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P Pujol

Publications and source records attributed to P Pujol.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Anti-estrogens, selective estrogen receptor modulators (SERM), tibolone: modes of action].

The regulation of estrogen-induced cellular effects is a multistep molecular process. The diversity of estrogen and anti-estrogen effects on cellular functions is also modulate by tissue and gene specificity. This diversity may be explained by different levels of molecular regulation, including the presence of two distinct estrogen receptor isoforms (ER alpha and ER beta), their binding to activator or corepressor transcriptional proteins, and their affinity to different DNA binding domains of target genes (estrogen responsive element or API). These mechanisms may account for the specific responses to estrogens or anti-estrogens according to tissue, cell or gene level. The anti-estrogen tamoxifen, in vitro, inhibits the estrogen-induced proliferation of breast cancer cells and, in vivo, enhances long-term prognosis of patients having ER positive breast cancer when it is used as an adjuvant treatment. The partial agonist effect of anti-estrogens such as raloxifene, is observed only on bones and vessels but not in endometrium. Tibolone is another class of ER modulators which acts as a prodrug. It is metabolized in compounds activating nuclear receptors (androgen and progesterone receptors) which modify the ER level and estrogen metabolism. The improvement of current knowledge on the cellular mechanisms of estrogen and anti-estrogens action should allow the elaboration new therapeutic approaches on specific functions involved in estrogen-dependent pathologies.

Antineoplastic Agents, Hormonal↗
PubMed1998

Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis.

Although estrogen receptor (ER)-alpha is expressed in both benign and malignant ovarian tumors, the role of ER in ovarian carcinogenesis of epithelial tumors is still unknown. In view of the recent characterization of ER-beta, a second form of ER that seems to be highly expressed in ovaries, we reexamined this issue by studying the relative expression of ER-alpha and -beta in human ovarian tumor progression. We developed a competitive PCR assay based on coamplification of the two ERs in target nucleotide sequences displaying a high homology (exons 3 and 4). Coamplification experiments with varying amounts of plasmids containing ER-alpha and -beta cDNAs showed that this assay was reliable for discriminating as little as a 2-fold difference in the initial ER-alpha:ER-beta cDNA ratio. The relative expression of ER-alpha compared with ER-beta mRNAs was studied in human ovarian cancer cell lines (n = 5) and in normal ovaries (n = 6), then in human benign and malignant tumor samples including ovarian cysts (n = 24), borderline tumors (n = 3), and cancers (n = 10). In normal ovaries, ER-beta mRNA was the predominant ER form, whereas in ovarian cancer cell lines ER-alpha mRNA was markedly increased as compared with ER-beta. In benign and borderline tumors, ER-beta mRNA was detected in 78% of tumors, whereas ER-alpha mRNA was detected in 29%. In ovarian carcinomas, both ER-alpha and -beta mRNAs were expressed in 80% of tumors. The ER-alpha:ER-beta mRNA ratio was >1 in only one cyst sample (4%). In contrast, the ER-alpha:ER-beta mRNA ratio was markedly increased in ovarian cancers because 60% showed an ER-alpha:ER-beta mRNA >1. In situ hybridization experiments showed overlapping tissular distribution of ER-beta and -alpha expression in cancers and cysts, with a main localization in the epithelium and only a low level of expression in stromal cells. In summary, we found an increase in the ER-alpha:ER-beta mRNA ratio in ovarian carcinomas as compared with normal ovaries and cysts. These data suggest that overexpression of ER-alpha relative to ER-beta mRNA may be a marker of ovarian carcinogenesis.

Biomarkers, Tumor↗
PubMed1998

Changing estrogen and progesterone receptor patterns in breast carcinoma during the menstrual cycle and menopause.

BACKGROUND: Estrogen receptor (ER) and progesterone receptor (PgR) status at the time of breast carcinoma surgery is used as a marker of both prognosis and hormone dependency to guide adjuvant therapy. The authors studied the influence of hormonal milieu at the time of surgery on ER and PgR levels. METHODS: A population of 2020 patients with breast carcinoma, including 575 premenopausal women, was analyzed. ER and PgR levels were determined by radioligand binding assays (cutoff values, 10 fmol/mg). Serum estradiol (E2), progesterone (Pg), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels obtained on the day of surgery were used to define the menstrual cycle phase in premenopause. RESULTS: In premenopause, there was a higher proportion of ER positive (ER+) tumors in the follicular phase (62%, n = 316) than in the ovulatory phase (51%, n = 59) and the luteal phase (53%, n = 200, P = 0.03). The mean ER level was also higher in the follicular phase (30 fmol/mg) than in the ovulatory phase (20 fmol/ mg) and the luteal phase (25 fmol/mg, P < 0.001). The percentage of PgR positive (PgR+) tumors tended to be higher in the ovulatory phase (85%) than in the follicular (78%) and luteal (72%) phases (P = 0.11). The mean PgR was also higher in the ovulatory phase (177 fmol/mg) than in the follicular and luteal phases (134 and 92 fmol/mg, respectively; P < 0.001). The percentage of ER+ tumors was higher among menopausal women than among premenopausal women (67% vs. 59%, respectively; P < 0.001). Conversely, the percentage of PgR+ tumors was lower among menopausal women than among premenopausal women (65% vs. 78%, respectively; P < 0.001). In premenopause, there was a weak negative correlation between ER and E2 levels. No correlations were found between levels of ER and Pg and levels of FSH and LH or among levels of PgR and E2, Pg, and FSH and LH in premenopausal and menopausal women. CONCLUSIONS: Changes in ER and PgR levels in breast carcinoma during the menstrual cycle and menopause suggest that interpretations of hormone dependency on the basis of steroid receptor values should take into account hormonal status at the time of surgery.

