M. Devonec

The Significance of the Prostatic Hypoechoic Area: Results in 226 Ultrasonically Guided Prostatic Biopsies

A total of 666 patients with symptoms of urinary outflow obstruction underwent assessment of the patients 64 had a palpable abnormality suggestive of cancer (stages T1 to T4, or B to C). In the remainder the prostate was either palpably normal, firm or enlarged by benign prostatic hypertrophy. All 64 patients with a palpable abnormality and 162 of 602 with normal rectal examination findings had a hypoechoic area on transrectal ultrasound. Biopsy of the ultrasonic abnormality was done in 148 men by the transperineal route with linear array ultrasound guidance and in 78 by the transrectal route with a mechanical sector scanner in the sagittal plane. Of the 64 patients with a nodular prostate 34 (53%) had cancer (31% of those with stages T1 and 2, 83% with stage T3 and 100% with stage T4 disease). In 14% of the patients with stages T1 and T2 cancer the biopsy showed prostatic intraepithelial neoplasia grade 3. Of the 162 patients with a palpably normal prostate who underwent ultrasound-guided biopsy 11 (6.7%) had cancer and 6 (3.7%) had grade 3 prostatic intraepithelial neoplasia detected in the biopsy material. Patients with stages T1 to T2 cancer and those with ultrasound-diagnosed impalpable cancer were not significantly different with respect to patient age (67 versus 70 years), cancer size (3.0 +/- 1.6 versus 3.9 +/- 2.5 cm.2) or Gleason score (5.4 +/- 1.2 versus 6.5 +/- 0.9). The results demonstrate that ultrasound guidance improves the yield of prostate needle biopsy. Furthermore, it is suggested that prostate cancer found by ultrasound alone is not different from early palpable disease and should be treated in the same manner.

Flow cytometry study of cytokeratin 18 expression according to tumor grade and deoxyribonucleic acid content in human bladder tumors.

Cytokeratin 18 expression in transitional cells of 76 bladder tumors (11 grade 1, 33 grade 2 and 32 grade 3) and 10 normal biopsies was quantified by flow cytometry after immunolabeling with the anti-cytokeratin 18 monoclonal antibody RGE 53. Combined cytometric analysis of deoxyribonucleic acid content and cytokeratin 18 expression was conducted. Of 76 tumor biopsies 38 had a unimodal deoxyribonucleic acid profile with a deoxyribonucleic acid index close to 1.0, while the other 38 showed a bimodal profile: 1 peak with an index of 1.0 and a second peak with an index of greater than 1.0. The 11 grade 1 tumors belonged to the first group, whereas 10 of the 33 grade 2 and 28 of the 32 grade 3 tumors belonged to the second group. Antibody RGE 53 reacted with 4 per cent of the normal bladder cells (umbrella cells), 14 +/- 3 per cent of the cells from grade 1, 33 +/- 8 per cent from grade 2 and 56 +/- 10 per cent from grade 3 tumors. Analysis of cytokeratin 18 expression according to deoxyribonucleic acid content at the single cell level in tumors with a bimodal deoxyribonucleic acid profile showed that cytokeratin 18 was detected frequently in cells with a high deoxyribonucleic acid index but much less so in cells with an index of 1.0. Therefore, expression of cytokeratin 18 can be recognized as a marker of aggressiveness in bladder tumors, since it increases in parallel with tumor grade and cell deoxyribonucleic acid content.

Phenotyping of 76 human bladder tumors with a panel of monoclonal antibodies: Correlation between pathology, surface immunofluorescence and DNA content☆

Phenotyping of 76 bladder tumors (11 grade I, 33 grade II and 32 grade III) has been carried out by flow cytometry on cell suspensions with simultaneous determination of DNA content and surface immunofluorescence using G4 and 5 new monoclonal antibodies (10D1, 7C12, 6D1, 3C6 and 12F6) directed against bladder tumor cells. Ten normal bladder samples were used as control. Antibodies 6D1 and 12F6 were specific for tumor cells whereas the others also labelled umbrella cells. Cells from grade I tumors were labelled with 10D1, 6D1, 7C12 and 12F6 antibodies, and cells of grade II tumors with 7C12 and to a lesser degree with 12F6 but not with 10D1 and 6D1. Grade III tumor cells were specifically labelled with antibodies 3C6 and G4. Reactivity of antibodies with tissue sections was well correlated with cytometry results, except for the antibody 3C6. Finally, most of the cells stained by 3C6 and G4 were shown to have a DNA index greater than 1.0. In conclusion cells of low grade tumors can be identified with 10D1 and 6D1 antibodies, and antigens recognized by 3C6 and G4 antibodies are mostly expressed by aneuploid cells.

