BladMetrix: a novel urine DNA methylation test with high accuracy for detection of bladder cancer in hematuria patients.

BACKGROUND: Cystoscopy is the gold standard for bladder cancer detection, but is costly, invasive and has imperfect diagnostic accuracy. We aimed to identify novel and accurate DNA methylation biomarkers for non-invasive detection of bladder cancer in urine, with the potential to reduce the number of cystoscopies among hematuria patients. RESULTS: Biomarker candidates (n = 32) were identified from methylome sequencing of urological cancer cell lines (n = 16) and subjected to targeted methylation analysis in tissue samples (n = 60). The most promising biomarkers (n = 8) were combined into a panel named BladMetrix. The performance of BladMetrix in urine was assessed in a discovery series (n = 112), consisting of bladder cancer patients, patients with other urological cancers and healthy individuals, resulting in 95.7% sensitivity and 94.7% specificity. BladMetrix was furthermore evaluated in an independent prospective and blinded series of urine from patients with gross hematuria (n = 273), achieving 92.1% sensitivity, 93.3% specificity and a negative predictive value of 98.1%, with the potential to reduce the number of cystoscopies by 56.4%. CONCLUSIONS: We here present BladMetrix, a novel DNA methylation urine test for non-invasive detection of bladder cancer, with high accuracy across tumor grades and stages, and the ability to spare a significant number of cystoscopies among patients with gross hematuria.

Factors Associated With Energy Expenditure and Energy Balance in Acute Sport-Related Concussion.

CONTEXT: Sport-related concussion (SRC) is characterized by a pathologic neurometabolic cascade that results in an increased intracranial energy demand and a decreased energy supply. Little is known about the whole-body energy-related effects of SRC. OBJECTIVE: To examine factors associated with whole-body resting metabolic rate (RMR), total energy expenditure (TEE), energy consumption (EC), and energy balance (EBal) in student-athletes acutely after SRC and healthy matched control individuals. DESIGN: Case-control study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Student-athletes diagnosed with SRC (n = 28, 50% female, age = 18.4 ± 1.8 years, body mass index [BMI] = 24.1 ± 4.1 kg/m2) assessed ≤72 hours postinjury and a matched control group (n = 28, 50% female, age = 19.4 ± 2.9 years, BMI = 24.7 ± 4.78 kg/m2). MAIN OUTCOME MEASURE(S): Resting metabolic rate was measured via indirect calorimetry. Participants reported their physical activity and dietary intake for 3 days, which we used to estimate TEE and EC, respectively, and to calculate EBal (EC:TEE ratio). Resting metabolic rate, TEE, and EC were normalized to body mass. Group and group-by-sex comparisons were conducted for RMR·kg-1, TEE·kg-1, EC·kg-1, and EBal using independent t tests with the a priori α = .05. Associations of age, sex, concussion history, BMI, and symptom burden with RMR·kg-1 and EBal were explored with linear regression models. RESULTS: Total energy expenditure·kg-1 was lower (P < .01; mean difference ± SD = -5.31 ± 1.41 kcal·kg-1) and EBal was higher (P < .01; 0.28 ± 0.10) in SRC participants than in control participants. Both sexes with SRC had lower TEE·kg-1 than did the control participants (P values ≤ .04); females with SRC had higher EBal than controls (P = .01), but male groups did not differ. Higher RMR·kg-1 was associated with history of concussion (adjusted R2 = .10, ß = 0.65). Younger age (ß = -0.35), fewer concussions (ß = -0.35), lower BMI (ß = -0.32), greater symptom duration (ß = 1.50), and lower symptom severity (ß = -1.59) were associated with higher EBal (adjusted R2 = .54). CONCLUSIONS: Total energy expenditure·kg-1 and EBal appeared to be affected by acute SRC, despite no differences in RMR·kg-1. Sex, concussion history, BMI, and symptom burden were associated with acute energy-related outcomes.

A Prospective Blinded Evaluation of Urine-DNA Testing for Detection of Urothelial Bladder Carcinoma in Patients with Gross Hematuria.

