Type 1 diabetes mellitus and hyperadrenocorticism in a ferret.

Diabetes mellitus (DM) was diagnosed in a 6-year-old neutered male ferret with polyuria/polydipsia, symmetrical alopecia, and weight loss. Laboratory tests revealed severe hyperglycemia, glucosuria, and increased steroid hormone profile. Abdominal ultrasound revealed a bilateral enlargement of the adrenal glands. Significant clinical improvement was achieved with insulin- and leuprolide acetate-based therapy. After 2 months of therapy, the ferret showed a severe ketoacidosis, and the owner decided to euthanize the animal. Histological findings revealed carcinoma of the left adrenal cortex and cortical hyperplasia of the right adrenal gland. Moderate, chronic, and active pancreatitis with a marked decrease in the number of beta-cells was also present. This is the first reported case of type 1 DM associated with hyperadrenocorticism and chronic pancreatitis in a ferret.

Lipido-sterolic extract of Serenoa repens (LSESr, Permixon) treatment affects human prostate cancer cell membrane organization.

The molecular mechanism by which the lipido-sterolic extract of Serenoa repens (LSESr, Permixon) affects prostate cells remains to be fully elucidated. In androgen-independent PC3 prostate cancer cells, the LSESr-induced effects on proliferation and apoptosis were evaluated by counting cells and using a FACScan cytofluorimeter. PC3 cells were stained with JC-1 dye to detect mitochondrial membrane potential. Cell membrane lipid composition was evaluated by thin layer chromatography and gas chromatographic analysis. Akt phosphorylation was analyzed by Western blotting and cellular ultrastructure through electron microscopy. LSESr (12.5 and 25 microg/ml) administration exerted a biphasic action by both inhibiting proliferation and stimulating apoptosis. After 1 h, it caused a marked reduction in the mitochondrial potential, decreased cholesterol content and modified phospholipid composition. A decrease in phosphatidylinositol-4,5-bisphosphate (PIP2) level was coupled with reduced Akt phosphorylation. After 24 h, all of these effects were restored to pre-treatment conditions; however, the saturated (SFA)/unsaturated fatty acid (UFA) ratio increased, mainly due to a significant decrease in omega 6 content. The reduction in cholesterol content could be responsible for both membrane raft disruption and redistribution of signaling complexes, allowing for a decrease of PIP2 levels, reduction of Akt phosphorylation and apoptosis induction. The decrease in omega 6 content appears to be responsible for the prolonged and more consistent increase in the apoptosis rate and inhibition of proliferation observed after 2-3 days of LSESr treatment. In conclusion, LSESr administration results in complex changes in cell membrane organization and fluidity of prostate cancer cells that have progressed to hormone-independent status.

Cancer stem cells in prostate adenocarcinoma: a target for new anticancer strategies.

Prostate cancer (PC) is major common malignancy in males in most industrialized Western countries, where it is the most commonly diagnosed cancer affecting men after middle age (>50 years). Over 90% of PC patients with incurable disease respond to primary treatment, which consists of intervention to lower serum testosterone. However, the duration of response is short (12-33 months) and in almost all patients, is followed by the emergence of a phenotype resistant to androgen deprivation in therapy (known as hormone or androgen-resistant PC). Considerable research efforts have been directed towards the identification of markers associated with the initiation and progression of PC, yet there is little consensus about the target cell within prostate epithelium that is susceptible to malignant transformation. Stem cells may represent a major target for mutations leading to cancer as their longevity assures continued presence during the long latency between carcinogenic agents exposure and cancer development. Therefore in order to allow the development of more effective treatment strategies for PC, a better understanding of the molecular changes that underlie cancer stem cells is required.

A case of human polyomavirus Bk infection in a patient affected by late stage prostate cancer: could viral infection be correlated with cancer progression?

The basic molecular mechanisms regulating prostate cancer (PCA) development and progression are very poorly understood. Different tumor suppressor genes are implicated in PCA. In particular, since the mutation rate of the p53 gene is also low, researchers have speculated that an infectious agent might play an important role in PCA. Polyomaviruses are candidates for this agent. We selected a patient with a diagnosis of PCA and underwent radical prostatectomy, to investigate the presence of polyomavirus BK (BKV) sequences (urine and neoplastic tissues) and the mutation pattern of p53 gene. The results obtained showed the presence of BKV DNA and of p53 gene mutations in exons 6, 8 and 9. We speculate that BKV might contribute to cellular transformation process, triggered possibly by p53 gene mutations.

