Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer.

BACKGROUND: The first interim analysis of the phase III, randomized, double-blind, placebo-controlled, multinational TITAN study demonstrated improved overall survival (OS) and radiographic progression-free survival (rPFS) with apalutamide added to ongoing androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer. The final analysis confirmed improvement in OS and other long-term outcomes. We evaluated prostate-specific antigen (PSA) kinetics and the association between PSA decline and outcomes in patients with metastatic castration-sensitive prostate cancer from TITAN. PATIENTS AND METHODS: Patients received apalutamide (240 mg/day) or placebo plus ADT (1 : 1). This post hoc exploratory analysis evaluated PSA kinetics and decline in relation to rPFS (22.7 months' follow-up) and OS, time to PSA progression, and time to castration resistance (44.0 months' follow-up) in patients with or without confirmed PSA decline using a landmark analysis, the Kaplan-Meier method, and Cox proportional hazards model. RESULTS: One thousand and fifty-two patients (apalutamide, 525; placebo, 527) were enrolled. Best confirmed PSA declines (≥50% or ≥90% from baseline or to ≤0.2 ng/ml) were achieved at any time during the study in 90%, 73%, and 68% of apalutamide-treated versus 55%, 29%, and 32% of placebo-treated patients, respectively. By 3 months of apalutamide treatment, best deep PSA decline of ≥90% or to ≤0.2 ng/ml occurred in 59% and 51% of apalutamide- and in 13% and 18% of placebo-treated patients, respectively. Achievement of deep PSA decline at landmark 3 months of apalutamide treatment was associated with longer OS [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.25-0.48), rPFS (HR 0.44; 95% CI 0.30-0.65), time to PSA progression (HR 0.31; 95% CI 0.22-0.44), and time to castration resistance (HR 0.38; 95% CI 0.27-0.52) compared with no decline (P < 0.0001 for all). Similar results were observed at landmark 6 and 12 months of apalutamide treatment. CONCLUSIONS: Apalutamide plus ADT demonstrated a robust (rapid, deep, and durable) PSA decline that was associated with improved clinical outcomes, including long-term survival.

Deep learning algorithm performs similarly to radiologists in the assessment of prostate volume on MRI.

OBJECTIVES: Prostate volume (PV) in combination with prostate specific antigen (PSA) yields PSA density which is an increasingly important biomarker. Calculating PV from MRI is a time-consuming, radiologist-dependent task. The aim of this study was to assess whether a deep learning algorithm can replace PI-RADS 2.1 based ellipsoid formula (EF) for calculating PV. METHODS: Eight different measures of PV were retrospectively collected for each of 124 patients who underwent radical prostatectomy and preoperative MRI of the prostate (multicenter and multi-scanner MRI's 1.5 and 3 T). Agreement between volumes obtained from the deep learning algorithm (PVDL) and ellipsoid formula by two radiologists (PVEF1 and PVEF2) was evaluated against the reference standard PV obtained by manual planimetry by an expert radiologist (PVMPE). A sensitivity analysis was performed using a prostatectomy specimen as the reference standard. Inter-reader agreement was evaluated between the radiologists using the ellipsoid formula and between the expert and inexperienced radiologists performing manual planimetry. RESULTS: PVDL showed better agreement and precision than PVEF1 and PVEF2 using the reference standard PVMPE (mean difference [95% limits of agreement] PVDL: -0.33 [-10.80; 10.14], PVEF1: -3.83 [-19.55; 11.89], PVEF2: -3.05 [-18.55; 12.45]) or the PV determined based on specimen weight (PVDL: -4.22 [-22.52; 14.07], PVEF1: -7.89 [-30.50; 14.73], PVEF2: -6.97 [-30.13; 16.18]). Inter-reader agreement was excellent between the two experienced radiologists using the ellipsoid formula and was good between expert and inexperienced radiologists performing manual planimetry. CONCLUSION: Deep learning algorithm performs similarly to radiologists in the assessment of prostate volume on MRI. KEY POINTS: • A commercially available deep learning algorithm performs similarly to radiologists in the assessment of prostate volume on MRI. • The deep-learning algorithm was previously untrained on this heterogenous multicenter day-to-day practice MRI data set.

