Tumor heterogeneity of fibroblast growth factor receptor 3 (FGFR3) mutations in invasive bladder cancer: implications for perioperative anti-FGFR3 treatment.

BACKGROUND: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. PATIENTS AND METHODS: We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201). RESULTS: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type. CONCLUSIONS: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting.

Angiosarcoma of the prostate: a more frequent finding in the future owing to radiotherapy? A literature review with treatment implications based on a case report.

OBJECTIVE: An increase in the incidence of prostate angiosarcoma may be expected owing to the exponential increase in the use of radiotherapy for prostate carcinoma in recent decades and the possible aetiology of radiation exposure on the development of angiosarcoma in general. The objective of this study was to give an overview of cases in the literature based on a case report of prostate angiosarcoma in a hospital in the Netherlands, and to discuss optimal treatment. MATERIAL AND METHODS: All (related) articles In PubMed/Medline and Embase with possible cases of angiosarcoma were screened on title and abstract. A case of prostate angiosarcoma identified in the authors' institution was included. RESULTS: The literature search yielded 13 cases of prostate angiosarcoma. The earliest six publications lack essential data. Four patients had a history of radiotherapy. The present patient developed angiosarcoma following brachytherapy for prostate cancer. Therapy consisted of radical surgery with or without chemotherapy in five cases. In eight cases curative therapy was not reported or not possible. Mean follow-up was only 1 year. Four patients died within 1 year of diagnosis, irrespective of treatment choice. One patient, treated with a combination of radical surgery and adjuvant chemotherapy, was still alive 36 months after therapy. CONCLUSIONS: The findings confirm that prostate angiosarcoma is mostly radiation induced. This patient is the first case of prostate angiosarcoma after primary brachytherapy. Angiosarcoma may occur more often in the future owing to widespread use of brachytherapy and radiotherapy of the prostate. Current guidelines on management of angiosarcoma suggest radical surgery in local disease as the primary treatment of choice.

Should follow-up biopsies for men on active surveillance for prostate cancer be restricted to limited templates?

OBJECTIVE: To investigate if prostate biopsy templates with fewer cores can be used during active surveillance (AS) for prostate cancer. METHODS: At present, we use an AS protocol template (ASPT) consisting of 13-17 cores. We hypothesize in the setting of known cancer, sextant (6 cores) or standard extended (10-12 cores) templates, could be used with similar effect. We identified patients in our referral institution database (1997-2009) with entry prostate-specific antigen <10 ng/mL, stage ≤cT2, Gleason sum ≤6, ≤3 cores positive for cancer, <50% of single core involved, and age ≤75 years (N = 272). Patients fulfilling standard criteria for pathologic reclassification (N = 94) at any follow-up biopsy were selected for evaluation. By mapping tumor location on the pathologic reclassification determining biopsy, hypothetical scenarios of sextant or standard extended templates (SET) were compared with our ASPT and examined for frequency of cancer detection and pathologic reclassification. RESULTS: For the 94 patients analyzed, the median number of cores taken was 9.7 (6-22) at baseline and 15 (14-17) for the reclassification biopsy. The median time between baseline and the pathologic reclassification determining biopsy was 15.4 months. Analysis of subgroupings showed that sextant template would identify 84% of cancers and 47.9% of the reclassification events, whereas SET detected 99% of cancers and 81.9% of patients who pathologically reclassified. When only considering Gleason sum ≥7 related progression events, SET found 16.2% less (n = 57) compared with ASPT (n = 68). CONCLUSION: When monitoring patients on AS, a 13-17 core template detects more pathologic reclassification than standard sextant (18.1%) or extended (52.1%) biopsy templates.

Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer.