Prostate--specific G protein couple receptor genes and STAG1/PMEPA1 in peripheral blood from patients with prostatic cancer.

We investigated whether prostate - specific G protein couple receptor genes and STAG1/PMEPA1 gene expression in peripheral- blood could be useful as a diagnostic or prognostic marker of prostate cancer. Circulating cells were identified by reverse transcription-polymerase chain reaction (RT-PCR) to detect PSGR and STAG1/PMEPA1 mRNA in peripheral blood (PB) from 11 patients with treated prostate cancer (CaP), 11 with newly-diagnosed untreated CaP and 20 with benign prostatic hyperplasia (BPH) (controls). RT-PCR amplified PSGR in 8 of 11 untreated and in 9 of 11 treated patients with CaP and in 16 of 20 with BPH; whereas it amplified PMEPA1 in 1 of 11 untreated and in 7 of 11 treated patients with CaP and in 4 of 20 with BPH. In our control tissues and cell lines nearly all the prostatic and non- prostatic tissues and cell lines expressed PSGR mRNA, whereas only one prostatic neoplastic tissue and the androgen-responsive (LNCaP) and androgen non-responsive (PC3) prostatic cell lines expressed PMEPA1. These findings suggest that the investigated genes are poorly specific and probably of little use as diagnostic or prognostic markers in peripheral blood for monitoring prostate cancer progression and recurrence.

New perspective in the management of neuroendocrine differentiation in prostate adenocarcinoma.

In this review, we will present some of the information that is known about neuroendocrine (NE) cells and differentiation in the prostate. We will then speculate on the potential role that NE differentiation in prostate carcinoma may play and how this differentiation may be clinically analysed and treated. The androgen-independent growth of prostate cancer can be caused by different mechanisms; one of these is receptor-specific paracrine or autocrine growth modulation of human prostatic cancer cells by neuropeptides secreted by NE cells. Our results affirm that different methods of androgen deprivation can influence the serum chromogranin A (CgA) levels to different extents in prostate cancer. In particular, bicalutamide produces a significantly lower increase in serum CgA compared with castration therapy. In the light of other evidence that supports a significant relationship between serum CgA levels, tissue CgA expression and NE activity, we hypothesise that bicalutamide may reduce the risk of NE cell hyperactivation in prostate cancer. It is important to determine whether increases in CgA levels and NE cell activation are associated with progression towards hormone-independent prostate cancer. We recently proposed as therapy of NE activation in hormone-independent prostate cancer, a combination of oestrogens and somatostatin analogues. The combination of ethinyl estradiol and lanreotide had a favourable toxicity profile, offered objective and symptomatic responses in patients with limited treatment options and refractoriness to conventional hormonal therapy strategies and, in particular, offered a median overall survival that was superior to the 10-month median survival in patients with hormone refractory disease. This combination therapy also sustains the novel concept in cancer treatment in which therapies may target not only cancer cells but also its microenvironment in combination, which can confer protection from apoptosis.

Preliminary observations on the use of propionyl-L-carnitine in combination with sildenafil in patients with erectile dysfunction and diabetes.

PURPOSE: To investigate the efficacy and tolerability of oral propionyl-L-carnitine (PLC) plus sildenafil in men with erectile dysfunction (ED) and diabetes unresponsive to sildenafil monotherapy. MATERIALS AND METHODS: Patients with medically documented ED of organic or mixed aetiology and diabetes (type 1 and 2) were randomised to receive oral PLC (2 g/day) plus sildenafil (50 mg twice weekly) (20 patients, Group 1) or sildenafil alone (20 patients, Group 2), in a double-blind, fixed-dose study. All patients had been previously treated unsuccessfully with a minimum of eight administrations of sildenafil. Efficacy was evaluated using the International Index of Erectile Function (IIEF) questionnaire: total score, subscores for questions 3 (Q3; achieving an erection) and 4 (Q4; maintaining an erection) and global efficacy question (GEQ: 'Has treatment improved your erections?'). Patients Event Logs were also used. RESULTS: After 24 weeks of treatment, mean scores for IIEF Q3 and Q4 had improved significantly in patients of Group 1 (4.25 +/- 0.63 and 3.95 +/- 1.0) compared with Group 2 (2.9 +/- 0.71 and 2.7 +/- 0.96) (p < 0.01). Moreover, the percentage of patients with improved erections (GEQ 68% vs. 23%) and successful intercourse attempts (76% vs. 34%) was significantly increased in Group 1 compared with Group 2 (p < 0.01). Fourteen (70%) patients in Group 1 and four (20%) in Group 2 reported an increase in mean IIEF EF domain score of > or = 4 (p < 0.01). Treatments were well tolerated and no patient discontinued study medication. Two patients in Group 1 reported mild gastric pain. CONCLUSIONS: Salvage therapy with PLC plus sildenafil was more effective than sildenafil in the treatment of ED in patients with diabetes refractory to sildenafil monotherapy.