Risk of hernia formation after radical prostatectomy: a comparison between open and robot-assisted laparoscopic radical prostatectomy within the prospectively controlled LAPPRO trial.

PURPOSE: In addition to incisional hernia, inguinal hernia is a recognized complication to radical retropubic prostatectomy. To compare the risk of developing inguinal and incisional hernias after open radical prostatectomy compared to robot-assisted laparoscopic prostatectomy. METHOD: Patients planned for prostatectomy were enrolled in the prospective, controlled LAPPRO trial between September 2008 and November 2011 at 14 hospitals in Sweden. Information regarding patient characteristics, operative techniques and occurrence of postoperative inguinal and incisional hernia were retrieved using six clinical record forms and four validated questionnaires. RESULTS: 3447 patients operated with radical prostatectomy were analyzed. Within 24 months, 262 patients developed an inguinal hernia, 189 (7.3%) after robot-assisted laparoscopic prostatectomy and 73 (8.4%) after open radical prostatectomy. The relative risk of having an inguinal hernia after robot-assisted laparoscopic prostatectomy was 18% lower compared to open radical retropubic prostatectomy, a non-significant difference. Risk factors for developing an inguinal hernia after prostatectomy were increased age, low BMI and previous hernia repair. The incidence of incisional hernia was low regardless of surgical technique. Limitations are the non-randomised setting. CONCLUSIONS: We found no difference in incidence of inguinal hernia after open retropubic and robot-assisted laparoscopic radical prostatectomy. The low incidence of incisional hernia after both procedures did not allow for statistical analysis. Risk factors for developing an inguinal hernia after prostatectomy were increased age and BMI.

Quality of life with pharmacological treatment in patients with benign prostatic enlargement: results from the Evolution European Prospective Multicenter Multi-National Registry Study.

BACKGROUND: Lower urinary tract symptoms due to benign prostate enlargement (LUTS/BPE) can lead to significant disturbances to health-related quality of life (HRQoL) and psychological well-being. The aim of this study was to evaluate the effect of pharmacological treatment of LUTS/BPE on disease specific and generic QOL measures. METHODS: Evolution was a European prospective, multicenter multi-national, observational registry collecting real-life clinical data over 2 years on the management of LUTS/BPE in primary and secondary care. This study investigated disease-specific QOL using questionnaires such as IPSS Q8, BPH Impact Index (BII) and generic QOL using questionnaires like EuroQOL Five Dimension (EQ5D) which encompassed EQ5D VAS and EQ5D health index. RESULTS: The registry enrolled 1838 BPE patients and 1246 patients were evaluable at the end of 24 months. Nearly 70% of patients in the study were previously treated with medical therapy and 17% of these had already discontinued medical treatment previously for various reasons with lack of efficacy being the most common. The mean time since diagnosis of LUTS in the previously treated group was 4.7 years (0-26 years). Medical management produced statistically significant improvement in QOL (disease specific and generic) in previously untreated patients and an insignificant change in generic QOL in previously treated patients. CONCLUSIONS: After 5-years from the onset of symptoms, LUTS/BPE patients previously treated with medication had significantly impaired QOL in patients in a manner comparable to other chronic diseases. Earlier intervention with minimally invasive surgical techniques (MIT) should be considered in LUTS/BPE patients that do not show a significant improvement in QOL with medical therapy.

Contemporary use of phytotherapy in patients with lower urinary tract symptoms due to benign prostatic hyperplasia: results from the EVOLUTION European registry.