Retrospective studies have provided proof of principle that bladder cancer can be detected by testing for the presence of tumor DNA in urine. We have conducted a prospective blinded study to determine whether a urine-based DNA test can replace flexible cystoscopy in the initial assessment of gross hematuria. A total of 475 consecutive patients underwent standard urological examination including flexible cystoscopy and computed tomography urography, and provided urine samples immediately before (n=461) and after (n=444) cystoscopy. Urine cells were collected using a filtration device and tested for eight DNA mutation and methylation biomarkers. Clinical evaluation identified 99 (20.8%) patients with urothelial bladder tumors. With this result as a reference and based on the analysis of all urine samples, the DNA test had a sensitivity of 97.0%, a specificity of 76.9%, a positive predictive value of 52.5%, and a negative predictive value of 99.0%. In three patients with a positive urine-DNA test without clinical evidence of cancer, a tumor was detected at repeat cystoscopy within 16 mo. Our results suggest that urine-DNA testing can be used to identify a large subgroup of patients with gross hematuria in whom cystoscopy is not required. PATIENT SUMMARY: We tested the possibility of using a urine-based DNA test to check for bladder cancer in patients with visible blood in the urine. Our results show that the test efficiently detects bladder cancer and therefore may be used to greatly reduce the number of patients who would need to undergo cystoscopy.

Local involvement of the lower urinary tract in primary colorectal cancer - outcome after en-bloc resection.

UNLABELLED: Invasion of urinary organs due to advanced colorectal cancer can comprise a surgical challenge in achieving negative resection margins. The aim of the study was to asses the outcome of patients with colorectal cancer invading the lower urinary organs. MATERIAL AND METHODS: This is a cohort study that retrospectively evaluated the surgical and pathological findings after the resection of colorectal cancer with adjacent urological organs due to advanced colorectal cancer. Patients with primary colorectal cancer invading urological organs where primary resection was attempted were included. RESULTS: The study included 31 patients who underwent surgery in our department between 1997 and 2012. Median age was 65 years (range 44-77 years). Seventeen patients underwent partial cystectomy, one had partial prostatectomy performed, eight patients underwent cystoprostatectomy, two had cystectomy performed and three had prostatectomy performed. Overall morbidity rate was 71% (95% Confidence Interval (CI): 55-84%, n=22). The 30-day mortality rate was 10% (95% CI: 0-23%, n=3). Twentyseven of 31 patients had free resection margins. Four of 28 patients developed distant metastasis (14%, 95% CI: 4-29%), 11% developed local recurrence (95% CI: 0-25%, n=3). Median follow-up was 41 months (range 0-150 months). Histopathological examination revealed tumour invasion in 52% (95% CI: 35-69%, n=15) of the resected urological organs. The overall five-year survival rate was 70%. The five-year survival rate in the radical resection group was 74%. CONCLUSIONS: En-bloc resection of colorectal cancer with adjacent urological organs has a high morbidity rate. However it is still possible to achieve negative resection margins in most cases.

Use of Artificial Intelligence and Machine Learning Algorithms with Gene Expression Profiling to Predict Recurrent Nonmuscle Invasive Urothelial Carcinoma of the Bladder.

PURPOSE: Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor. MATERIALS AND METHODS: Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction. RESULTS: The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set. CONCLUSIONS: Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management.

Filtration Device for On-Site Collection, Storage and Shipment of Cells from Urine and Its Application to DNA-Based Detection of Bladder Cancer.

Molecular analysis of cells from urine provides a convenient approach to non-invasive detection of bladder cancer. The practical use of urinary cell-based tests is often hampered by difficulties in handling and analyzing large sample volumes, the need for rapid sample processing to avoid degradation of cellular content, and low sensitivity due to a high background of normal cells. We present a filtration device, designed for home or point-of-care use, which enables collection, storage and shipment of urinary cells. A special feature of this device is a removable cartridge housing a membrane filter, which after filtration of urine can be transferred to a storage unit containing an appropriate preserving solution. In spiking experiments, the use of this device provided efficient recovery of bladder cancer cells with elimination of >99% of excess smaller-sized cells. The performance of the device was further evaluated by DNA-based analysis of urinary cells collected from 57 patients subjected to transurethral resection following flexible cystoscopy indicating the presence of a tumor. All samples were tested for FGFR3 mutations and seven DNA methylation markers (BCL2, CCNA1, EOMES, HOXA9, POU4F2, SALL3 and VIM). In the group of patients where a transitional cell tumor was confirmed at histopathological evaluation, urine DNA was positive for one or more markers in 29 out of 31 cases (94%), including 19 with FGFR3 mutation (61%). In the group of patients with benign histopathology, urine DNA was positive for methylation markers in 13 out of 26 cases (50%). Only one patient in this group was positive for a FGFR3 mutation. This patient had a stage Ta tumor resected 6 months later. The ability to easily collect, store and ship diagnostic cells from urine using the presented device may facilitate non-invasive testing for bladder cancer.

