (95%CI: 0.593– 0.799). When the cutoff value was set as 20.0 pg/mL, sensitivity and specificity were 67.5% and 62.9%, respectively. There was a significant correlation between urinary RANTES level and tumor stage (Ta vs T1–2; P⫽0.02), but there was no significant correlation between urinary RANTES level and tumor grade. By immunohistology, there was a statistically significant association between increased CCR5 expression in the cytoplasm of primary bladder tumors and tumor stage or grade. High-grade or high-stage tumors had a significantly higher expression level of CCR5 (grade 1–2 vs grade 3, P⬍0.001; Ta–1 vs T2– 4, P⫽0.01; Mann-Whitney U test). CONCLUSIONS: A high urinary RANTES level may be a candidate novel tumor marker not only for bladder cancer but also for disease progression. Furthermore, increased CCR5 expression in the cytoplasm of bladder cancer cells may be associated with aggressive bladder cancer. Further molecular and clinical studies are warranted to delineate the role of the RANTES/CCR5 system in carcinogenesis of bladder cancer and to apply urine or tissue expression levels as clinical markers.
DIAGNOSTIC, PREDICTIC AND PROGNOSTIC IMPORTANCE OF URINE INTERLEUKIN (IL)8, IL6, IL5 AND IL4 CONCENTRATION IN PATIENTS WITH BLADDER CARCINOMA Radovan Milosevic*, Danilo Vojvodic, Snezana Cerovic, Novak Milovic, Predrag Aleksic, Zoran Campara, Vladimir Bancevic, Mirko Jovanovic, Predrag Maric, Branko Kosevic, Ivica Nikolic, Goran Teodorovic, Aleksandar Spasic, Dejan Simic, Ivan Stanojevic, Zvonko Magic, Ivana Majstorovic, Belgrade, Yugoslavia INTRODUCTION AND OBJECTIVES: The aims of our investigations were to: investigate urine cytokine levels in patients with TCC correlating them to clinical and pathological signs of tumor advances and to find out is it possible for urine cytokine levels to determine prognosis and final outcome of the illnes. METHODS: Naturally, micturated urine samples were obtained from 78 patients (pts). 51 pts have newly diagnosed TCC, and 27 pts did not have any clinical signes of TCC. Patients with TCC were divided
THE JOURNAL OF UROLOGY姞
Vol. 185, No. 4S, Supplement, Monday, May 16, 2011
1238
1239
IMMUNOCYTOLOGY IS A STRONG PREDICTOR OF BLADDER CANCER PRESENCE IN PATIENTS WITH ASYMPTOMATIC HEMATURIA
ELEVATED URINE LEVELS OF RANTES AND HIGH EXPRESSION LEVELS OF THE RANTES RECEPTOR (CCR5) IN BLADDER CANCER
Eugene Cha*, New York, NY; Lenuta-Ancuta Tirsar, Furth, Germany; Shahrokh Shariat, Douglas Scherr, New York, NY; Christian Schwentner, Joerg Hennenlotter, Arnulf Stenzl, Tuebingen, Germany; Christine Mian, Bolzano, Italy; Paul Christos, Madhu Mazumdar, New York, NY; Michele Lodde, Armin Pycha, Bolzano, Italy; Bernd Schmitz-Drager, Furth, Germany
Hiroshi Tsuruta*, Yohei Horikawa, Shintaro Narita, Takamitsu Inoue, Takashi Obara, Kazuyuki Numakura, Shinya Maita, Shigeru Sato, Norihiko Tsuchiya, Tomonori Habuchi, Akita, Japan
Model 3
Model 2
Model 1
Base Model
INTRODUCTION AND OBJECTIVES: The ImmunoCyt immunocytology assay detects cellular biomarkers for bladder cancer (BCa) in exfoliated urothelial cells. The role of ImmunoCyt for BCa detection remains controversial. Therefore, we assessed the performance of ImmunoCyt for detecting BCa in a large multi-institutional cohort of patients undergoing initial evaluation for asymptomatic hematuria. METHODS: Data from 1,182 consecutive subjects without a history of BCa undergoing evaluation for hematuria were collected at three centers. Clinical risk factors including age, gender, smoking status, and degree of hematuria were recorded. All subjects underwent standard workup (i.e., voided cytology, upper tract imaging, and cystoscopy) and immunocytology. Factors associated with the presence of BCa were evaluated by univariate and multivariable logistic regression analyses. Internal validation was performed using 200 bootstrap samples. RESULTS: Overall, 245 subjects (20.7%) had BCa. The sensitivity/specificity/negative predictive value for ImmunoCyt and cytology were 82.4%/86.6%/95.0% and 46.5%/94.9%/87.2%, respectively. ImmunoCyt (OR 18.3, p⬍0.001), cytology (OR 2.9, p⬍0.001), age (OR 1.03, p⬍0.001), smoking status (OR 3.7, p⬍0.001), and degree of hematuria (OR 1.6, p⫽0.01) were associated with BCa in a multivariable analysis. The base model (age, gender, smoking status, degree of hematuria) predicted BCa with an accuracy of 74.1%. Addition of cytology to the base model (Model 1) improved predictive accuracy (PA) to 83.5% (p⬍0.001), while addition of ImmunoCyt to the base model (Model 2) improved PA to 90.1% (p⬍0.001). Addition of ImmunoCyt to the model with cytology significantly improved PA further (⫹7.6%, p⬍0.001), but addition of cytology to the model with ImmunoCyt did not (⫹1.0%, p⫽0.057). ImmunoCyt performed equally well in patients with microscopic and gross hematuria (OR 30 vs 27), in contrast to cytology (OR 18 vs 12). CONCLUSIONS: ImmunoCyt is a strong, independent predictor of BCa presence in patients with hematuria; it outperforms cytology. Addition of ImmunoCyt into the clinical decision-making process may help with patient counseling, improve referral patterns (via increased awareness and prioritization), and possibly spare patients at extremely low risk of BCa from unnecessary hematuria workups.