BACKGROUND: To use the European Association of Urology Research Foundation (EAURF) registry data to determine the proportion of contemporary Lower Urinary Tract Symptoms associated with Benign Prostatic Enlargement (LUTS/BPE) patients prescribed phytotherapy, and to determine their subjective quality of life and clinical progression responses. METHODS: This was a prospective multicenter multinational observational registry study, conducted over 2 years. Men ≥ 50 years seeking LUTS/BPE were divided at baseline into two cohorts, presently/recently untreated patients (PUP) commencing pharmacotherapy at baseline and presently/recently treated patients (c-PTP) continuing previously received pharmacotherapy, with 24-month follow-up (FU). RESULTS: Overall, 2175 patients were enrolled with 1838 analyzed. Of the PUP cohort (n = 575), 92 (16%) received phytotherapy and 65 (71%, n = 65/92) completed 24-month FU, with France prescribing 34% (n = 30/89) the highest proportion of phytotherapy among all LUTS/BPE medications. In the c-PTP group (n = 1263), only 69 (5%) patients were using phytotherapy, falling to n = 35/69 (51%) at 24-month FU (highest in France 20% (n = 43/210)). Though defined disease progression occurred in ≤ 20%, with only 1% proceeding to surgical intervention, in both groups, clinically meaningful improvement was lower and symptom persistence was higher in PUP but similar in the treated (c-PTP) patients on phytotherapy compared to the other LUTS/BPE medication. CONCLUSION: Low heterogeneous prescribing rates for phytotherapy were reported in both PUP and c-PTP cohorts over the 24-month FU. Although phytotherapy led to subjective improvements, healthcare practitioners should prescribe them with caution until higher quality evidence and guideline recommendations supporting its use are available.

Medical therapy versus transurethral resection of the prostate (TURP) for the treatment of symptomatic benign prostatic enlargement (BPE): a cost minimisation analysis.

PURPOSE: A cost minimisation analysis compares the costs of different interventions' to ascertain the least expensive over time. We compared different prostate targeted drug treatments with TURP to identify the optimal cost saving duration of a medical therapy for symptomatic benign prostatic enlargement (BPE). METHODS: The Evolution registry is a prospective, multicentre registry, conducted by the European Association of Urology Research Foundation (EAUrf) for 24 months in 5 European countries. Evolution was designed to register the management of symptomatic BPE in clinical practice settings in 5 European countries. Direct cost evaluation associated with prostate targeted medical therapies and TURP was also recorded and analysed. RESULTS: In total, 1838 men were enrolled with 1246 evaluable at 24 months. Medical therapies were more cost saving than TURP for treatment durations ranging from 2.9 to 70.4 years. Cost saving depended on both medication class and individual country assessed. Daily tamsulosin monotherapy was more cost saving than TURP for ≤ 13.9 years in Germany compared to ≤ 32.7 years in Italy. Daily finasteride monotherapy was more cost saving for ≤ 5.9 years in France compared to ≤ 36.9 years in Spain. Combination therapy was more cost saving for ≤ 5.9 years for Italian patients versus ≤ 13.8 years in Germany. CONCLUSIONS: BPE medical management was more cost saving than TURP for different specific treatment durations. Information from this study will allow clinicians to convey medical and surgical costs over time, to both patients and payors alike, when considering BPE treatment.

The tumour suppressor miR-34c targets MET in prostate cancer cells.

BACKGROUND: The microRNA, miR-34c, is a well-established regulator of tumour suppression. It is downregulated in most forms of cancers and inhibits malignant growth by repressing genes involved in processes such as proliferation, anti-apoptosis, stemness, and migration. We have previously reported downregulation and tumour suppressive properties for miR-34c in prostate cancer (PCa). METHODS: In this study, we set out to further characterize the mechanisms by which miR-34c deregulation contributes to PCa progression. The genes regulated by miR-34c in the PCa cell line PC3 were identified by microarray analyses and were found to be enriched in cell death, cell cycle, cellular growth, and cellular movement pathways. One of the identified targets was MET, a receptor tyrosine kinase activated by hepatocyte growth factor, that is crucial for metastatic progression. RESULTS: We confirmed the inhibitory effect of miR-34c on both MET transcript and protein levels. The binding of miR-34c to two binding sites in the 3'-UTR of MET was validated using luciferase reporter assays and target site blockers. The effect of this regulation on the miR-34c inhibition of the migratory phenotype was also confirmed. In addition, a significant inverse correlation between miR-34c expression levels and MET immunostaining was found in PCa patients. CONCLUSION: These findings provide a novel molecular mechanism of MET regulation in PCa and contribute to the increasing evidence that miR-34c has a key tumour suppressive role in PCa.

miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients.