Benign prostatic hyperplasia: what about a campaign for prevention?

OBJECTIVES: In an era when prevention is considered better than cure, is there a rationale for benign prostatic hyperplasia (BPH) prevention? MATERIALS AND METHODS: Medline and Current Content databases were searched for studies conduced in the last 10 years on BPH and the feasibility of prevention program. RESULTS: Some important criteria for promoting prevention can be found in BPH disease. The significant impact of BPH on the male population and on its quality of life is well established. Knowledge of the etiopathogenesis of this disease is rapidly improving. However, the use of PSA or other markers to select a population at higher risk for developing BPH and its clinical manifestations needs to be better established. More data are available for secondary prevention against BPH progression. Although the action of some natural and nutritional agents on BPH tissue has been demonstrated experimentally, data from prospective clinical trials are not available. Synthetic agents such as 5alpha-reductase inhibitors or COX-2 inhibitors may be effective, but clinical results for primary prevention of BPH have not been reported. CONCLUSION: At present, we propose a BPH prevention program as a basis for discussion and future work.

Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study with pharmacodynamic evaluation.

OBJECTIVE: To determine, in a phase I trial, the local and systemic toxicity and pharmacodynamics of intravesical gemcitabine in patients with superficial bladder cancer. PATIENTS AND METHODS: Twelve patients with histologically confirmed carcinoma localized to the bladder wall (stage T1 or Ta) resistant to previous administration of anticancer drugs and/or of bacille Calmette-Guérin were enrolled. They initially received intravesical gemcitabine starting at 500 mg and increased in 500 mg increments to 2000 mg. Three patients were treated at each dose level. RESULTS: There was no evidence of systemic toxicity and local toxicity was minimal. A pharmacological evaluation showed that gemcitabine was undetectable in plasma and its inactive metabolite (2',2'-difluorodeoxyuridine) was present at a mean (SD) concentration of 1.39 (1.05) mumol/L Deoxycytidine kinase was present in tumour tissue samples, and its activity was 27.3 (12.6) pmol/h/mg tissue; deoxycytidine deaminase activity varied from undetectable to 616 pmol/h/mg tissue. CONCLUSION: Intravesical gemcitabine appears to be well tolerated with no systemic and minimal local toxicity even at the highest dose (2000 mg). A phase II trial of intravesical gemcitabine at 2000 mg given weekly for six consecutive weeks is now in progress in patients with superficial bladder cancer.

Variation of chromogranin A serum levels after radical retropubic prostatectomy for prostate adenocarcinoma.

This study evaluated perioperative and postoperative variations in serum CgA levels induced by radical retropubic prostatectomy (RRP) and their relationship with serum PSA levels in prostate cancer patients. Thirty consecutive patients with clinically localized adenocarcinoma of the prostate undergoing RRP were prospectively analyzed. Serum levels of CgA and total PSA were analyzed in each case preoperatively (time 0), at removal of the prostate (time 1), 1 h after the end of RRP (time 2) and then at regular postoperative intervals till 12 weeks (time 14). During the postoperative period no adjuvant therapies were performed and none of the 30 cases showed biochemical (PSA > 0.2 ng/mL) and/or clinical progression. Mean preoperative serum levels of CgA were 57 +/- 14 ng/mL. Immediately after the surgical removal of the prostate gland (time 1), in all 30 cases there was a significant (time 0-time 1: p = .001) increase in serum PSA, but a nonsignificant modification in serum CgA levels (60 +/- 15 ng/mL). After time 1, serum PSA levels progressively decreased to below the detection limit of 0.2 ng/mL. On the contrary, at time 2, serum CgA levels were postoperatively increased (time 2 = 145 +/- 47) and they remained significantly higher than preoperative values (time 0) till the 21-day postoperative interval (time 11). Moreover, at the last control (time 14) mean and median CgA levels were very similar to those shown preoperatively (time 14: 58 +/- 18 ng/mL). In patients with untreated clinically localized adenocarcinoma of the prostate submitted to RRP, surgical and postoperative stress, more than surgical manipulation of the prostate gland, could produce a significant increase in serum CgA levels maintained for a longer period when compared to the increase in serum PSA levels.

