Efficacy of voided urinary cytology and ultrasonography compared to cystoscopy in the detection of urinary bladder cancer

Introduction

Painless hematuria is the presenting symptom in 85–90% of patients with bladder cancer.

荧光原位杂交技术在膀胱肿瘤诊断中的应用

目的：评价荧光原位杂交技术（FISH）在膀胱肿瘤诊断中的应用价值。方法：20例正常人通过FISH技术检测9号染色体P16位点、3号染色体、7号染色体及17号染色体的变异情况,建立阈值。20例血尿患者留取晨尿,分别进行尿脱落细胞学检查和FISH检查。以至少两种探针检测结果超过阈值或一种探针检 测结果至少存在两种异常为诊断阳性。结果：20例血尿患者除1例为泌尿系结石、1例为BPH外,病理检查证实的18例膀胱肿瘤患者中,FISH检出16例,尿脱落细胞学检出4例。结论：FISH无创快速,检出率高,在膀胱肿瘤早期诊断中优于尿脱落细胞学检查方法。     

不同方法留取尿标本在FISH 技术诊断膀胱肿瘤的效果评价

目的 探讨如何留取有效尿标本,行荧光原位杂交(FISH)技术,以提高膀胱肿瘤的诊出率.方法 2009 年4 月至2011 年4 月230 例住院患者行FISH 试验,其中男性210 例,女性20 例,年龄7耀88 岁,平均年龄64.2 岁,随机分组留取尿标本,其中一次性留尿100 例(A 组),分次留尿80 例(B 组),膀胱冲洗留尿50 例(C 组).比较其尿脱落细胞总数超过100 个的比例.结果 采用一次性留尿脱落细胞超过100 个以上占83.0%,采用分次留尿脱落细胞超过100 个以上占62.5%,采用膀胱冲洗留尿脱落细胞超过100 个以上占84.0%.字2 检验提示,三组差异具有统计学意义(字2 =12.464,P=0.002).B 组与C 组有统计学差异(字2 =6.876,P=0.007),A 组与B 组有统计学差异(字2 =9.876,P=0.002).A 组与C 组无统计学差异(字2 =0.024,P=0.538),但膀胱冲洗留尿需要插入尿管及冲洗,为有创伤性方法.结论 FISH 试验是膀胱肿瘤的早期辅助诊断手段,采用一次性留取尿标本脱落细胞数优于其他方法,临床上值得推广.     

荧光原位杂交技术在膀胱移行细胞癌诊断中的应用

目的 应用荧光原位杂交技术对膀胱癌患者尿液中脱落细胞染色体基因异常做出判断,从而探究其在诊断膀胱癌中的应用价值,为膀胱癌患者寻求一种无创的诊断膀胱癌的新方法.方法 应用荧光标记的3、7、17号染色体着丝粒探针及定位于p16基因的探针检测膀胱癌患者尿液中脱落细胞的染色体基因变化,从而对膀胱癌作出诊断,同时将FISH诊断膀胱移行细胞癌敏感性与尿细胞学结果进行比较.结果 FISH和尿细胞学诊断膀胱癌的总敏感性分别为85.5%和34.2%.FISH诊断膀胱癌的总敏感性高于尿细胞学(P<0.05).在肿瘤的各种分期分级中,FISH诊断膀胱癌的敏感性也高于尿细胞学.且FISH敏感性随肿瘤病理级别的增高而增高(P<0.05),但不随肿瘤临床分期的增高而增高(P＞0.05).结论 FISH对于膀胱移行细胞癌的诊断有较高的敏感性,有可能成为在中国人群中检测膀胱移行上皮癌的有效手段.     

荧光原位杂交技术对膀胱癌尿脱落细胞诊断价值的荟萃分析

目的通过荟萃分析比较荧光原位杂交技术（fluorescence in situ hybridization,FISH）和细胞学检测膀胱癌尿脱落细胞的灵敏度和特异度。方法从中国生物医学文献数据库、PubMed等专业数据库中收录的有关FISH、细胞学与膀胱癌尿脱落细胞检测相关分析文献中,纳入符合条件的文献,应用Revman5．0进行荟萃分析。结果HSH用于诊断膀胱癌尿脱落细胞的灵敏度为78．1％（0R值为4．98,95％CJ：3．63～6．83）,显著优于细胞学的46．3％（P〈0．00001）;HSH检查的特异度为93．9％（OR值为0．41,95％CI：0．193-0．930）,稍低于细胞学检查的96．3％（P=0．03）。结论荟萃分析肯定了FISH用于膀胱癌尿脱落细胞检测的价值,其灵敏度高,特异度接近细胞学检查。     

Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer

PURPOSE: The UroVysion fluorescence in situ hybridization assay (UroVysion Bladder Cancer Recurrence Kit, Vysis, Inc., Downers Grove, Illinois) is a multi-target assay that detects aneuploidy of chromosomes 3, 7 and 17, and loss of the 9p21 band in exfoliated cells in urine from patients with transitional cell carcinoma. We performed 2 multicenter trials. In 1 trial we compared the sensitivity of the FISH assay to the BTA Stat test (Bion Scientific, Redmond, Washington) and voided cytology in the detection of transitional cell carcinoma. In a separate study of healthy volunteers and patients with other (nontransitional cell carcinoma) conditions we determined the specificity of the FISH assay. MATERIALS AND METHODS: A total of 176 patients with transitional cell carcinoma in the previous 9 months provided voided urine before cystoscopy. Each specimen was split, preserved and shipped to a central laboratory where all 3 tests were performed. All sites were blinded to results. Sensitivity calculations were based on central pathology review of resected tissue. Specificity was determined by testing 275 volunteers who were healthy and with nontransitional cell carcinoma conditions. RESULTS: The 21 sites enrolled 176 patients with a history of transitional cell carcinoma, with 62 recurrences while undergoing surveillance. Overall sensitivities (with 95% CI) were FISH 71% (95% CI 58 to 82), BTA Stat test 50% (37 to 63) and cytology 26% (16 to 39). FISH was negative in 260 of the 275 healthy volunteers or patients with no history of transitional cell carcinoma (specificity 94.5%). CONCLUSIONS: Sensitivity of the FISH assay is superior to that of cytology and at least equivalent to the BTA Stat test in detecting recurrent transitional cell carcinoma. Its specificity approaches that of cytology. Further testing of its clinical use is warranted.     

荧光原位杂交技术在前列腺癌诊断中的临床应用

目的建立TMPRSS2/ETS(ERG、ETV1、ETV4)融合基因的荧光原位杂交(FISH)检测和评估方法,并探讨其对于前列腺癌的诊断价值。方法对50例前列腺癌样本、15例正常前列腺组织及20例良性前列腺增生样本应用三组国产FISH探针顺序检测TMPRSS2/ERG、TMPRSS2/ETV1及TMPRSS2/ETV4融合基因,建立FISH技术诊断前列腺癌的阈值,并计算敏感性、特异性、阳性预测值(+PV)和阴性预测值(-PV)。结果三组探针的联合敏感性达到90%,其中TMPRSS2-ERG检测敏感性为78%,总体特异性为100%,阳性预测值为100%,阴性预测值为87.5%。结论应用FISH技术检测TMPRSS2/ETS(ERG、ETV1、ETV4)融合基因诊断前列腺癌具有较高的敏感性和特异性,显示出良好的临床应用前景。     

A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine

What's known on the subject? and What does the study add? Multiple studies report on the detection of methylation in voided urine samples as a possible approach for the follow‐up of non‐muscle invasive bladder cancer patients. Previous studies analyze methylation gene panels in a mixture of primary and recurrent tumours. As primary tumours are larger than recurrent tumours and thus easier to detect in urine, validation of methylation markers in urine samples from patients with primary tumours will result in a test sensitivity that does not reflect the true sensitivity of the assay. This study is the first to select a subset of genes specifically methylated in non‐muscle invasive bladder cancer recurrences and validates the gene panel in two independent sets of urine samples from recurrent patients, thus simulating the disease course according to the clinical presentation.

OBJECTIVE

• ? To develop a methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) assay for the detection of non‐muscle invasive bladder cancer (NMIBC) recurrences in voided urine.