BACKGROUND: The microRNA-205 (miR-205) has been shown to be deregulated in prostate cancer (PCa). Here we continue to investigate the prognostic and therapeutic potential of this microRNA. METHODS: The expression of miR-205 is measured by qRT-PCR and in situ hybridisation in a well-documented PCa cohort. An AGO2-based RIP-Chip assay is used to identify targets that are verified with western blots, luciferase reporter assay, ELISA and immunohistochemistry. RESULTS: The expression of miR-205 is inversely correlated to the occurrence of metastases and shortened overall survival, and is lower in castration-resistant PCa patients. The miR-205 expression is mainly localised to the basal cells of benign prostate tissues. Genes regulated by miR-205 are enriched in, for example, the MAPK/ERK, Toll-like receptor and IL-6 signaling pathways. We demonstrate binding of miR-205 to the 3'UTR of androgen receptor (AR) and decrease of both AR transcript and protein levels. This finding was corroborated in the patient cohort were miR-205 expression inversely correlated to AR immunostaining in malignant prostate cells and to serum levels of prostate-specific antigen, an androgen-regulated protein. CONCLUSION: Taken together, these findings imply that miR-205 might have therapeutic potential, especially for the castration resistant and currently untreatable form of PCa.

A high-density tissue microarray from patients with clinically localized prostate cancer reveals ERG and TATI exclusivity in tumor cells.

BACKGROUND: Prostate cancer (PCa) is characterized by high tumor heterogeneity. In 2005, the fusion between the androgen-regulated gene TMPRSS2 and members of the ETS family was discovered in prostate cancer. In particular, fusion of TMPRSS2 with ERG was found in approximately 50% of prostate cancers and considered as an early event in the onset of the disease. The prognostic value of this fusion is still contradictory. Bioinformatics showed that overexpression of SPINK1 gene in a subset of fusion-gene-negative prostate cancers was associated with a poor prognosis. In theory, overexpression of the tumor-associated trypsin inhibitor (TATI) protein encoded by SPINK1 in fusion-gene-negative tumor cells opens the way to selected treatments for genotypically different cases. However, their expression has never been assessed at the cellular level in the same tissue samples. METHODS: As ERG expression has been shown to be a surrogate of fusion gene occurrence in prostate cancer, we have used double immunohistochemical staining to assess expression of ERG and TATI on a large tissue microarray comprising 4177 cases of localized prostate cancer. RESULTS: We did not detect any co-expression of ERG and TATI in the same cancer cells, which confirms previous suggestions from in silico studies. ERG was associated with Gleason score (GS), surgical margins and pathological stage, but had no prognostic value in this cohort. TATI was weakly associated with pathological stage but had no significant association with outcome. CONCLUSIONS: We here provide a morphological basis for ERG and TATI exclusivity in prostate cancer cells. Future therapies should be based on a combination of different targets in order to eradicate tumor cells with gene fusions and cells expressing other tumor-associated antigens. Further studies are needed to understand why ERG and TATI are not co-expressed in the same prostatic tumor cells.

Expression of Id proteins is regulated by the Bcl-3 proto-oncogene in prostate cancer.

B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. As high levels of Bcl-3 expression and activation have been detected in different types of human cancer, Bcl-3 has been labeled a proto-oncogene. Our study uncovered a markedly upregulated Bcl-3 expression in human prostate cancer (PCa), where inflammatory cell infiltration was observed. Elevated Bcl-3 expression in PCa was dependent on the proinflammatory cytokine interleukin-6-mediated STAT3 activation. Microarray analyses, using Bcl-3 knockdown in PCa cells, identified the inhibitor of DNA-binding (Id) family of helix-loop-helix proteins as potential Bcl-3-regulated genes. Bcl-3 knockdown reduced the abundance of Id-1 and Id-2 proteins and boosted PCa cells to be more receptive to undergoing apoptosis following treatment with anticancer drug. Our data imply that inactivation of Bcl-3 may lead to sensitization of cancer cells to chemotherapeutic drug-induced apoptosis, thus suggesting a potential therapeutic strategy in PCa treatment.