PURPOSE: High intensity focused ultrasound for the treatment of primary prostate cancer is increasing in a subset of men seeking definitive treatment with reduced morbidity. We review outcomes in men undergoing salvage radical prostatectomy after failed whole gland high intensity focused ultrasound. MATERIALS AND METHODS: Prospective data were collected for men presenting with an increasing prostate specific antigen and biopsy proven prostate cancer after high intensity focused ultrasound from 2007 to 2010 who underwent salvage open radical prostatectomy with a 22-month median followup, including prostate specific antigen, prostate volume, pathology results, continence and erectile function. RESULTS: Data for 15 men were available, including median age 64 years (IQR 55-69), Gleason score before high intensity focused ultrasound of 6 (8), Gleason score 7 (7), median cores positive 39% (IQR 17%-63%) and median prostate specific antigen 7 ng/ml (IQR 5-8). Whole gland high intensity focused ultrasound achieved median nadir prostate specific antigen 1.1 ng/ml (IQR 0.5-3.1). Biopsy after high intensity focused ultrasound demonstrated Gleason score 6 (in 3 patients), 7 (9) and 8/9 (3), and 42% (IQR 25%-50%) cores positive and a median time from high intensity focused ultrasound to radical prostatectomy of 22 months (IQR 7-26). Perioperative morbidity was limited to 1 transfusion in a patient with a rectal injury. Pathologically extensive periprostatic fibrosis was found with persistent prostate cancer, as pT3 disease (in 9 of 14), Gleason scores 6 (2), 7 (9) and 8 of 9 (4), with focally positive margins in 3 of 11 (pT3a). Postoperative prostate specific antigen was unrecordable in 14 of 15 patients with further treatment in 2. Postoperative continence (more than 12 months of followup) yielded no pad use in 6 of 10 men with universally poor erectile function. CONCLUSIONS: Radical prostatectomy as salvage is feasible for men in whom high intensity focused ultrasound failed, but with a higher morbidity than for primary surgery. Pathology results are alarming given the number of cases with extraprostatic extension yet early followup data suggest acceptable oncologic control. These results should be factored in when counseling men who wish to undergo primary high intensity focused ultrasound.

Prostate cancer: trends in incidence, survival and mortality in the Netherlands, 1989-2006.

BACKGROUND: Prostate cancer occurrence and stage distribution changed dramatically during the end of the 20th century. This study aimed to quantify and explain trends in incidence, stage distribution, survival and mortality in the Netherlands between 1989 and 2006. METHODS: Population-based data from the nationwide Netherlands Cancer Registry and Causes of Death Registry were used. Annual incidence and mortality rates were calculated and age-adjusted to the European Standard Population. Trends in rates were evaluated by age, clinical stage and differentiation grade. RESULTS: 120,965 men were newly diagnosed with prostate cancer between 1989 and 2006. Age-adjusted incidence rates increased from 63 to 104 per 100,000 person-years in this period. Two periods of increasing incidence rates could be distinguished with increases predominantly in cT2-tumours between 1989 and 1995 and predominantly in cT1c-tumours since 2001. cT4/N+/M+-tumour incidence rates decreased from 23 in 1993 to 18 in 2006. The trend towards earlier detection was accompanied by a lower mean age at diagnosis (from 74 in 1989 to 70 in 2006), increased frequency of treatment with curative intent and improved 5-year relative survival. Mortality rates decreased from 34 in 1996 to 26 in 2007. CONCLUSIONS: The increase of prostate cancer incidence in the early 1990s was probably caused by increased prostate cancer awareness combined with diagnostic improvements (transrectal ultrasound, (thin) needle biopsies), but not PSA testing. The subsequent peak since 2001 is probably attributable to PSA testing. The decline in prostate cancer mortality from 1996 onwards may be the consequence of increased detection of cT2-tumours between 1989 and 1995. Unfortunately, data on the use of PSA tests and other prostate cancer diagnostics to support these conclusions are lacking.

Unsupervised segmentation of the prostate using MR images based on level set with a shape prior.