PATIENTS AND METHODS

• ? Genes frequently methylated in NMIBC tumours (n= 37) were selected to develop a BC‐specific MS‐MLPA assay.
• ? Genes methylated in blood from patientswith BC (n= 29) and genes methylated in urine from patients with no history of BC (n= 46) were excluded.
• ? A four‐gene panel with the highest predictive value was selected from the initial assay. This four‐gene panel was tested and validated on urine from patients with a histologically confirmed recurrence (n= 68 test set; n= 49 validation set) and urine samples from patients without BC (n= 91, test set) and urine from recurrence‐free BC (rec‐free BC) patients (n= 60, validation set).
• ? A model was developed to predict the probability of having a recurrence based on methylation of the four‐gene panel and a threshold probability with the highest sensitivity and specificity was determined.
• ? The outcome of the model was validated on BC urine samples (n= 65) and on urine samples from rec‐free BC patients (n= 29).

RESULTS

• ? The BC MS‐MLPA assay consisted of 23 methylation probes. The selected four‐gene panel included: APC_a, TERT_a, TERT_b, and EDNRB. This panel reached an area under the receiver operating characteristic curve (AUC) of 0.82 (test set) and AUC 0.69 (validation set). Sensitivity and specificity for the detection of a concomitant tumour were 63.3% and 58.3% respectively (test set) and 72.3% and 55.2%, respectively (validation set).

CONCLUSIONS

• ? We have developed a methylation detection assay specifically for the detection of recurrences in patients with NMIBC in voided urine.
• ? The findings are promising and improvement of this test could eventually contribute to a more individualized patient friendly surveillance.

     

Comparison of the ImmunoCyt test and urinary cytology with other urine tests in the detection and surveillance of bladder cancer

Despite several new urine markers urinary cytology remains the gold standard for the non-invasive detection of bladder carcinoma. The use of monoclonal antibodies against tumor associated antigens offers a promising approach to improve urinary cytology. The aim of this study was to compare fluorescence immunocytology (ImmunoCyt/Ucyt+ test), alone and in combination with the conventional cytology, with other urine markers. Urine samples from 126 patients undergoing cystoscopy were included in the study. Among them, 42 patients had urothelial carcinoma, two dysplasia, two other malignancies, and 78 had no evidence of bladder cancer. Urine samples were taken before any manipulation. We used the ImmunoCyt test and Papanicolaou staining for conventional cytology. The ImmunoCyt slides were examined under a fluorescence microscope. Evaluations of the tests were blinded to clinical and pathological data and were carried out by three independent observers. The results of cytology and ImmunoCyt were compared with the BTAstat, NMP22, Lewis X, 486p3/12, and Urovision tests. The sensitivity for the ImmunoCyt test was 78.3% and for conventional cytology 84.6%. The combination of ImmunoCyt and cytology showed a sensitivity of 89.1%. The specificity was 73.8% for the ImmunoCyt alone, 80.0% for the cytology, and 72.5% for the combination of ImmunoCyt and cytology. Sensitivities for the other tests were 68.8% for (FISH), 66.6% (BTA-Stat), 68.8% (486p3/12), 95.5% (Lewis X), and 71.1% for (NMP22). Specificity was 89.1% for (FISH), 78.2% (BTA-Stat), 76.4% (486p3/12), 32.8% (Lewis X), and 65.5% for (NMP22). Urinary cytology can be improved by immunostaining with monoclonal antibodies against tumor-associated antibodies. The combination of ImmunoCyt with conventional cytology offers a superior sensitivity to other commercial tests. The ImmunoCyt test provides a useful supplement to urinary cytology in the diagnosis of bladder cancer.M.I. Toma, M.G. Friedrich contributed equally to this study     

核基质蛋白22检测与尿脱落细胞学检查在膀胱癌诊断中的价值

目的　探讨尿核基质蛋白 2 2 (NMP 2 2 )检测和尿脱落细胞学检查在膀胱移行细胞癌诊断中的价值。　方法　对 15 5例怀疑膀胱癌者进行尿NMP 2 2与尿细胞学检查 ,其中 95例经组织学证实为膀胱移行细胞癌。比较两者诊断膀胱癌的敏感性和特异性。　结果　尿NMP 2 2的敏感性为6 5 .3%、特异性为 70 .0 % ;尿细胞学的敏感性为 4 3.2 %、特异性为 83.3%。NMP 2 2在膀胱癌不同分级和分期中的敏感性优于尿细胞学 (P <0 .0 5 )。　结论　尿NMP 2 2检测在早期诊断膀胱癌方面优于尿细胞学检查 ,可以作为膀胱癌的早期检测指标。     

Raman molecular imaging: a novel spectroscopic technique for diagnosis of bladder cancer in urine specimens

Background

Raman molecular imaging (RMI) is an optical technology that combines the molecular chemical analysis of Raman spectroscopy with high-definition digital microscopic visualization. This approach permits visualization of the physical architecture and molecular environment of cells in the urine. The Raman spectrum of a cell is a complex product of its chemical bonds.