Smoking and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Smoking is not associated with prostate cancer incidence in most studies, but associations between smoking and fatal prostate cancer have been reported. METHODS: During 1992 and 2000, lifestyle information was assessed via questionnaires and personal interview in a cohort of 145,112 European men. Until 2009, 4623 incident cases of prostate cancer were identified, including 1517 cases of low-grade, 396 cases of high grade, 1516 cases of localised, 808 cases of advanced disease, and 432 fatal cases. Multivariable Cox proportional hazards regression models were used to examine the association of smoking status, smoking intensity, and smoking duration with the risk of incident and fatal prostate cancer. RESULTS: Compared with never smokers, current smokers had a reduced risk of prostate cancer (RR=0.90, 95% CI: 0.83-0.97), which was statistically significant for localised and low-grade disease, but not for advanced or high-grade disease. In contrast, heavy smokers (25+ cigarettes per day) and men who had smoked for a long time (40+ years) had a higher risk of prostate cancer death (RR=1.81, 95% CI: 1.11-2.93; RR=1.38, 95% CI: 1.01-1.87, respectively). CONCLUSION: The observation of an increased prostate cancer mortality among heavy smokers confirms the results of previous prospective studies.

Effect of androgen deprivation therapy on the expression of prostate cancer biomarkers MSMB and MSMB-binding protein CRISP3.

We have investigated the effects of short-term neoadjuvant and long-term androgen deprivation therapies (ADTs) on ß-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) expression in prostate cancer patients. We also studied if MSMB expression was related to genotype and epigenetic silencing. Using an Affymetrix cDNA microarray analysis, we investigated the expression of MSMB, CRISP3, androgen receptor (AR), KLK3 and Enhancer of Zeste Homologue-2 (EZH2) in tissue from prostate cancer patients receiving (n=17) or not receiving (n=23) ADT before radical prostatectomy. MSMB, CRISP3 and AR were studied in tissue from the same patients undergoing TURP before and during ADT (n=16). MSMB genotyping of these patients was performed by TaqMan PCR. MSMB and KLK3 expression levels decreased during ADT. Expression levels of AR and CRISP3 were not affected by short-term ADT but were high in castration-resistant prostate cancer (CRPC) and metastases. Levels of EZH2 were also high in metastases, where MSMB was low. Genotyping of the MSMB rs10993994 polymorphism showed that the TT genotype conveys poor MSMB expression. MSMB expression is influenced by androgens, but also by genotype and epigenetic silencing. AR and CRISP3 expression are not influenced by short-term ADT, and high levels were found in CRPC and metastases.

Molecular pathways in the progression of hormone-independent and metastatic prostate cancer.

Once prostate cancer becomes castration resistant, cancer cells may rapidly gain the ability to invade and to metastasize to lymph nodes and distant organs. The progression through hormone-dependent to hormone-independent/castration-resistant and metastatic PCa is poorly understood. In this review paper, we provide an overview on the cellular and molecular mechanisms underlying the process of tumor cell invasion and metastasis in prostate cancer. We specifically present the most recent findings on the role of multiple cellular signaling pathways including androgen receptor (AR), mitogen-activated protein kinases (MAPK), Akt, transforming growth factor b (TGFb interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in the development of hormone-independent/castration-resistant prostate cancer. In addition, we also discuss the recent findings on signatures of gene expression during prostate cancer progression. Our overviews on the novel findings will help to gain better understanding of the complexity of molecular mechanisms that may play an essential role in the development of castration-resistant and metastatic prostate cancer. It will also shed light on the identification of specific targets and the design of effective therapeutic drug candidates.

Biokinetics of 18F-choline studied in four prostate cancer patients.

Biokinetic data are important when calculating the absorbed dose to the patients and can also be used to find the optimal time between injection and imaging. To the authors' knowledge, there are no published biokinetic data in humans for (18)F-choline, except some distribution data at single time points. Four patients with suspicion of metastases due to biochemical recurrence (measurable prostate-specific antigen in plasma) after radical prostatectomy were injected with (18)F-choline. Four whole-body PET/CT images were taken with 1 h interval, starting immediately after injection. Blood samples were taken and all urine was collected for 3.5 h. The corrected decay activity content in the kidneys was 22-37 % higher immediately after injection when compared with the later time points. The highest activity concentration was found in kidneys (43 kBq ml(-1)). The organ with highest activity content was the liver (11 % of injected activity, % IA). Thirty minutes after the injection 4-16 % IA was left in the blood. Less than 9 % IA was excreted with the urine during the first 3.5 h after injection.