[Penile metastasis from bladder cancer. A case report]. / Metastasi peniene da tumore vescicale. Un caso clinico.

Penile metastases from bladder cancer are unusual. A case of a man, 50 years old, with undifferentiated bladder carcinoma submitted to radical cystoprostatectomy and ileal conduit is presented. Twelve months after the primary diagnosis the patient presented metastases of the penis.

[Heredity and urologic tumors]. / Ereditarietà e tumori di interesse urologica.

Most human malignant tumours derive from a series of several mutations in cell growth regulatory genes. Neoplastic transformation is a multistep, or at times multigenic event where several mutations must intervene. Hereditary forms have been identified for a number of human neoplasias. In hereditary forms, the individual already inherits one or more of these mutations and assumes an increased risk of developing a specific carcinoma and at an earlier age. On the other hand, in sporadic forms, the risk is lower because the environmental factors must provoke in sequence all the mutations necessary for neoplastic transformation. These genic mutations are often associated with the deletion of oncosuppressor genes which negatively regulate cell proliferation and/or with the hyper-expression and activation of protoncogenes which favour cell proliferation. The products of these genes are often growth factors or receptors of growth factors. The present review analyses the definition and more or less proven identification of familial and hereditary forms in neoplasias of urological interest.

Symptoms, bothersomeness and quality of life in patients with LUTS suggestive of BPH.

The QUIBUS study is the largest investigation ever performed in Italy with an extensive use of the ICS-BPH questionnaire. The internal consistency of each of its three domains was high for ICS-Male (Cronbach's alpha = 0.83 and 0.89 for symptoms and bother, respectively) and lower for ICS-Sex (Cronbach's alpha = 0.63 and 0.75, see a following paper of this issue) and ICS-QoL (Cronbach's alpha = 0.53), as previously reported in the validation study of this tool. Voiding symptoms were more frequently reported, with reduced urinary stream, terminal dribble and incomplete bladder emptying as the most frequently represented. The first storage symptom in the ranking by frequency was 'rush to toilet' (70% of the population), in 7th position; however, the relevant bother was among the highest reported. Items related to urinary incontinence appeared, when present, highly bothersome (87-92% of patients), even though exhibited by a minority of the population (5-34%). The mean (+/-SD) IPSS, calculated on 970 patients, was 15 (+/-7). Two major discrepancies were found in the comparison between IPSS and ICS-Male. First, terminal dribble, which is not considered in the IPSS, is often reported in the ICS-Male. Second, some storage symptoms (nocturia and day-time frequency) are less frequently reported in the ICS-Male than in the IPSS, while being, in general, highly bothersome. As regards QoL, 95% of subjects declared that they would not be completely happy to spend the rest of their life with their actual symptoms (ICS-QoL item 33) and 79% that BPH influences their life from 'a little' to 'a lot' (ICS-QoL item 30). The mean (+/-SD) IPSS-QoL single question score was 3.0 +/- 1.4 (n = 970), and the frequency distribution of scores was equivalent to the one detected by the corresponding question of ICS-QoL (item 33). SF-36, a disease-independent questionnaire about QoL, after a 1-year follow-up is expected to clarify which among the IPSS and ICS-BPH items better describe the impact of BPH on QoL.

Transforming growth factor-beta pathway in human renal cell carcinoma and surrounding normal-appearing renal parenchyma.

