First time intravesically administered trifunctional antibody catumaxomab in patients with recurrent non-muscle invasive bladder cancer indicates high tolerability and local immunological activity.

Transurethral resection of the tumor (TUR-B) followed by adjuvant intravesical treatment with cytostatic drugs or Bacillus Calmette-Guérin (BCG) as standard therapy of non-muscle-invasive bladder cancer (NMIBC) is associated with a high recurrence rate of about 60-70%, considerable side effects and requires close monitoring. Alternative treatment options are warranted. Two patients with epithelial cell adhesion molecule (EpCAM)-positive recurrent non-muscle invasive bladder cancer were treated the first time by an intravesical administration of the trifunctional bispecific EpCAM targeting antibody catumaxomab (total dosage of 470 and 1120 µg, respectively). The binding and killing activity of catumaxomab in urine milieu was evaluated in vitro. In contrast to its previous systemic application catumaxomab was well tolerated without any obvious signs of toxicity. Relevant cytokine plasma levels were not detected and no significant systemic drug release was observed. The induction of a human anti-mouse-antibody (HAMA) reaction was either absent or untypically weak contrary to the high immunogenicity of intraperitoneal applied catumaxomab. Tumor cells that were detectable in urine patient samples disappeared after catumaxomab therapy. Endoscopically confirmed recurrence-free intervals were 32 and 25 months. Our data suggest that intravesical administration of catumaxomab in NMIBC is feasible, safe and efficacious, thus arguing for further clinical development of catumaxomab in this indication.

Naturally occurring human urinary peptides for use in diagnosis of chronic kidney disease.

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides.

Seminal plasma as a source of prostate cancer peptide biomarker candidates for detection of indolent and advanced disease.

BACKGROUND: Extensive prostate specific antigen screening for prostate cancer generates a high number of unnecessary biopsies and over-treatment due to insufficient differentiation between indolent and aggressive tumours. We hypothesized that seminal plasma is a robust source of novel prostate cancer (PCa) biomarkers with the potential to improve primary diagnosis of and to distinguish advanced from indolent disease. METHODOLOGY/PRINCIPAL FINDINGS: In an open-label case/control study 125 patients (70 PCa, 21 benign prostate hyperplasia, 25 chronic prostatitis, 9 healthy controls) were enrolled in 3 centres. Biomarker panels a) for PCa diagnosis (comparison of PCa patients versus benign controls) and b) for advanced disease (comparison of patients with post surgery Gleason score <7 versus Gleason score >7) were sought. Independent cohorts were used for proteomic biomarker discovery and testing the performance of the identified biomarker profiles. Seminal plasma was profiled using capillary electrophoresis mass spectrometry. Pre-analytical stability and analytical precision of the proteome analysis were determined. Support vector machine learning was used for classification. Stepwise application of two biomarker signatures with 21 and 5 biomarkers provided 83% sensitivity and 67% specificity for PCa detection in a test set of samples. A panel of 11 biomarkers for advanced disease discriminated between patients with Gleason score 7 and organ-confined (

Discovery and validation of urinary biomarkers for prostate cancer.

Only 30% of patients with elevated serum prostate specific antigen (PSA) levels who undergo prostate biopsy are diagnosed with prostate cancer (PCa). Novel methods are needed to reduce the number of unnecessary biopsies. We report on the identification and validation of a panel of 12 novel biomarkers for prostate cancer (PCaP), using CE coupled MS. The biomarkers could be defined by comparing first void urine of 51 men with PCa and 35 with negative prostate biopsy. In contrast, midstream urine samples did not allow the identification of discriminatory molecules, suggesting that prostatic fluids may be the source of the defined biomarkers. Consequently, first void urine samples were tested for sufficient amounts of prostatic fluid, using a prostatic fluid indicative panel ("informative" polypeptide panel; IPP). A combination of IPP and PCaP to predict positive prostate biopsy was evaluated in a blinded prospective study. Two hundred thirteen of 264 samples matched the IPP criterion. PCa was detected with 89% sensitivity, 51% specificity. Including age and percent free PSA to the proteomic signatures resulted in 91% sensitivity, 69% specificity.

A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections.

OBJECTIVE: To investigate the long-term preventive effect of the immunotherapeutic OM-89 versus placebo in uncomplicated recurrent UTI in a large cohort of female patients only. METHODS: Adult female patients could enroll in this multicenter, double-blind study if they had acute UTI at the enrollment visit and positive results of urinalysis (> or =10(3)bacteria/ml). Patients received the immunotherapeutic OM-89 or a matching placebo; 1 capsule per day for 90 days, 3 months without treatment, then the first 10 days in Months 7, 8 and 9 and were followed up during 12 months. Primary efficacy criteria were UTI rates over 12 months, distribution of UTIs and proportion of patients with UTI. RESULTS: A total of 453 patients were treated, 231 in the active group and 222 in the placebo group. Mean rate of post-baseline UTIs was significantly lower in the active group than in the placebo group (0.84 vs. 1.28; p<0.003), corresponding to a 34% reduction of UTIs in patients treated with OM-89. In the active group, 93 patients (40.3%) had 185 post-baseline UTIs, compared to 276 UTIs in 122 patients (55.0%) in the placebo group (p=0.001). The safety profile of OM-89 was good and consistent with that reported in previous studies. CONCLUSIONS: OM-89 significantly reduced the incidence of UTI during the 12 months of the study including 3 months of treatment and three 10-day booster courses. These results confirm that OM-89 is a valuable component of the management of recurrent UTI.