OR p Value OR p Value 1.04 ⬍0.001 1.03 ⬍0.001
OR p Value 1.03 ⬍0.001
OR p Value 1.03 ⬍0.001
Gender
1.22
1.00
0.97
Smoker
3.17 ⬍0.001 3.72 ⬍0.001
3.38 ⬍0.001
Hematuria (gross vs micro)
1.90 ⬍0.001 1.71
1.71
0.007
1.63
Cytology
-
-
-
-
2.92 ⬍0.001
ImmunoCyt
-
-
Predictive Accuracy
74.1%
1.10
0.66
0.002
14.71 ⬍0.001 -
83.5%
0.99
0.89
3.66 ⬍0.001
0.014
27.71 ⬍0.001 18.26 ⬍0.001 90.1%
91.1%
OR, odds ratio. Model 1, base model ⫹ cytology; model 2, base model ⫹ ImmunoCyt; model 3, base model ⫹ ImmunoCyt ⫹ cytology.
Source of Funding: None
Source of Funding: None
1240
Predictors Age
0.31
INTRODUCTION AND OBJECTIVES: It has been suggested that expression of the inflammatory chemokine CCL5 (RANTES; regulated upon activation, normal T-cell expressed and secreted) by tumor cells is associated with tumor progression in several types of cancer. The aim of this study was to determine if RANTES and CCR5, its main receptor, are produced locally in patients with bladder cancer, whether urine RANTES level is a tumor marker, and whether there is a correlation between tumor progression and the expression levels of RANTES or CCR5. METHODS: Urine RANTES level was measured using a sandwich enzyme-linked immunosorbent assay in 84 patients with bladder cancer and 35 healthy control subjects, and CCR5 expression was determined using immunohistochemical staining in paraffin-embedded sections of primary tumors from 39 patients with bladder cancer. Tumors were classified according to CCR5 protein expression levels in both cytoplasm and nucleus. The correlation between clinicopathological variables such as tumor stage/grade and urine RANTES or CCR5 expression level was assessed. RESULTS: The mean urinary RANTES level in patients with bladder cancer was significantly higher than that in healthy control subjects (patients, 63.1 ⫾ 12.7 pg/mL; control subjects, 22.4 ⫾ 3.8 pg/mL; P⬍0.001, Mann-Whitney U test). The AUC-ROC was 0.696 (95%CI: 0.593– 0.799). When the cutoff value was set as 20.0 pg/mL, sensitivity and specificity were 67.5% and 62.9%, respectively. There was a significant correlation between urinary RANTES level and tumor stage (Ta vs T1–2; P⫽0.02), but there was no significant correlation between urinary RANTES level and tumor grade. By immunohistology, there was a statistically significant association between increased CCR5 expression in the cytoplasm of primary bladder tumors and tumor stage or grade. High-grade or high-stage tumors had a significantly higher expression level of CCR5 (grade 1–2 vs grade 3, P⬍0.001; Ta–1 vs T2– 4, P⫽0.01; Mann-Whitney U test). CONCLUSIONS: A high urinary RANTES level may be a candidate novel tumor marker not only for bladder cancer but also for disease progression. Furthermore, increased CCR5 expression in the cytoplasm of bladder cancer cells may be associated with aggressive bladder cancer. Further molecular and clinical studies are warranted to delineate the role of the RANTES/CCR5 system in carcinogenesis of bladder cancer and to apply urine or tissue expression levels as clinical markers.
DIAGNOSTIC, PREDICTIC AND PROGNOSTIC IMPORTANCE OF URINE INTERLEUKIN (IL)8, IL6, IL5 AND IL4 CONCENTRATION IN PATIENTS WITH BLADDER CARCINOMA Radovan Milosevic*, Danilo Vojvodic, Snezana Cerovic, Novak Milovic, Predrag Aleksic, Zoran Campara, Vladimir Bancevic, Mirko Jovanovic, Predrag Maric, Branko Kosevic, Ivica Nikolic, Goran Teodorovic, Aleksandar Spasic, Dejan Simic, Ivan Stanojevic, Zvonko Magic, Ivana Majstorovic, Belgrade, Yugoslavia INTRODUCTION AND OBJECTIVES: The aims of our investigations were to: investigate urine cytokine levels in patients with TCC correlating them to clinical and pathological signs of tumor advances and to find out is it possible for urine cytokine levels to determine prognosis and final outcome of the illnes. METHODS: Naturally, micturated urine samples were obtained from 78 patients (pts). 51 pts have newly diagnosed TCC, and 27 pts did not have any clinical signes of TCC. Patients with TCC were divided