OBJECTIVE: To analyze the role of the transforming growth factor (TGF)-beta pathway in renal tumors and to verify whether alterations in TGF-beta 1 pathway expression are associated with the grade of tumor differentiation and pathologic stage in renal cell carcinomas. STUDY DESIGN: The expression of TGF-beta 1 and TGF-beta receptors (T beta RI and T beta RII), SMAD-2 and SMAD-4 was investigated by immunohistochemistry in normal peritumoral and tumoral tissue from 53 renal cell carcinomas (clear cell type). The gene expression of SMAD-2 and SMAD-4 was also studied by reverse transcription polymerase chain reaction (RT-PCR) in normal peritumoral and tumoral tissue from 6 of 56 primary tumors. RESULTS: TGF-beta 1, T beta RI and T beta RII immunoreactivity was more frequent in tumoral than in normal peritumoral renal tissue (96.22%, 79.25% and 75.41% vs. 88.37%, 69.76% and 62.69%), whereas SMAD-2 and SMAD-4 immunoreactivity was more frequent in normal peritumoral than in tumoral tissue (23.25% and 30.23% vs. 15.09% and 7.54%). In tumor areas, immunohistochemical scores were lower for T beta RII than for T beta RI and TGF-beta 1 and higher than SMAD-4 and SMAD-2 scores. TGF-beta 1, T beta RI, T beta RII and SMAD-4 histologic scores correlated with neither the histologic grade of malignancy nor TNM clinical stage, whereas SMAD-2 protein levels were significantly lower in grade 3 than in grade 1 tumors. In the samples of normal kidney and carcinoma studied, RT-PCR detected the correct transcripts for SMAD-2 and SMAD-4, indicating that the RNA of the samples analyzed contained RNA sequences coding for these genes. CONCLUSION: Our data support the concept that the reduction of T beta RII and SMAD proteins in renal cell carcinomas is involved in tumor development and suggest an altered TGF-beta/SMAD signaling pathway in kidney neoplasia.

Regional variations of insulin-like growth factor I (IGF-I), IGF-II, and receptor type I in benign prostatic hyperplasia tissue and their correlation with intraprostatic androgens.

Benign prostatic hyperplasia (BPH) is an androgen-dependent disease; it originates exclusively in the inner prostate, which includes tissue surrounding the urethra. Stromal-epithelial interaction has a pivotal role in the regulation of the development and growth of the prostate, and locally produced peptide growth factors are considered important mediators of this interaction. Insulin-like growth factor I (IGF-I) and IGF-II, acting mainly through type 1 IGF receptor (IGFR1), have mitogenic and antiapoptotic effects on epithelial and stromal prostatic cells. In this study the expression of IGF-I, IGF-II, and IGFR1 messenger ribonucleic acid (mRNA), the immunoreactive content of IGF-I (irIGF-I) and IGF-II (irIGF-II) were determined in periurethral, intermediate, and subcapsular regions of BPH tissue to verify their possible regional variation; a correlation to the tissue levels of dihydrotestosterone (DHT) and 3 alpha-androstanediol (3 alpha Diol) was also determined to verify their possible androgen dependence. Prostates were removed by suprapubic prostatectomy from 14 BPH patients and sectioned in the periurethral, intermediate, and subcapsular regions. Gene expression of IGF-I, IGF-II, and IGFR1 was evaluated by semiquantitative RT-PCR, using beta-actin as a control. irIGF-I was measured by RIA, and irIGF-II was measured by IRMA after acidification and chromatography on Sep-Pak C(18) cartridges. DHT and 3 alpha Diol concentrations were evaluated by RIA after extraction and purification on Celite microcolumns. IGF-II and IGFR1, but not IGF-I, mRNA was higher in the periurethral than in the intermediate (P < 0.05) and subcapsular (P < 0.01) region. Also, prostatic levels of irIGF-II, expressed as picomoles per g tissue, were higher in the periurethral (20.84 +/- 1.84) than in the intermediate (14.81 +/- 2.11; P < 0.05) and subcapsular (10.88 +/- 1.21; P < 0.001) region. No significant differences were found in irIGF-I content. Considering prostatic androgen levels, DHT and 3alphaDiol presented a regional variation, with the highest concentrations in the periurethral region. IGF-II mRNA and irIGF-II levels were positively correlated with both DHT and 3 alpha Diol content. These results demonstrate that in BPH tissue a greater IGF-II activity is present in the periurethral region, the site of origin of BPH. Moreover, we can hypothesize that the tissue androgen content may modulate prostatic production of IGF-II, acting at the transcriptional and probably the posttranscriptional level. Therefore, even though further studies will need to confirm this hypothesis, DHT may increase IGF-II activity, mainly in the periurethral region, which, in turn, induces, through IGFR1, benign proliferation of both epithelial and stromal cells, characteristic of BPH.

Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study.