Prostate cancer is the second leading cause of cancer death in American men. Current prostate MRI can benefit from automated tumor localization to help guide biopsy, radiotherapy and surgical planning. An important step of automated prostate cancer localization is the segmentation of the prostate. In this paper, we propose a fully automatic method for the segmentation of the prostate. We firstly apply a deformable ellipse model to find an ellipse that best fits the prostate shape. Then, this ellipse is used to initiate the level set and constrain the level set evolution with a shape penalty term. Finally, certain post processing methods are applied to refine the prostate boundaries. We apply the proposed method to real diffusion-weighted (DWI) MRI images data to test the performance. Our results show that accurate segmentation can be obtained with the proposed method compared to human readers.

My approach to intraductal lesions of the prostate gland.

The morphologically heterogeneous (intra)ductal lesions of the prostate frequently present a diagnostic challenge, particularly when found within prostate needle biopsies. By current convention, all high-grade intra-acinar and intraductal neoplastic lesions of prostatic origin fall under the diagnostic umbrella term: prostatic intraepithelial neoplasm (PIN). Although a long-standing contentious issue, some lesions currently adhering to the diagnostic criteria of PIN may actually represent the intraductal spread of (generally high grade) invasive cancer. Illustrating this fact, the well-described ductal subtype of prostatic adenocarcinoma is frequently associated with conventional-type acinar adenocarcinoma, and has a tendency to propagate within adjacent intact prostatic ducts. Clearly, the misdiagnosis of lesions representing invasive disease as preinvasive has the potential for unfavourable clinical sequelae. As yet, however, many of these lesions have escaped the establishment of reliable morphologic criteria or immunohistochemical differentiation for diagnosis. By defining stringent architectural and cytonuclear features specific for each of these lesions, it may be feasible to separate potentially sinister lesions from the subset of traditional (preinvasive) PIN lesions with limited clinical urgency. This review discusses the (intra)ductal lesions of the prostate, along with their differential diagnoses. Given the current state of knowledge, a pragmatic approach to their effective reporting is outlined, taking into consideration the clinical implications, as well as current guidelines for treatment and follow-up.

Prediction of indolent prostate cancer: validation and updating of a prognostic nomogram.

PURPOSE: Screening with serum prostate specific antigen testing leads to the detection of many prostate cancers early in their natural history. Statistical models have been proposed to predict indolent cancer. We validated and updated model predictions for a screening setting. MATERIALS AND METHODS: We selected 247 patients with clinical stage T1C or T2A from the European Randomized Study on Screening for Prostate Cancer who were treated with radical prostatectomy. We validated a nomogram that had previously been developed in a clinical setting. Predictive characteristics were serum prostate specific antigen, ultrasound prostate volume, clinical stage, prostate biopsy Gleason grade, and total length of cancer and noncancer tissue in biopsy cores. Indolent cancer was defined as pathologically organ confined cancer 0.5 cc or less in volume without poorly differentiated elements. Logistic regression was used to update the previous model and examine the contribution of other potential predictors. RESULTS: Overall 121 of 247 patients (49%) had indolent cancer, while the average predicted probability was around 20% (p <0.001). Effects of individual variables were similar to those found before and discriminative ability was adequate (AUC 0.76). An updated model was constructed, which merely recalibrated the nomogram and did not apply additional predictors. CONCLUSIONS: Prostate cancers identified in a screening setting have a substantially higher likelihood of being indolent than those predicted by a previously proposed nomogram. However, an updated model can support patients and clinicians when the various treatment options for prostate cancer are considered.

Tumor characteristics and prognostic factors in two subsequent screening rounds with four-year interval within prostate cancer screening trial, ERSPC Rotterdam.