Objective

In this work, we studied the possibility of using the Raman spectrum of epithelial cells in voided urine for diagnosing urothelial carcinoma (UC).

Design, setting, and participants

Raman signals were obtained from UC tissue, then from UC touch preps obtained from surgical specimens and studied using the FALCON microscope (ChemImage, Pittsburgh, PA, USA), with a ×100 collection objective and green laser illumination (532 nm). Then, urine samples were obtained from 340 patients, including 116 patients without UC, 92 patients with low-grade tumors, and 132 patients with high-grade tumors. Spectra were obtained from an average of five cells per slide.

Measurements

Raman spectroscopy of cells from bladder cancer (BCa) tissues and patients.

Results and limitations

The Raman spectra from UC tissue demonstrate a distinct peak at a 1584 cm⁻¹ wave shift not present in benign tissues. The height of this peak correlated with the tumor's grade. The signal obtained from epithelial cells correctly diagnosed BCa with sensitivity of 92% (100% of the high-grade tumors), specificity of 91%, and a positive predictive value of 94% and a negative predictive value of 88%. The signal correctly assigned a tumor's grade in 73.9% of the low-grade tumors and 98.5% of the high-grade tumors. RMI for diagnosis of BCa is limited by the need for specialized equipment and training of laboratory personnel.

Conclusions

RMI has the potential to become a powerful diagnostic tool that allows noninvasive, accurate diagnosis of UC.     

Multitarget fluorescence in situ hybridization assay detects transitional cell carcinoma in the majority of patients with bladder cancer and atypical or negative urine cytology

PURPOSE: The multitarget fluorescence in situ hybridization (FISH) probe set UroVysion (Vysis, Downers Grove, Illinois), containing probes to chromosomes 3, 7 and 17, and to the 9p21 band, has been recently shown to have high sensitivity and specificity for detecting transitional cell carcinoma. In this study we retrospectively tested 120 urine samples from patients with atypical, suspicious and negative cytology for whom concurrent and followup bladder biopsy data were available. We evaluated the ability of FISH to identify malignant cells in cytologically equivocal or negative cases. MATERIALS AND METHODS: Archived slides from 120 voided (47) or instrumented (73) urine cytology specimens from patients with concurrent bladder biopsy and a minimum of 12 months of biopsy followup were subjected to hybridization with UroVysion. The cohort included patients with biopsy proven transitional cell carcinoma, which was grades 1 to 3 in 23, 35 and 24, respectively, and stages pTis in 3, pTa in 64, pT1 in 6, pT2 in 6 and pT4 in 3, while it showed negative histology in 38. Cytology findings were suspicious, atypical and negative for transitional cell carcinoma in 31, 49 and 40 cases, respectively. A positive FISH result was defined as 5 transitional cells or greater with a gain of 2 or more of chromosomes 3, 7 or 17, 12 cells or greater with 9p21 deletion, or 10% or greater of cells with isolated trisomy of 1 of chromosomes 3, 7 and 17. RESULTS: All except 12 of the 82 biopsy proven transitional cell carcinoma cases (11 pTa and 1 pT1 tumors) were positive by FISH (85% sensitivity). Sensitivity in patients with suspicious, atypical and negative cytology was 100%, 89% and 60%, respectively. Nine patients with atypical cytology had positive FISH in the setting of a negative concurrent bladder biopsy. However, 8 of these 9 patients (89%) had biopsy proven transitional cell carcinoma within 12 months following the date when the sample tested by FISH was obtained. The last of these patients with false-positive results had previously documented pTis disease, which was also present in the next bladder biopsy 15 months following the positive FISH result. The remaining 29 specimens from patients with negative biopsy and a negative 12-month followup tested negative by FISH (97% overall specificity). CONCLUSIONS: The UroVysion FISH assay provides high sensitivity and specificity to detect transitional cell carcinoma in cytologically equivocal and negative urine samples. These results emphasize the important role of this assay in the management of bladder cancer.     