A prospective Swedish study on body size, body composition, diabetes, and prostate cancer risk.

Obesity may be associated with increased risk of prostate cancer (PCa). According to one hypothesis, obesity could lower the risk of non-aggressive tumours, while simultaneously increasing the risk of aggressive cancer. Furthermore, central adiposity may be independently associated with PCa risk; it is also associated with diabetes, which itself may influence risk of PCa. We studied the associations between height, body composition, and fat distribution, diabetes prevalence and risk of total, aggressive, and non-aggressive PCa in 10,564 initially cancer-free men (aged 45-73 years) of the population-based Malmö Diet and Cancer cohort. Anthropometric and body composition measurements, including bioelectrical impedance for estimation of fat mass, were performed by study nurses. Diabetes prevalence was self-reported. Cancer cases and clinical characteristics were ascertained through national and regional registry data. Dietary and other background data were obtained through a modified diet history method and an extensive questionnaire. During a mean follow-up of 11.0 years, 817 incidental PCa cases were diagnosed. Of these, 281 were classified as aggressive. There were 202 cases occurring before 65 years of age. Height was positively associated with total and non-aggressive PCa risk. Waist-hip ratio (WHR), a measure of central adiposity, was positively associated with PCa before age 65, and less strongly, with total PCa. This association was independent of body mass index (BMI) and other potential confounders. General adiposity, expressed as BMI or body fat percentage, and prevalent diabetes were not associated with PCa risk. In this study, WHR and body height were stronger PCa predictors than general adiposity.

High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer.

Increased expression of tumour-associated trypsin inhibitor (TATI) in tumour tissue and/or serum has been associated with poor survival in various cancer forms. Moreover, a proinvasive function of TATI has been shown in colon cancer cell lines. In this study, we have examined the prognostic significance of tumour-specific TATI expression in colorectal cancer, assessed by immunohistochemistry (IHC) on tissue microarrays (TMAs) with tumour specimens from two independent patient cohorts. Kaplan-Meier analysis and Cox proportional hazards modelling were used to estimate time to recurrence, disease-free survival and overall survival. In both cohorts, a high (>50% of tumour cells) TATI expression was an independent predictor of a significantly shorter overall survival. In cohort II, in multivariate analysis including age, gender, disease stage, differentiation grade, vascular invasion and carcinoembryonal antigen (CEA), high TATI expression was associated with a significantly decreased overall survival (HR=1.82; 95% CI=1.19-2.79) and disease-free survival (HR=1.56; 95% CI=1.05-2.32) in curatively treated patients. Moreover, there was an increased risk for liver metastasis in both cohorts that remained significant in multivariate analysis in cohort II (HR=2.85; 95% CI=1.43-5.66). In conclusion, high TATI expression is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer.

Differential expression of trypsinogen and tumor-associated trypsin inhibitor (TATI) in bladder cancer.

Tumor-associated trypsin inhibitor (TATI) is a marker of mucinous ovarian carcinoma, but it is also widely expressed in other malignant tumors and normal human tissues. Elevated serum concentrations of TATI are of prognostic value in ovarian, kidney, and bladder cancer. Tumor-associated trypsin is co-expressed with TATI in many malignancies and is thought to be involved in tumor invasion. TATI mRNA has been shown to be overexpressed in bladder cancer. We therefore studied whether trypsinogen expression also can be detected in bladder cancer and how this and TATI expression are associated with the clinicopathological characteristics of the tumors. We used RT-PCR, in situ hybridization and immunohistochemistry to detect trypsinogen- and TATI mRNA and protein in tissue samples from 28 bladder cancer patients and ten benign urothelia. TATI expression was detected in all benign tissues and non-invasive tumors. However, the expression was lower in the muscle-invasive tumors (pT2; n=5), whereas trypsinogen expression was seen in all but one non-invasive tumor. We conclude that trypsinogen is expressed in both malignant and benign bladder epithelium, whereas TATI expression decreases with increasing stage and grade of the tumor. This may suggest that a balanced expression of TATI and trypsinogen is required in normal tissue and that this balance is disrupted during tumor progression.