OBJECTIVES: To evaluate the tumor characteristics and prognostic factors in screen-detected prostate cancers in two successive screening rounds with a 4-year screening interval in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam. METHODS: From 1993 to 2000, 42,376 men (21,210 in the screening arm and 21,166 in the control arm) were randomized and screened. Prostate-specific antigen testing, digital rectal examination, transrectal ultrasonography, and sextant biopsies were offered to the participants in the screening arm. A total of 1218 men with a biopsy indication at the first screening received an additional screening after 1 year (early recall). By 2004, all men had received their second screening. Interval carcinomas were defined as cancers detected during the screening interval and were identified by linkage with the Cancer Registry. RESULTS: In the first round, 1014 prostate cancers were detected--24 in the men noncompliant to screening, 63 at the early recall screening, and 433 in the second round of screening. Also, 62 interval carcinomas were diagnosed. In the second screening round, the mean prostate-specific antigen value was lower (5.6 versus 11.1 ng/mL), advanced clinical stage T3-T4 was 7.1-fold less common, and 76.4% versus 61.5% of the biopsy Gleason scores were less than 7. In the first screening round, 13 regional and 9 distant metastases were detected; in the second round, 2 cases with distant metastasis were found. CONCLUSIONS: Overall, a shift toward more favorable tumor characteristics was seen for the second round of screening. These results support the screening methods used and the interscreening interval of 4 years.

The high post-test probability of a cytological examination renders further investigations to establish a diagnosis of epithelial malignant pleural mesothelioma redundant.

The aim of the study was to establish in a prospective and blinded manner the diagnostic yield of morphology, immunocytochemistry (ICH) and electron microscopy (EM) in the cytological analysis of malignant pleural mesothelioma (MPM). Pleural fluid from consecutive patients, 14 with a histologically proven MPM, 12 with a malignant pleuritis due to adenocarcinoma (AC), and 13 with a reactive pleural effusion (RM), was separately analyzed. Smears were incubated with monoclonal antibodies (Tag72, Ber-Ep4, anti-CEA, EMA). These were considered suggestive for MPM when only EMA stained positive, for AC when three out of four markers stained positive, and for RM when no marker stained positive. The post-test probability of the morphological, ICH, and EM analysis were 92, 100, 92% or MPM, 91, 100, 86% for AC, and 88, 88, 90% for RM, respectively. We concluded that the high post-test probability of a combined morphological and ICH diagnosis of MPM warrants to cease further diagnostic procedures in these patients. Electron microscopy did not add to accuracy of diagnosis.

The PTEN gene in locally progressive prostate cancer is preferentially inactivated by bi-allelic gene deletion.

PTEN is frequently inactivated during the development of many cancers, including prostate cancer, and both bi-allelic and mono-allelic PTEN inactivation may contribute to tumorigenesis. PTEN mutations in clinical cancer specimens can easily be recorded but mono- or bi-allelic gene deletions are often difficult to assess. We performed a comprehensive study to detect PTEN inactivation in 40 locally progressive clinical prostate cancer specimens obtained by transurethral resection of the prostate, utilizing a variety of complementary technical approaches. The methods to detect PTEN deletion included allelotype analysis, dual-colour FISH and array-based CGH. We also applied a novel semi-quantitative approach, assessing the PTEN-WT (wild-type): PTEN-Psi (pseudogene) ratio (WPR). Structural analysis of PTEN was performed by single-strand conformational polymorphism (PCR-SSCP) and sequencing. PTEN protein expression was assessed by immunohistochemistry. Our data predict complete PTEN inactivation in 12 samples (30%), nine of these by bi-allelic deletion. Loss of one PTEN copy was also detected by several methodologies but the number could not be accurately assessed. Immunohistochemistry indicated the absence of PTEN protein in 15 samples, and heterogeneous expression of the protein in eight tumours. Taken together, these data show that bi-allelic deletion is a major mechanism of PTEN inactivation in locally progressive prostate cancer.

Virus specific immune responses after human neoadjuvant adenovirus-mediated suicide gene therapy for prostate cancer.