Size-based enrichment of exfoliated tumor cells in urine increases the sensitivity for DNA-based detection of bladder cancer.

Bladder cancer is diagnosed by cystoscopy, a costly and invasive procedure that is associated with patient discomfort. Analysis of tumor-specific markers in DNA from sediments of voided urine has the potential for non-invasive detection of bladder cancer; however, the sensitivity is limited by low fractions and small numbers of tumor cells exfoliated into the urine from low-grade tumors. The purpose of this study was to improve the sensitivity for non-invasive detection of bladder cancer by size-based capture and enrichment of tumor cells in urine. In a split-sample set-up, urine from a consecutive series of patients with primary or recurrent bladder tumors (N = 189) was processed by microfiltration using a membrane filter with a defined pore-size, and sedimentation by centrifugation, respectively. DNA from the samples was analyzed for seven bladder tumor-associated methylation markers using MethyLight and pyrosequencing assays. The fraction of tumor-derived DNA was higher in the filter samples than in the corresponding sediments for all markers (p<0.000001). Across all tumor stages, the number of cases positive for one or more markers was 87% in filter samples compared to 80% in the corresponding sediments. The largest increase in sensitivity was achieved in low-grade Ta tumors, with 82 out of 98 cases positive in the filter samples (84%) versus 74 out of 98 in the sediments (75%). Our results show that pre-analytic processing of voided urine by size-based filtration can increase the sensitivity for DNA-based detection of bladder cancer.

Integrated genetic and epigenetic analysis of bladder cancer reveals an additive diagnostic value of FGFR3 mutations and hypermethylation events.

The bladder cancer genome harbors numerous oncogenic mutations and aberrantly methylated gene promoters. The aim of our study was to generate a profile of these alterations and investigate their use as biomarkers in urine sediments for noninvasive detection of bladder cancer. We systematically screened FGFR3, PIK3CA, TP53, HRAS, NRAS and KRAS for mutations and quantitatively assessed the methylation status of APC, ARF, DBC1, INK4A, RARB, RASSF1A, SFRP1, SFRP2, SFRP4, SFRP5 and WIF1 in a prospective series of tumor biopsies (N = 105) and urine samples (N = 113) from 118 bladder tumor patients. We also analyzed urine samples from 33 patients with noncancerous urinary lesions. A total of 95 oncogenic mutations and 189 hypermethylation events were detected in the 105 tumor biopsies. The total panel of markers provided a sensitivity of 93%, whereas mutation and methylation markers alone provided sensitivities of 72% and 70%, respectively. In urine samples, the sensitivity was 70% for all markers, 50% for mutation markers and 52% for methylation markers. FGFR3 mutations occurred more frequently in tumors with no methylation events than in tumors with one or more methylation events (78% vs. 33%; p < 0.0001). FGFR3 mutation in combination with three methylation markers (APC, RASSF1A and SFRP2) provided a sensitivity of 90% in tumors and 62% in urine with 100% specificity. These results suggest an inverse correlation between FGFR3 mutations and hypermethylation events, which may be used to improve noninvasive, DNA-based detection of bladder cancer.

Custom-designed MLPA using multiple short synthetic probes: application to methylation analysis of five promoter CpG islands in tumor and urine specimens from patients with bladder cancer.

