Michel Petein

In vitro characterization of prolactin-induced effects on proliferation in the neoplastic LNCaP, DU145, and PC3 models of the human prostate.

Proliferation of normal and tumoral prostate tissue is regulated by androgens and various growth factors. We characterized the in vitro proliferative influence of prolactin (PRL) in androgen‐sensitive and androgen‐insensitive human prostate cancers.

High serum galectin-3 in advanced melanoma: preliminary results

Background.  Galectin‐3 (Gal‐3) is a member of the family of β‐galactoside‐binding mammalian lectins, and has been implicated in tumour invasion and metastatic process in vitro and in vivo.

Objective measurement of the different collagen types in the corpus cavernosum of potent and impotent men: an immunohistochemical staining with computerized-image analysis

SummaryQuantitative measurements of the collagen types (I, III, and IV) in the corpora cavernosa of potent and impotent men were carried out to investigate whether quantitative immunohistochemistry might contribute additional information as to the cause of erectile dysfunction. The study group consisted of 22 men with various etiologies of impotence and 4 normal, potent men. The quantitative immunohistochemistry measurements were performed by means of a cell-image processor. Three variables for each of the three types of collagen were studied, namely, the mean optical density (MOD), which relates to histochemical staining intensity; the labeling index (LI), which is positively related to the percentage of immunostaining; and the quick score (QS) index, which takes into account both LI and MOD values. None of the quantitative parameters taken individually (monovariate statistical analyses) made it possible to obtain any statistically significant difference between the types of collagen of the group under study. The mean QS value recorded for collagen type IV was significantly lower than that noted for collagen type I in the psychogenic (P = 0.019), arteriogenic (P = 0.012), and venogenic (P = 0.001) groups, whereas the MOD value was significantly lower in the normal (P = 0.043), arteriogenic (P = 0.013), and venogenic (P = 0.001) groups but not in the psychogenic group. The mean MOD of collagen type III was intermediate between that of the other types. In contrast, the mean LI value recorded for collagen type IV was significantly lower only in the venogenic (P = 0.032) and psychogenic (P = 0.049) groups as compared with the other groups. No objective qualitative change in the collagen types was observed that could be correlated to the etiology of erectile dysfunction. The significant difference seen in the quantitative parameters with regard to collagen type IV and the observed increase in the type I/III collagen ratio might attest to the notion that the response of the erectile tissue to ischemia is similar to that of other organs. The net effect of these changes is a restricted capacity for corporal expansion and alteration of the veno-occlusive mechanism.

PROSTATE SPECIFIC ANTIGEN DENSITY OF THE TRANSITION ZONE FOR PREDICTING PATHOLOGICAL STAGE OF LOCALIZED PROSTATE CANCER IN PATIENTS WITH SERUM PROSTATE SPECIFIC ANTIGEN LESS THAN 10 NG./ML.

PURPOSE Prostate specific antigen (PSA) density of the transition zone, which is the density of serum PSA related to the volume of the transition zone, has been recently demonstrated to enhance prostate cancer prediction in patients with intermediate PSA levels. We further investigated the usefulness of PSA-transition zone for predicting extraprostatic extension in clinically localized prostate cancer. MATERIALS AND METHODS Measuring the transition zone of the prostate by ultrasound using the prolate ellipsoid method, PSA-transition zone values were calculated prospectively in 198 patients with clinically localized prostate cancers and serum PSA less than 10.0 ng./ml. who underwent radical retropubic prostatectomy. The ability of PSA-transition zone to predict extracapsular disease in the surgical specimen was compared to Gleason score, serum PSA, PSA density of the total prostate and percent free PSA using univariate or multivariate analysis as well as receiver operating characteristics curves. RESULTS A total of 104 patients (52.5%) had pathologically organ confined prostate cancer while 94 of 198 (47.5) had extracapsular disease. PSA-transition zone levels were significantly higher in extracapsular disease than organ confined cancers (0.84 versus 0.42 ng./ml./cc, p <0.00001). Using multivariate analyses PSA-transition zone and Gleason score were the most significant predictors of extracapsular disease. The area under the curve was larger for PSA-transition zone (0.825) than any other parameter (p <0.004 versus PSA density and p <0.001 versus PSA, percent free PSA or Gleason score). A cutoff of 1.00 ng./ml./cc for PSA-transition zone provided 95.1% specificity and 28.8% sensitivity for predicting extracapsular disease. Probability plots using the best combination of independent variables for predicting extraprostatic extension were developed. CONCLUSIONS These data demonstrate that the use of the PSA-transition zone may be of additional value for indicating which patients with clinically localized prostate cancer and PSA less than 10.0 ng./ml. are at high risk for extracapsular disease.