PURPOSE: Neoadjuvant gene therapy potentially improves the outcome of primary treatment of prostate cancer by radical prostatectomy in patients with high risk of recurrence. We conducted a Phase I escalating dose study with a replication-defective adenovirus expressing the herpes simplex virus-thymidine kinase gene (Adv-HSV-tk vector). The primary end point was toxicity, while the evaluation of the patients' cellular and humoral immune responses served as a secondary endpoint. MATERIAL AND METHODS: The Adv-HSV-tk vector was injected into the prostate in two doses (2x10(10) to 2x10(11) viral particles), followed by ganciclovir twice daily for 14 days and retropubic radical prostatectomy on day 21. Adenovirus-specific neutralizing, IgG and IgA antibodies were evaluated. Peripheral blood mononuclear cells (PBMC) were stimulated by Adv-HSV-tk and analysed for IFN-gamma production and 3H-thymidine incorporation. Prostate specimens were immunostained for B (CD20+) and for T (CD3+) lymphocytes. RESULTS: Toxicity was minor in all 8 patients treated. In the prostate, no virus related cytopathic effect could be observed. Dose-dependent infiltration of T and B lymphocytes in the whole prostate and in tumor areas was observed. Boosting of adenovirus-specific antibody responses was observed in 7 patients, and an increased adenovirus-specific PBMC proliferation and IFN-gamma production was seen after Adv-HSV-tk stimulation. CONCLUSION: Neo-adjuvant adenovirus-mediated cytotoxic gene therapy prior to prostatectomy for prostate cancer is feasible and safe in an outpatient setting for intraprostatic vector doses up to 2x10(11) viral particles. Activation of the immune system was observed. Application of higher vector doses may be considered.

Atrophy in prostate needle biopsy cores and its relationship to prostate cancer incidence in screened men.

OBJECTIVES: To evaluate whether the incidence of atrophy reported on sextant biopsies is associated with subsequent prostate cancer detection and to obtain a more thorough analysis of the different categories and extent of atrophy, we performed a review of benign biopsy cores. METHODS: In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, 4117 and 1840 men underwent sextant biopsy in the first and second screening round (4-year interval), respectively. Sextant biopsy was prompted by elevated prostate-specific antigen levels. For review, randomly taken benign sextant biopsies (n = 202) with a follow-up of at least 8 years were chosen. RESULTS: Before review, atrophy was reported in the biopsies of 11.4% and 8.7% of the first and second round, respectively. The prostate cancer incidence during 8 years of follow-up after an initial diagnosis of atrophy was 10.4%, which was not significantly different than the 12.3% of cancers detected after a benign diagnosis without reference to atrophy. After review, the incidence of simple atrophy, post-atrophic hyperplasia, and sclerotic atrophy in sextant biopsies was 91%, 47%, and 9%, respectively. Extensive atrophy was observed in 5% of biopsies. Only 2 men (4.7%) in the reviewed group had a subsequent diagnosis of prostate cancer in the 8 years of follow-up. Additionally, prostatic intraepithelial neoplasia was diagnosed in 3 men (7.0%) in the second screening round. CONCLUSIONS: Atrophy, especially its simple form, is a very common lesion in prostate biopsy cores (94%). Atrophy in an asymptomatic population undergoing screening was not associated with a greater prostate cancer or prostatic intraepithelial neoplasia incidence during subsequent screening rounds.

Interval carcinomas in the European Randomized Study of Screening for Prostate Cancer (ERSPC)-Rotterdam.

BACKGROUND: The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. We evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. METHODS: We determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer-Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. RESULTS: During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A-C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers. CONCLUSION: The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable.

Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure.