Ligation of two oligonucleotide probes hybridized adjacently to a DNA template has been widely used for detection of genome alterations. The multiplex ligation-dependent probe amplification (MLPA) technique allows simultaneous screening of multiple target sequences in a single reaction by using pairs of probes that carry tails for binding of common amplification primers. Resolution of the various targets is achieved by electrophoresis on the basis of predefined differences in amplicon length. In the conventional MLPA approach, one of the two target probes is generated by cloning in a single-stranded bacteriophage vector to introduce a sequence of defined length between the primer binding site and the specific target sequence. Here we demonstrate that differences in amplicon length can be achieved by using multiple short synthetic probes for each target sequence. When joined by a DNA ligase, these probes will form a single amplifiable template whose length is defined by the number and lengths of the individual probes. We have used this principle to establish a methylation-specific MLPA (MS-MLPA) assay that simultaneously determines the methylation status of five promoter CpG islands, and we have used this assay to analyze DNA from tumor tissue and corresponding urine samples from patients with bladder cancer. Our data show that the use of multiple short synthetic probes provides a simple means for custom-designed MS-MLPA analysis.

Predicting recurrence and progression of noninvasive papillary bladder cancer at initial presentation based on quantitative gene expression profiles.

BACKGROUND: Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based on specific tumor biology, are yet to be identified. OBJECTIVE: To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of patients with Ta G2/3 bladder tumors at initial presentation with three distinct clinical outcomes: absence of recurrence (n=16), recurrence without progression (n=16), and progression to carcinoma in situ or invasive disease (n=16). MEASUREMENTS: Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder cancer were quantified by real-time polymerase chain reaction on tumor biopsies from the patients at initial presentation. RESULTS AND LIMITATIONS: CCND3 (p=0.003) and HRAS (p=0.01) were predictive for recurrence by univariate analysis. In a multivariable model based on CCND3 expression, sensitivity and specificity for recurrence were 97% and 63%, respectively. HRAS (p<0.001), E2F1 (p=0.017), BIRC5/Survivin (p=0.038), and VEGFR2 (p=0.047) were predictive for progression by univariate analysis. Multivariable analysis based on HRAS, VEGFR2, and VEGF identified progression with 81% sensitivity and 94% specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed. CONCLUSIONS: Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis. These results could help differentiate between patients who need aggressive versus expectant management.

Radical cystectomy and extended pelvic lymphadenectomy: survival of patients with lymph node metastasis above the bifurcation of the common iliac vessels treated with surgery only.

PURPOSE: We assessed the clinical outcome in patients with invasive bladder cancer and lymph node metastasis above the bifurcation of the common iliac vessels treated with radical cystectomy including extended pelvic lymph node dissection without adjunct therapy. MATERIALS AND METHODS: Between 1993 and June 2005 a total of 336 consecutive patients underwent radical cystectomy and extended pelvic lymphadenectomy without preoperative or postoperative chemotherapy by 1 surgeon. A total of 263 patients (78.3%) had orthotopic bladder reconstruction. The pelvic lymph node dissection began at the distal aorta including the common and external iliac lymph nodes, and the periaortic, presacral and obturator fossa nodes. The lymphatic tissue removed above and below the bifurcation of the common iliac vessels was submitted separately for histopathological analysis. Data were prospectively entered into a database that forms the basis of this cohort study. RESULTS: The 5-year overall and recurrence-free survival rates in the entire study population of 336 patients were 68% and 69%, respectively. Overall 64 patients (19%) had lymph node metastases of whom 22 (34.4%) had lymph node involvement above the bifurcation of the common iliac vessels outside the template of the standard lymph node dissection. The median number of retrieved lymph nodes was 27 (range 7 to 78) and in those with lymph node metastases 27 (range 11 to 49) included 8 (range 0 to 17) above the bifurcation and 18 (range 8 to 41) below the bifurcation of the common iliac vessels in the true pelvis. Lymph node involvement proved a significant adverse prognostic factor with a 5-year probability of survival of 39% vs 76%. The overall 5-year survival rates was similar in patients with lymph node involvement above the bifurcation of the common iliac vessels (37%) compared to the entire population with lymph node metastasis (41%) and to those with lymphatic metastases in the true pelvis below the bifurcation of the common iliac vessels (42%). The survival rate was significantly higher in patients with 5 or less involved lymph nodes (50% vs 13%, p <0.002) and in those with a lymph node density (number of lymph nodes involved/total number of lymph nodes removed) less than 20% (25% vs 47%, p <0.05), but it did not relate to the total number of retrieved lymph nodes. CONCLUSIONS: Overall 34% of our patients with lymph node metastases had nodal involvement in the common iliac, periaortic and presacral regions after radical cystectomy for bladder cancer. Survival was similar in this group of patients with lymphatic metastasis outside the boundaries of the standard pelvic lymph node dissection template compared to the entire population with lymph node metastasis. This finding underscores the contention that extended dissection not only provides the most accurate staging but also offers the patient the best chance of survival. Following radical cystectomy patients can be stratified into risk groups according to tumor stage, lymph node involvement, number of metastatic nodes and lymph node density. Our results support the idea that the benchmark for radical cystectomy should include extensive pelvic lymph node dissection with anatomical boundaries including the common iliac and presacral nodes.