TNF‐α‐related apoptosis‐inducing ligand decoy receptor DcR2 is targeted by androgen action in the rat ventral prostate

The apoptotic cell death process in the prostate is known to be under the control of androgens. Tumor necrosis factor‐α (TNF‐α)‐related apoptosis‐inducing ligand (TRAIL) is a member of the TNF‐α family of cytokines, known to induce apoptosis upon binding to its death domain‐containing receptors, DR4/TRAIL‐R1 and DR5/TRAIL‐R2. Two additional TRAIL receptors, DcR1/TRAIL‐R3 and DcR2/TRAIL‐R4, lack functional death domains and act as decoy receptors for TRAIL. In this study, we examined whether TRAIL and cellular receptors expression was targeted by androgens during the apoptotic cell death process in the hormone sensitive ventral prostate. The role of androgens was investigated using two sets of experiment. (1) Androgen deprivation associated with an apoptotic process resulted in a decrease in DcR2 mRNA and protein expression in the ventral prostate 3 days after castration. Testosterone administration to castrated adult rats prevented the decrease in DcR2 mRNA and protein levels in the ventral prostate. In contrast, DcR2 expression was modified, neither in the dorsolateral nor in the anterior prostate following castration. No changes were observed in DR4, DR5, DcR1, and TRAIL mRNA and protein levels in prostate after castration. (2) A specific decrease in DcR2 expression was observed in the ventral prostate after treatment of rats with the anti‐androgen flutamide. Together, the present results suggest that testosterone specifically controls DcR2 expression in the adult rat ventral prostate. Androgen withdrawal, by reducing DcR2 expression, might leave the cells vulnerable to cell death signals generated by TRAIL via its functional receptors. J.Cell.Physiol.

Identification of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) and its receptors in adult rat ventral prostate

Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor-alpha (TNF-alpha) family of cytokines that is known to induce apoptosis upon binding to its death domain-containing receptors, DR4/TRAIL-R1 and DR5/TRAIL-R2. Two additional TRAIL receptors, DcR1/TRAIL-R3 and DcR2/TRAIL-R4, lack functional death domains and act as decoy receptors for TRAIL. In this study, the presence of TRAIL and its receptors was investigated in adult rat hormonosensitive ventral prostate. TRAIL and its receptors were identified in the rat ventral prostate in terms of protein and mRNA. TRAIL and its receptors were immunolocalized in prostatic epithelial cells.

Le score PCA3 et l’IRM prostatique permettent-ils de sélectionner les patients candidats a une première série de biopsies prostatiques ?

INTRODUCTION Determinate if the adjunction of PCA3 score and/or prostatic MRI can improve the selection of the patients who have an indication of first prostate biopsy. PATIENTS AND METHODS Multiparametric prostatic MRI and PCA3 score were made before biopsy to men scheduled for initial prostate biopsy for abnormal digital rectal examination and/or PSA superior to 4 ng/mL. T2-weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced imaging looked for suspect target classified on a scale of four. It was a prospective, single centre study. The diagnostic accuracy of PCA3 score and MRI was to evaluate in comparison with biopsy results. RESULTS Sixty-eight patients were included, median PSA was 5.2 ng/mL (3.2-28). Negative predictive value (NPV) of MRI score 0, 1 and 2 were respectively 80%, 43% and 69%. Positive predictive value (PPV) of MRI score 3 and 4 were 50% and 81%. The PCA3 cutoff with best accuracy was 21 (Se: 0.91; Sp: 0.50). Only one patient with positive biopsy (0.5mm of Gleason score 3+3) had negative MRI and PCA3 inferior to 21. CONCLUSION MRI and PCA3 score in association allowed, in this study, to consider reduction of unnecessary initial biopsy without ignoring potential aggressive tumor.

Clinically occult bladder cancer diagnosis. Trial using ultraviolet cystoscopy

Ultraviolet cystoscopy was used to demonstrate flat cancerous and precancerous bladder lesions by two techniques based on different principles: the loss of epithelium blood group antigenic expression using immunofluorescence reaction, and submucosa neoangiogenesis after fluorescein intravenous injection. The results obtained with these two techniques were disappointing, but do not preclude the use of ultraviolet cystoscopy in this type of study.

Activation of Caspases-3, -6, and -9 During Finasteride Treatment of Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) results from an increase in both epithelial and stromal compartments of the human prostate. Although inhibitors of 5alpha-reductase such as finasteride have been shown to reduce the size of BPH tissues by inducing apoptosis, their mechanisms of action still remain unknown. The present study supports that such a process triggered by finasteride is caspase dependent with a possible involvement of two effector caspases (caspase-3 and 6) and two initiator caspases (caspase-8 and 9). Indeed, by using tissues from patients affected by BPH and treated by finasteride (5 mg/d) for 2-3, 6-8, or 27-32 d, we observed that the 5alpha-reductase inhibitor induced apoptosis in epithelial cells (evaluated through cell number positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) as early as 2-3 d of treatment, with a maximal activity (250-fold increase, P < 0.0001) at 6-8 d of treatment. However, after 27-32 d of treatment, the number of apoptotic cells was reduced and was close to control. Caspases-3, -6, -8, and -9 were immunolocalized to (basal and secretory) epithelial cells and to a lesser extent to stromal cells. Activated caspase-3 immunoexpression was restricted to epithelial secretory cells, and its immunostaining intensity appeared to be higher in BPH tissues from patients treated for 2-3 or 6-8 d. Consistently, in Western blotting analyses, activated caspases-3 and -6 were detected as early as 2-3 d of treatment in BPH tissues, and their levels were increased after 6-8 d of treatment. In real time quantitative PCR experiments, caspase-3 and -6 mRNA levels were found to be unchanged after finasteride treatment. Activated caspase-8 was not detected in the different conditions tested, whereas activated caspase-9 protein levels were maximally enhanced after 2-3 d of finasteride treatment. In conclusion, we report here that finasteride treatment of BPH tissues induced a caspase-dependent apoptotic process restricted to epithelial cells by activating effector caspases-3 and -6 and exhibited a transient action because the apoptotic process was no longer observed after 27-32 d of treatment.