Growth inhibition of human in vitro and mouse in vitro and in vivo mammary tumor models by retinoids in comparison with tamoxifen and the RU-486 anti-progestagen

Retinoids constitute a very promising class of agents for the chemoprevention or treatment of breast cancer. These retinoids exert their biological activity through two distinct classes of retinoic acid (RA) receptors (R), the RAR isotypes (α, β, and γ) and the three RXR isotypes (α, β, and γ) and their numerous isoforms which bind as RXR/RAR heterodimers to the polymorphic cis-acting response elements of RA target genes. With respect to these numerous receptor sub-types, the retinoid-induced effects at the biological level include marked modifications with respect to both cell proliferation and cell death (apoptosis), and also in the induction of differentiation processes. The present study aims to characterize the effect which four retinoids (TTNPB, 9-cis-RA, LGD 1069, 4-HPR) with distinct RAR/RXR binding properties induced on various in vitro and in vivo mouse and human breast cancer models. The experiments with the retinoids were carried out in comparison with the anti-estrogen tamoxifen and the anti-progestagen RU-486 compounds. The results show that the 6 compounds under study were markedly more efficient in terms of growth inhibition in the human T-47D cell line when maintained under anchorage-independent culture conditions than when maintained under anchorage-dependent ones. While RU-486 exhibited a weak statistically significant (p < 0.05) influence on the growth of the T-47D stem cells, tamoxifen had a marked inhibitory influence on the growth of these cells. Of the four retinoids, 4-HPR was the least effective since the lowest doses tested (1 and 0.1 nM) exhibited no statistically (p > 0.05) significant influence on the growth of the stem cells. The most efficient retinoid was TTNPB. It was only at the highest dose (10 μM) that tamoxifen and RU-486 showed a weak inhibitory influence on the growth of the T-47D non-stem cells while all 4 retinoids exerted a significant inhibitory influence on the growth of these non-stem cells, with 4-HPR being the most efficient (P < 0.001) at the highest dose, but ineffective (P > 0.05) at the lowest. Tamoxifen and TTNPB were tested in vivo on hormone-senstive (HS) and hormone-insensitive (HI) strains of the MXT murine mammary carcin oma. While TTNPB appeared to be equally efficient in terms of growth inhibition in both MXT-HS and MXT-HI models, tamoxifen had only a marginal inhibitory influence on the growth of the MXT-HI strain but did inhibit growth in the case of the MXT-HS one. TTNPB was markedly more efficient than tamoxifen in terms of both inhibiting the cell proliferation level (measured by means of computer-assisted microscopy applied to Feulgen-stained nuclei, a method which enables the percentage of cells in the S phase of the cell cycle to be determined) and triggering cell death (measured by means of the determination of the transglutaminase activity) in both the MXT-HI and MXT-HS models. The very significant TTNPB-induced inhibition of the macroscopic MXT-HS growth rate relates to the triggering of cell death (apoptosis) rather than to an inhibition of cell proliferation. All these results clearly indicate that retinoids are very efficient agents against breast cancer, at least as efficient as tamoxifen.

Expression of galectin-3 in primary and metastatic melanoma: immunohistochemical studies on human lesions and nude mice xenograft tumors.

Galectins are a large family of proteins which bind galactoside-containing glycans. Their role in cancer seems to be important since members of the family may mediate cell adhesion and modulate cell growth. Galectin-3 (Gal-3) is expressed in the nucleus, in the cytoplasm and on the cell surface, and can also be secreted into the extracellular matrix. A series of experimental and clinical data have been reported which indicate that Gal-3 may play a putative role in carcinogenesis, cancer progression and the process of metastasis. To study the possible correlation between Gal-3 expression and malignant potential in primary melanoma lesions, we conducted an immunohistochemical study with monoclonal anti-Gal-3 antibody in a series of primary and metastatic melanoma lesions as well as benign skin pigmented lesions. We also developed a xenograft melanoma model in nude mice with two melanoma cell lines (ATCC G-361 and ATCC HT-144) and assessed staining with the Gal-3 antibody in the xenografts and the metastases. The expression of anti-Gal-3 staining was determined semiquantitatively. The expression of Gal-3 was higher in thin primary melanoma lesions than in benign pigmented skin lesions or metastases and seemed to correlate inversely with the aggressiveness as estimated by the Breslow index which is recognized as the main prognostic factor in melanoma. We propose Gal-3 expression in melanoma as a diagnostic and/or a prognostic parameter and suggest that further studies of such a role for Gal-3 are warranted.