Transitional cell bladder tumor: predicting recurrence and progression by analysis of microsatellite loss of heterozygosity in urine sediment and tumor tissue.

Transitional cell bladder tumors (TCT) is prone to recurrence (60-80%) after tumor resection. Up to 25% of these patients will progress, so it is important to find reliable predictive markers. We analyzed for loss of heterozygosity (LOH) with respect to 13 microsatellites located on 10 different chromosomal arms. This analysis was performed on the urine sediment and tumor tissue from 59 patients with bladder TCT and on the urine and normal-looking mucosa from 25 patients with a history of bladder TCT but no evidence of disease at the time of the study inclusion. The median follow-up period was 23.1 months (range, 2-48 months) for the 59 patients with bladder TCT and 25 months (range, 4-57 months) for the 25 patients without evidence of ongoing active disease. Correlation between LOH and eventual recurrence, progression, and mortality was investigated. In patients with noninvasive TCT, correlation between 11p tumor tissue LOH and recurrence was found. Similarly, 8p LOH in both urine sediment and tumor tissue correlated with progression. Finally, in the group of patients with a history of bladder TCT, normal tissue 8p and/or 11p LOH correlated with recurrence.

Under-representation of bladder transitional cell tumour 9q, 11p and 14q LOH in urine and impact on molecular diagnosis.

BACKGROUND: To investigate whether the recently reported evidence of differences in the overall loss of heterozygosity (LOH) frequency between urine and tumour tissue in patients with transitional cell tumours (TCT) of the urinary bladder involved specific chromosomal sites, and their impact in diagnosis. MATERIALS AND METHODS: Blood, tissue and urine specimens were obtained from 55 patients and 25 controls. Sixteen microsatellites were PCR-amplified and blindly analyzed for LOH through a laser-based capillary electrophoresis system. RESULTS: Significant frequence differences between tumour tissue and urine sediment LOH were found in 9q and 11p in non-invasive disease and 14q in invasive disease. There was no significant difference for all the other chromosomal arms analyzed. CONCLUSION: The contribution in the urine sediment of cells belonging to tumours of the same histological classification differs according to the specific genetic alterations these cells carry. Furthermore, the location regarding these differences could indicate regions involved in tumour exfoliation or apoptosis.

New evaluation of plasma DNA microsatellite analysis in patients with TCC of the urinary bladder.

BACKGROUND: To determine the diagnostic value of plasma DNA microsatellite analysis in patients with transitional cell carcinoma (TCC) of the urinary bladder, by redefining plasma LOH from the equivalent analysis in controls. The method was further tested for MSI (microsatellite instability) and compared with tissue DNA analysis. MATERIALS AND METHODS: Sixteen microsatellites were amplified in leukocyte, plasma and tissue DNA from 40 patients and 28 controls, and analysed in a laser-based, capillary electrophoresis system. Plasma LOH was determined from the controls' cut-off values. RESULTS: The difference between plasma LOH frequency in patients (25% (10/40)) and controls (14% (4/28)) was not significant. Nevertheless, it occurred significantly more often in low rather than high-grade tumors (p=0.03) and controls (p=0.04). Plasma MSI was dependent upon the number of PCR cycles. Tissue LOH was present in 78% (31/40) of the patients and in none of the controls. Tissue MSI was uncommon. CONCLUSION: The results of plasma DNA microsatellite analysis in TCC need cautious interpretation.