Currently, axillary lymph node dissection is increasingly being replaced by the sentinel node procedure. This method is time-consuming and the full immunohistochemical evaluation is usually only first known postoperatively. This study was designed to evaluate the accuracy of preoperative ultrasound-guided fine needle aspirations (FNAs) for the detection of non-palpable lymph node metastases in primary breast cancer patients. We evaluated the material of 183 ultrasound-guided FNAs of non-palpable axillary lymph nodes of primary breast cancer patients. The cytological results were compared with the final histological diagnosis. Ultrasound-guided FNA detected metastases in 44% (37/85) of histologically node-positive patients, in 20% of the total patient population studied. These pecentages are likely to be higher when women with palpable nodes are included. Cytologically false-negative and false-positive nodes were seen in 28 (15%) and three cases (1.6%), respectively. Interestingly 25% (n=7) of the false-negative nodes, revealed micrometastases on postoperative histology. The sensitivity was 57%, the specificity 96%. We conclude that ultrasound-guided FNA of the axillary lymph nodes is an effective procedure that should be included in the preoperative staging of all primary breast cancer patients. Whether lymph nodes are palpable or not, it will save considerable operating time by selecting those who need a complete axillary lymph node dissection at primary surgery and would save a significant number of sentinel lymph node dissections (SLNDs).

The clinical significance of a small focus of well-differentiated carcinoma at prostate biopsy.

OBJECTIVE: To compare a series of 121 sextant needle biopsy sets with their corresponding radical prostatectomy specimens in screened participants in the European Randomized study of Screening for Prostate Cancer (ERSPC), investigating the effect of screening for prostate cancer on disease-specific mortality and quality of life, as the clinical significance of a small focus of well-differentiated prostate cancer on biopsy is unclear. PATIENTS AND METHODS: The expected clinical significance of the discovered tumours was estimated using an arbitrary model combining volume, grade, and stage characteristics. RESULTS: Of 34 patients who had a small focus (< 3 mm on a single biopsy core) of well-differentiated carcinoma on biopsy, only 18 (53%) were found to have minimal carcinoma (a small focus of well-differentiated carcinoma) at radical prostatectomy, while 16 (47%) had moderately advanced or advanced carcinoma at radical prostatectomy. The preoperative prediction of minimal carcinoma improved when the amount of cancer in the sextant biopsy set was combined with the preoperative serum prostate specific antigen (PSA) level. Of 12 patients with a small focus of well-differentiated carcinoma on biopsy and a serum PSA of < 4 ng/mL, 11 had minimal carcinoma at radical prostatectomy, while there was minimal carcinoma in only seven of 22 (32%) patients with a small focus of well-differentiated carcinoma on biopsy and a serum PSA of > or = 4 ng/mL. CONCLUSIONS: The predictive value of a small focus of well-differentiated cancer on systematic sextant biopsy for a small well-differentiated tumour in the prostate is limited. The predictive value improves when serum PSA levels are considered concurrently, but is still considered insufficient to support a base for selecting therapy for the individual patient.

Consistency of prostate cancer grading results in screened populations across Europe.

OBJECTIVE: To assess the consistency of grading outcome among seven of eight participating centres of the European Randomised Screening Program of Prostate Cancer (ERSPC), a multicentre randomized trial intended to detect a difference in prostate cancer-related mortality between screened participants and a control group. Currently, tumour stage and grade in prostatectomy specimens represent the most predictive variables for biological behaviour. In prostate needle biopsies the tumour grade is a strong factor for deciding therapy. PATIENTS AND METHODS: Within the ERSPC all prostate cancers detected in needle biopsies were graded according to the Gleason score system. Gleason scores were compressed in three categories of < or = 6, 7 and 8-10. Data for grading outcome were obtained from the databases from seven individual centres; in one centre the slide sets with cancer were separately reviewed. RESULTS: Combining the data of seven ERSPC centres 66% of cancers detected in the screening arm were Gleason score < or = 6 and 92% were < or = 7. Gleason score 8-10 cancers varied from 2 to 11%. This variation in Gleason scores may be attributed to differences in the population characteristics and biopsy indications. CONCLUSIONS: These data indicate that in the seven ERSPC centres most screen-detected cancers have favourable characteristics on biopsy. Men with these cancers are amenable for treatment with curative intent. The observed differences in Gleason score distribution in different centres may partly be attributed to geographical differences and differences in the age range of the screened populations.