The importance of measuring the prostatic transition zone: an anatomical and radiological study.

 To assess the accuracy and reliability of measurements of the volume of the transition zone (TZ, representing the hypertrophied benign component) and whole prostate by TRUS in patients with BPH or cancer, by comparing the radiological with pathological findings after surgery.

Differential histochemical peanut agglutinin stain in benign and malignant human prostate tumors: Relationship with prostatic specific antigen immunostain and nuclear DNA content

The histochemical binding pattern of the peanut (Arachis hypogaea) lectin (PNA) was quantitatively described by means of computer-assisted microscope analysis in 28 benign prostatic hyperplasias (BPH), 15 prostatic intraepithelial neoplasias (PIN), and 119 prostatic adenocarcinomas. PNA exhibits nonimmune but selective binding to glycoproteins with beta-D-galactosyl(1,3)-N-acetyl-D-galactosamine residues. We also investigated whether a relationship existed between the number of histochemical-related PNA acceptors and the histochemical prostate-specific antigen (PSA) stain intensity, and between the number of PNA receptors and DNA ploidy level. The results show that neoplastic prostate tissues and high-grade intraepithelial prostatic neoplasias (PIN2_3) exhibit a significantly higher number of PNA acceptors than benign prostatic hyperplasias and low (PIN1) grade prostatic intraepithelial neoplasias. A statistically significant correlation was observed between the number of histochemically related PNA acceptors and PSA immunostain intensity. Lastly, diploid prostatic tumors, whether benign or malignant, exhibited a significantly higher number of PNA acceptors than aneuploid ones. These results suggest that PNA acceptors play an important role in the biology of prostate tumors.

Image cytometry determination of ploidy level, proliferative activity, and nuclear size in a series of 314 transitional bladder cell carcinomas☆

Image cytometry was carried out on 281 superficial (Ta and T1) and 33 invasive (T2 to T4) bladder cancers. The parameters used to characterize these bladder tumors were: (1) histopathological grading, (2) clinical staging, (3) tumor size, (4) deoxyribonucleic acid (DNA) index (DI), (5) DNA histogram type (DHT), (6) percentage of euploid (diploid plus tetraploid) cells, (7) percentage of polyploid cells (> 5C DNA content), (8) proliferative activity (S phase fraction value), and (9) nuclear area (NA). The proliferative activity of the tumors was not related to either histopathological grade or to clinical stage, but it was related to the DHT parameter, which made it possible to identify diploid, hyperdiploid, triploid, hypertriploid, tetraploid, and polymorphic tumors. The hypertriploid tumors exhibited a significantly lower proliferative activity than the nonhypertriploid ones. Although both the DI and the NA values correlated significantly with histopathological grading, only the NA values correlated significantly with clinical staging. We further observed that some grade III bladder tumors were definitely diploid, whereas some grade I tumors were highly aneuploid. We thus hypothesize that the ploidy level of a given tumor reflects its age directly and its aggressiveness only very indirectly. In our opinion aneuploidy is only an indirect marker of aggressiveness because it reflects the fact that a malignant tumor is old, ie, has been present in a patient over a long period of time and has had ample time to express its malignancy at the clinical level. A significant relationship was accordingly obtained between tumor size and ploidy level with the highest proportion of aneuploid tumors and the highest percentage of polyploid cell nuclei being observed among the largest bladder tumors.

The use of digital image analysis of chromatin texture in Feulgen-stained nuclei to predict recurrence of low grade superficial transitional cell carcinoma of the bladder

Background. Identifying a marker enabling prediction of recurrence in the group of superficial transitional cell carcinomas (sTCCs) of the bladder remains an important challenge today. This report quantitatively describes chromatin patterns with respect to such sTCC recurrence.