Microsatellite analysis of urine sediment versus urine cytology for diagnosing transitional cell tumors of the urinary bladder.

The aim was to evaluate microsatellite analysis of urine sediment (MAUS) as an alternative method to urine cytology for routine diagnosis of patients with transitional cell tumors (TCT) of the urinary bladder. Urine cytology has the advantage of being non-invasive, fast and cheap, but is of limited value because of its low sensitivity. MAUS has previously been found to be a successful alternative method. However, the experimental set-up of such investigations implied exclusion of samples with unfavorable characteristics and use of a large number of markers. In the present study, MAUS was tested on all samples routinely available and a small panel of markers was selected. The urine sediments of 66 TCT patients and 24 controls were analyzed by MAUS with 16 fluorescent markers and by urine cytology. All samples were analyzed, including the ones of later micturition, with gross hematuria, leukocyturia or absence of visible sediment. In patients with tumors of low grade (grades I-II), MAUS was significantly more sensitive than urine cytology. The two methods were of equivalent diagnostic power in high-grade (grades III-IV), high-stage (pT1-pT4) tumors. A panel of the six most informative markers for MAUS was selected. Although MAUS has an advantage over routine cytology in low-grade, low-stage tumors, an overall sensitivity of 45% is not sufficient for routine clinical use.

Microbial flora in ileal and colonic neobladders.

OBJECTIVE: To describe bacterial colonization in patients with ileal and colonic neobladders. METHODS: Twenty-three patients with right colon neobladders, 30 with ileal neobladders, 11 who had undergone radical prostatectomy, and 6 healthy controls were included. Culture of clean-catch, midstream urine specimens was done weekly for 3 weeks, and this was repeated after 6 months. Residual urine was measured, and the patients were interviewed about leakage. All patients and controls were antibiotic free during the study except for 13 of the ileal neobladder patients, who were treated with trimethoprim 100mg daily. RESULTS: Urine cultures from controls and prostatectomy patients were negative for bacteria, whereas 67% of the specimens from patients with neobladders, not on antibiotic therapy, were culture positive, and half of these contained uropathogenic species, such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis. Bacterial colonization (including uropathogenic strains) was strongly correlated with residual urine (p<0.005), but not with leakage. Anaerobic strains were found more frequently (p=0.04) in urine from ileal neobladders than in urine from colonic neobladders. The 13 patients with ileal neobladders and on prophylactic antibiotic therapy carried bacteriuria in 80% of the samples, the majority being anaerobic strains. Uropathogenic strains, mainly Enterecoccus faecalis was revealed in 30% of the samples. CONCLUSIONS: The lower urinary tract of patients with ileal or colonic neobladders is heavily colonized with potentially uropathogenic and anaerobic bacteria. Complete bladder emptying reduces the bacterial burden. Anaerobic colonization is increased in neobladders reconstructed from ileum. Prophylactic antibiotic therapy does not seem to reduce the bacterial burden, but interferes with the bacterial composition.

Relative importance of sources of symptom-induced distress in urinary bladder cancer survivors.