Functions of epidermal growth factor-like growth factors during human urothelial reepithelialization in vitro and the role of erbB2.

Transitional epithelium of the urinary bladder can be damaged during, for example, catheterization, overstretching due to obstructed voiding, or partial resection. The subsequent repair process can be stimulated by specific proteins such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGFalpha). However, little is known about the role of EGF-like growth factors and their respective receptors in human urothelial repair. In this study, we examined the effects of EGF, TGFalpha, amphiregulin and heregulin-alpha (HRGalpha) on proliferation, wound closure, and the expression of their receptors c-erbB1-c-erbB4 in primary cultures of human urothelial cells in vitro. Under conditions representing intact urothelium, all EGF-like growth factors except HRGalpha induced proliferation. TGFalpha induced proliferation up to four times. Amphiregulin increased expression of c-erbB1. Treatment with either TGFalpha or amphiregulin resulted in higher c-erbB1 activation and c-erbB3 levels. None of the growth factors affected the constitutive expression of c-erbB2 and c-erbB4. In the repair model, both EGF and TGFalpha stimulated the wound closure most strongly. This was mainly achieved by increased cellular migration. Receptor expression was not affected by the addition of exogenous growth factor. The role of c-erbB2 in wound healing was further investigated with the use of antisense DNA. Wound closure could be delayed up to 50% by antisense c-erbB2 but not by mismatched or sense oligonucleotides. Excessive production (e.g. in bladder tumors) or application of EGF, TGFalpha or amphiregulin, but not HRGalpha may lead to either hyperplasia or a faster repair of damaged urothelium in vivo. These effects seem to be mediated not only via c-erbB1 but also via c-erbB2. Our results suggest that modified members of the EGF-EGFR family are potential targets for future therapies for bladder wound healing and malignancy.

Expression and prognostic value of epidermal growth factor receptor, transforming growth factor-alpha, and c-erb B-2 in nephroblastoma.

BACKGROUND: Wilms tumor is one of the most common solid tumors in children. A transforming growth factor-alpha (TGF-alpha)/epidermal growth factor receptor (EGF-R) autocrine loop plays an important role in tumor growth. Abnormal expression of TGF-alpha, EGF-R and c-erb B-2 has been demonstrated in several human malignancies. METHODS: The immunohistochemical expression of TGF-alpha, EGF-R, and c-erb B-2 was studied in paraffin material of 62 clinical Wilms tumors. Patients had a mean follow-up of 5.7 years. RESULTS: Generally, TGF-alpha, EGF-R, and c-erb B-2 were expressed in tissue of the normal kidney and at variable levels in the three cell types of Wilms tumor, i.e., blastemal, epithelial, and stromal cells. Immunoreactive blastema cells were found in 48%, 44%, and 34% of tumors for TGF-alpha, EGF-R, and c-erb B-2, respectively. It was found that TGF-alpha, EGF-R, and c-erb B-2 blastemal and epithelial expression gradually increased from T1 to T3. The blastemal expression of TGF-alpha was statistically significantly correlated with clinicopathologic stages. Both univariate and multivariate analysis showed that blastemal TGF-alpha expression was indicative for clinical progression, but neither blastemal TGF-alpha, nor EGF-R or c-erb B-2 expression correlated with patients survival. Epithelial staining was of no prognostic value. The simultaneous expression of TGF-alpha/EGF-R was indicative for clinical progression at univariate level. CONCLUSIONS: Increased expression of TGF-alpha in the blastemal part of Wilms tumor correlated with tumor classification and clinical progression. These findings suggest that significant expression of TGF-alpha and EGF-R may play a role in promoting transformation and/or proliferation of Wilms tumor, perhaps by an autocrine mechanism. Therefore, their expression may be of value in identifying patients at high risk of tumor recurrence.