AIMS: To assess the effects of more than 4 years' treatment with the anti-androgen bicalutamide on human testis by clinical, ultrastructural and morphometric analysis. METHODS AND RESULTS: Two patients (aged 74 and 69 years) with prostate cancer were treated for more than 4 years with bicalutamide 50 mg daily. Clinical characterization and follow-up included luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and prostate-specific antigen (PSA) measurements and clinical response of the tumours. Due to progression of the disease, patients underwent surgical orchidectomy as a further androgen withdrawal therapy. Testis biopsies were studied by light and electron microscopy and analysed by morphometry. Control samples were obtained from the normal testis of two patients with testicular cancer who underwent orchidectomy. Clinical follow-up showed a good response in the control of tumour growth and serum PSA decreased to < 4 ng/mL; concentrations of serum LH, FSH and testosterone were within the normal range. Testicular morphology of treated patients was unexpectedly well preserved; the organization of seminiferous tubules was normal with all the germ line elements and mature spermatozoa present. In some areas, a net increase of peritubular connective tissue was evident which may be a consequence of the age of the patients. CONCLUSIONS: Long-term bicalutamide (50 mg) treatment appears to have very little impact on testis ultrastructure and sperm maturation, while it is effective in the control of androgen-dependent prostatic tumours.

Transforming growth factor beta 1 and androgen receptors in prostate neoplasia.

OBJECTIVE: To investigate the interplay between transforming growth factor (TGF) beta 1, androgen receptors and stromal-epithelial interactions in benign prostatic hyperplasia (BPH), prostate intraepithelial neoplasia (PIN) and prostate carcinoma areas of prostate neoplasia. STUDY DESIGN: In this immunohistochemical study we investigated staining patterns and then determined the correlation between TGF-beta 1 expression and androgen receptor status in the epithelium and stroma of 60 paraffin-embedded tissues from radical prostatectomies. RESULTS: Staining patterns differed in the epithelium and stroma of tumor and peritumor prostatic tissue. TGF-beta 1 immunostaining (H-scores) in the epithelium and stroma increased significantly from BPH to PIN and from BPH to prostate carcinoma in the epithelium (P < .05), whereas androgen receptor (AR) immunoreactivity significantly (P < .05) increased from BPH to PIN to prostatic carcinoma in epithelium and stroma. TGF-beta 1 did not correlate with histologic grade of differentiation, whereas AR proteins were more strongly expressed in Gleason score 5 and 6 than score 7 tumors (P < .05). Nonlinear regression showed a significant correlation (P < .01) between TGF-beta 1 and AR expression only in the stromal compartment of PIN. CONCLUSION: These findings argue in favor of an interaction between TGF-beta 1 and AR in the early stages of prostate carcinogenesis and suggest that TGF-beta 1 plays a central role in stromal-epithelial interactions during the early stages of malignant transformation.

Epidermal growth factor receptor, MUC-1 and MUC-2 in bladder cancer.

The aim of this study was to investigate the immunohistochemical expression of epidermal growth factor receptor (EGFR), mucin-1 (MUC-1) and mucin-2 (MUC-2) proteins in primary bladder carcinomas and to compare EGFR and MUC staining patterns with the histological findings, grade and stage of bladder carcinoma. Fifty-six surgical specimens obtained from superficial and deeply invasive bladder carcinomas were studied. Of the 56 bladder tumors 42 (75%) expressed EGFR, 34 (60.71%) MUC-1 and 15 (26.78%) MUC-2; while 7 tumors (12.5%) coexpressed MUC-1 and MUC-2 proteins. Immunohistochemical scores showed higher levels of EGFR than of MUC-1 (P <0.05) and MUC-2 (P = 0.000) and higher levels of MUC-1 than MUC-2 (P = 0.0010). EGFR and MUC-1 expression was stronger in high-grade tumors (grade 2/3) than in low-grade (grade 1/2) ones (P <0.05) and stronger in muscle invasive tumors (T2-T4) than in superficial (Ta-T1) ones. Linear regression showed a significant (P <0.05) correlation between EGFR and MUC-1 proteins, but no correlation between EGFR and MUC-2 or between MUC-1 and MUC-2. Immunohistochemical expression of EGFR, MUC-1 and MUC-2 increases as primary bladder carcinomas acquire a more aggressive phenotype. Differences in the distribution of EGFR and mucins within the urothelium may be of diagnostic and prognostic value. These antigens may be useful as markers for bladder malignancy.