Comparative evaluation of the nuclear matrix protein,fibronectin, urinary bladder cancer antigen and voided urine cytology in the detection of bladder tumors

PURPOSE: We evaluate the diagnostic efficacy of nuclear matrix protein-22 (NMP22, Matritech, Newton, Massachusetts), fibronectin and urinary bladder cancer antigen (UBC, IDL Biotech, Borlange, Sweden) compared with voided urine cytology in the detection of bladder cancer. MATERIALS AND METHODS: A total of 168 patients provided a single voided urine sample for NMP22, fibronectin an ideal monoclonal for urinary bladder cancer and cytology before cystoscopy. Cystoscopy was done for all patients as the reference standard for identification of bladder cancer. Biopsy of any suspicious lesion was performed for histopathological examination. Of the 168 cases 100 were histologically diagnosed as bladder cancer, whereas the remaining 68 had benign urological disorders. A group of 47 healthy volunteers were also enrolled in this study. Voided urine was evaluated by NMP22, fibronectin and UBC, and their values were expressed relative to mg. creatinine. RESULTS: The optimal threshold values for NMP22, fibronectin and UBC were calculated by receiver operator characteristics curves as 27 units per mg. creatinine, 198 mg./mg. creatinine and 13 ng./mg. creatinine, respectively. The levels and positive rates of the 3 parameters were significantly higher in the malignant group compared to either the benign group or normal controls. Of the entire group NMP22, fibronectin and UBC were positive in 93.2%, 91% and 68.2%, respectively in bladder cancer cases with positive cytology. Moreover, these positive rates were significantly higher in bilharzial bladder cancer cases (58.8%, 67.5%, 58.8%, respectively) compared to nonbilharzial cases (35.6%, 36.3%, 31.1%). Overall sensitivity and specificity were 85% and 91.3% for NMP22, 83% and 82.6% for fibronectin, 67% and 80.8% for UBC and 44% and 100% for voided urine cytology. Combined sensitivity of voided urine cytology with the 3 biomarkers together was higher than either combined sensitivity of voided urine cytology with 1 of the biomarkers or than that of the biomarker alone. CONCLUSIONS: Our data indicate that NMP22 and fibronectin had superior sensitivities compared to UBC and voided urine cytology, while NMP22 and voided urine cytology had the highest specificities. The combined use of markers increased the sensitivity of cytology from 44% to 95.3%. The higher sensitivities of markers in bilharzial than nonbilharzial bladder cancer highlight their clinical use in screening patients with urinary bilharziasis.     

17号染色体数目异常在预测浅表性膀胱癌复发中的研究

目的：探讨17号染色体数目异常在预测浅表性膀胱癌复发中的作用。方法：取随访3年经病理检查证实的25例复发性和15例未复发性浅表性膀胱癌石蜡切片标本,应用17号染色体特异性荧光探针行荧光原位杂交（Fluorescence in situ hybridization．FISH）分析。结果：复发性膀胱癌中17号染色体数目异常19例,明显高于未复发组3例异常患者（P〈0．05）．6例单倍体全部复发,17号染色体数目异常与膀胱癌的进展无相关性（P〉0．05）,其无病生存时间较17号染色体正常患者明显缩短（P〈0．05）．17号染色体数目异常者复发的可能性是17号染色体正常的3．07倍。结论：17号染色体数日异常与浅表性膀胱癌复发有关,可以作为预测浅表性膀胱癌术后复发的有用指标。     