OBJECTIVE: The influence of specific symptoms on emotions and social activities in the individual patient varies. Little is known about this variation in urinary bladder cancer survivors (in other words, about the relative importance of sources of symptom-induced distress). METHODS: We attempted to enroll 404 surgical patients treated with cystectomy and a conduit or reservoir in four Swedish towns (Stockholm, Orebro, Jönköping, Linköping), 101 surgical patients treated with cystectomy and orthotopic neobladder at the Herlev Hospital in Copenhagen, Denmark, and 71 patients treated with radical radiotherapy for bladder cancer, as well as 581 men and women controls in Stockholm and Copenhagen. An anonymous postal questionnaire was used to collect the information. RESULTS: A total of 503 out of 576 (87%) treated patients and 422 out of 581 (73%) controls participated but 59 patients were excluded. The primary source of self-assessed distress among cystectomised patients was compromised sexual function; reduced intercourse frequency caused great distress in 19% of the conduit patients, 20% of the reservoir patients and 19% of the bladder substitute patients. The primary source of self-assessed distress in patients treated with radical radiotherapy was symptoms from the bowel; 17% reported great distress due to diarrhoea, 16% due to abdominal pain, 14% due to defecation urgency and 14% due to faecal leakage. The highest proportion of subjects being distressed was 93% (substantial: 43%, moderate: 29% and little: 21%) for treated upper or lower urinary retention (indwelling catheter or nephrostomy). CONCLUSION: The distress caused by a specific symptom varies considerably and the prevalence of symptoms causing great distress differs between treatments in bladder cancer survivors. It is possible that patient care and clinical research can be made more effective by focusing on important sources of symptom-induced distress.

Neoadjuvant chemotherapy with cisplatin and methotrexate in patients with muscle-invasive bladder tumours.

This prospective, randomized study based on two associated trials was designed to evaluate the effect of neoadjuvant chemotherapy with cisplatin and methotrexate with folinic acid rescue or no chemotherapy prior to local treatment in patients with T2-T4b, NX-3, MO transitional cell carcinoma of the bladder. In the first trial, local treatment consisted of cystectomy (DAVECA 8901) and in the other trial the treatment was radiotherapy (DAVECA 8902); 153 eligible patients were randomized. The majority of the patients (89%) completed the protocol. The overall time to progression for all 153 patients was 12.9 months. Median time to progression was 14.2 months with chemotherapy and 11.4 months without chemotherapy. The actuarial 5-year overall survival rate for all 153 patients was 29%, and 29% for both treatment groups. Multivariate analyses showed that T-stage, tumour size and serum creatinine were independent prognostic factors for survival. The cystectomy trial included 33 patients. Median survival was 78.9 months, 82.5 months with chemotherapy and 45.8 months without chemotherapy (p = 0.76). The radiotherapy trial included 120 patients. The median survival was 17.6 months. Median survival was 19.2 months in the group receiving chemotherapy and 16.3 in the group not receiving chemotherapy. The 5-year survival rate was 19% in the group receiving chemotherapy and 24% in the groups not receiving chemotherapy (p = 0.98). Late toxicity grade 3 or 4 of the bladder was recorded in 25% of the patients (actuarial rate). Neoadjuvant chemotherapy with cisplatin and methotrexate did not significantly improve disease-free or overall survival in 153 randomized patients with invasive bladder cancer.

Distressful symptoms and well-being after radical cystectomy and orthotopic bladder substitution compared with a matched control population.

PURPOSE: We compared subjective quality of life, well-being, urinary tract symptoms and distress in patients after radical cystectomy and orthotopic urinary reconstruction with those in a matched control population. MATERIALS AND METHODS: Included in this study were 101 consecutive recurrence-free patients who underwent radical cystectomy and orthotopic bladder substitution with an ileal urethral Kock neobladder at Herlev Hospital with a minimum followup of 1 year. A frequency matched control group comprising 147 individuals was selected from the same geographical region. Information was collected by an anonymous postal questionnaire and analyzed externally in Sweden. RESULTS: The prevalence of low or moderate psychological well-being (32% versus 36%) and subjective quality of life (30% versus 38%), and high or moderate anxiety (23% versus 18%) and depression (26% versus 37%) was similar in patients with an orthotopic neobladder and population controls. Patients with a neobladder felt as attractive as the control population. Of the operated men 94% had erectile dysfunction compared with 48% of controls. Daytime and nighttime urinary frequency was similar in patients and controls (3% and 3%, and 15% and 13%, respectively), while the prevalence of urinary leakage at least once monthly was higher in patients (18% versus 5%). Intermittent self-catheterization was performed by 26% of patients with a neobladder. Urinary tract infection (14% versus 6%) was more common and the prevalence of distressful bowel symptoms (14% versus 9%) was slightly more common in patients than in controls. CONCLUSIONS: Well-being and subjective quality of life in patients after radical cystectomy and orthotopic bladder substitution were similar to those in a matched control population.