尿脱落细胞黏蛋白7 mRNA检测在膀胱癌诊断中的价值

目的 探讨尿脱落细胞黏蛋白7(Muc 7)mRNA检测在膀胱尿路上皮癌诊断中的价值.方法 采用RT-PCR方法检测52例膀胱癌患者和34例泌尿系非肿瘤患者尿脱落细胞中Muc7 mRNA表达情况,同时行尿细胞学检查,比较两种方法诊断膀胱癌的敏感性和特异性.膀胱癌患者52例,男30例,女22例.年龄41～87岁,平均65岁.TNM分期:Ta 1例、T1 22例、≥T2 29例.WHO分级:G1 18例、G2 14例、G3 20例.泌尿系非肿瘤患者34例,男23例,女11例.年龄30～75岁,平均58岁.结果 52例膀胱癌患者中Muc 7 mRNA检测阳性44例,敏感性为84.6%;34例非泌尿系肿瘤患者Muc 7 mRNA阴性29例、假阳性5例,特异性为85.2%,假阳性率为14.7%.膀胱癌患者尿脱落细胞检测阳性18例,敏感性为34.6%;非泌尿系肿瘤患者尿脱落细胞检测阴性31例、假阳性3例,特异性为91.2%,假阳性率为8.8%.尿Muc 7 mRNA检测诊断膀胱癌的敏感性优于尿脱落细胞学检查,差异有统计学意义(P<0.01);2种检测方法特异性及假阳性率比较,差异均无统计学意义(P>0.05).结论 尿Muc 7 mRNA检测诊断膀胱尿路上皮癌的敏感性优于尿脱落细胞学检查,可以作为膀胱癌的辅助检测指标.     

荧光原位杂交技术尿脱落细胞检测在上尿路尿路上皮细胞癌诊断中的应用价值

目的 探讨荧光原位杂交技术( FISH)尿脱落细胞检测在上尿路尿路上皮细胞癌诊断中的应用价值.方法 病理诊断为上尿路尿路上皮细胞癌患者30例,留取新鲜晨尿,行FISH和尿脱落细胞学检查,并行多层螺旋CT和彩色多普勒超声检查;留取20例肾癌、6例输尿管结石和4例输尿管狭窄患者的尿液作对照,统计学分析FISH和尿脱落细胞学检查诊断的特征值.结果 FISH、尿脱落细胞学、CT和超声检查诊断上尿路尿路上皮细胞癌的敏感性分别为87％( 26/30)、37％(11/30)、90％(27/30)和43％ (13/30),FISH和CT诊断敏感性差异无统计学意义(P＞0.05),但明显高于超声和尿脱落细胞学检查(P＜0.05);FISH和尿脱落细胞学检查诊断的特异性分别为97％(29/30)和93％ (28/30),二者比较差异无统计学意义(P＞0.05).FISH和尿脱落细胞学检查阳性预测值分别为96％(26/27)和85％ (11/13),阴性预测值分别为88％(29/33)和60％( 28/47).结论 FISH诊断上尿路尿路上皮细胞癌具有较高的敏感性、特异性、阳性预测值和阴性预测值,可作为上尿路尿路上皮细胞癌诊断和术后随访检查的有效方法.     

荧光原位杂交技术在尿路上皮癌诊断中的应用

目的 探讨荧光原位杂交技术( FISH)在尿路上皮癌诊断中的应用价值.方法 采用FISH检测100例血尿患者尿脱落细胞中第3、7、17号染色体和第9号染色体p16位点异常,以组织病理学确诊尿路上皮癌为金标准,评估FISH诊断的敏感度和特异度,并与尿细胞学检查结果进行比较.结果 FISH检测和尿细胞学检查诊断尿路上皮癌的敏感度分别为82.5％和49.2％, 差异有统计学意义(P＜0.05);特异度分别为86.7％和96.6％,差异无统计学意义(P＞0.05).结论 与尿细胞学比较,FISH诊断尿路上皮癌具有较高的敏感度和相似的特异度.     

Urine-TPA (Tissue Polypeptide Antigen), flowcytometry and cytology as markers for tumor invasiveness in urinary bladder carcinoma

Summary Urine-Tissue Polypeptide Antigen (U-TPA) was measured in 81 patients with a previously diagnosed bladder carcinoma. U-TPA was elevated in 74% of the patients with invasive bladder cancer as compared to only 15% of the patients with superficial tumors. Only one patient without a tumor recurrence had an elevated U-TPA level (4%). The results were compared with cytological grading and flow-DNA measurements in a multivariate analysis with T-category as the result variable. U-TPA and grade showed each, independently, a significant relation (P0,001) to T-category whereas the result of the DNA measurements did not explain the variation in T-category when U-TPA and grade were already in the equation. For diagnostic purposes U-TPA seems to be of limited value but may serve as an indicator of tumor recurrence in bladder cancer patients.Supported by the Maud & Birger Gustavssons Foundation