Breast Neoplasms↗
PubMed1998

Increased immunostaining of fibulin-1, an estrogen-regulated protein in the stroma of human ovarian epithelial tumors.

Fibulin-1, an extracellular matrix protein, is secreted by human ovarian metastatic cancer cell lines under estrogen stimulation. Fibulin-1 expression was quantified by immunohistochemistry and computer-aided image analysis in 44 human ovarian epithelial tumors and 14 normal ovaries. The fibulin-1 staining intensity in proximal stroma, close to the surface of epithelial cells and tumor cells, progressively increased from normal ovaries to serous carcinomas. In all lesions, excluding cystadenomas, fibulin-1 accumulation was higher in proximal stroma than in distant stroma. In situ hybridization demonstrated strong fibulin-1 gene expression in epithelial cells of serous ovarian carcinomas and some cysts. The weak expression of fibulin-1 RNA in some stromal cells of these tumors could not explain the strong fibulin-1 protein accumulation in tumor stroma, which was therefore mostly produced by tumor epithelial cells. In carcinomas, fibulin-1 staining was not correlated with the percentage of estrogen receptor-alpha (ERalpha)-stained nuclei but was inversely correlated with the progesterone receptor. However, in cystadenomas and borderline tumors, both fibulin-1 and ERalpha protein levels increased, in comparison with normal ovaries, suggesting an effect of estrogens in the early steps of tumorigenesis. This fibulin-1 overexpression, demonstrated in vivo in ovarian carcinomas, might be a useful indicator for predicting cancer risk and/or aggressiveness.

Calcium-Binding Proteins↗
PubMed1998

TSH suppression combined with carbimazole for Graves' disease: effect on remission and relapse rates.

OBJECTIVE: We studied the influence of TSH suppressive therapy combined with carbimazole (CBZ) on treatment outcome in Graves' disease. DESIGN: Open non-randomized prospective study. SETTING: University Hospital of Montpellier, France. SUBJECTS: Sixty-six consecutive patients without prior treatment were included. All the patients were treated initially with 30 mg of CBZ. After 1 month of treatment, one group continued CBZ alone (n = 23), another group received a combination of CBZ plus T3 (n = 19) and a third group received CBZ and 3,5,3'-triiodothyroacetic acid (Triac, n = 24). Therapy was stopped when remission was obtained based on clinical euthyroidism, normalization of FT4 and of early radioiodine uptake. Nine patients with medical treatment failure or major side effects requiring to stop antithyroid drugs underwent surgery or radioiodine therapy. Nine patients were lost to follow-up. The remaining 48 patients were available for analysis of both remission and relapse. RESULTS: The median duration of therapy was 18 months (range, 4-41 months). Based on clinical examination, goitre size at 4 months decreased more in the CBZ + T3 and CBZ + Triac groups than in the CBZ group (P = 0.02). The overall remission rate tended to be higher in the groups treated with CBZ + T3 and CBZ + Triac than in the group treated with CBZ alone, but the difference did not reach statistical significance (P = 0.17). No difference in the relapse rate was observed between the three groups. CONCLUSION: TSH suppression combined with CBZ has little or no effect on remission and relapse rates in Graves' disease patients.

Adolescent↗
PubMed1998

Expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in endometrium of infertile patients.

Endometrium is one of the main target tissues of oestrogens. Although homozygous inactivation of oestrogen receptor-alpha leads to infertility in transgenic mice, oestrogen receptor-alpha is detected in endometrium of patients with unexplained infertility. Oestrogen receptor-alpha splicing variants and oestrogen receptor-beta have been studied in oestrogen target tissues, but their expression in endometrium throughout the menstrual cycle and in unexplained infertility is unknown. Using reverse transcription-polymerase chain reaction (RT-PCR), we studied the expression of oestrogen receptor-alpha splicing variants and oestrogen receptor-beta in uterine biopsies from 12 patients with endometriosis and 15 patients with unexplained infertility. A control group included 19 women who had had a previous pregnancy. Our study gave evidence of exon 2, 3, 4 or 7 deleted oestrogen receptor-alpha variants co-existing with the wild-type receptor. We did not find any exon 5 or 6-deleted variants. Exon 4 or 7-deleted variants were detected in all samples. Exon 2 or 3-deleted variants were detected at a similar frequency in fertile women (58 and 68% respectively), endometriotic patients (67 and 83% respectively) and infertile patients (73 and 80% respectively). During the follicular phase, there was a non-significant trend towards a lower frequency of exon-2 deleted variants in the fertile group when compared with the hypofertile group. Oestrogen receptor-beta was detected in all samples. Our preliminary study showed that altered expression of oestrogen receptor-alpha variants and oestrogen receptor-beta may not explain the hypofertility state.

Alternative Splicing↗
PubMed1997

Obesity and breast cancer risk.

Being overweight appears to be associated with a higher risk of post-menopausal breast cancer in most studies. Although the relative risk of breast cancer related to Quetelet's index is generally weak (range 1.1-1.9 in the major cohort studies), some studies have found that timing of weight gain and body fat distribution could be more significant factors of an increased risk. Conversely, obesity appears to be slightly correlated with a decreased risk of breast cancer in pre-menopausal women. These contrasting effects of excess weight on breast cancer incidence according to menopausal status, and the lack of a strong association between obesity and breast cancer in some studies, could be due to a number of confounding factors. Among these factors, age, country of origin, family history, alcohol consumption, nutrition, and hormonal treatment could account for the differences observed, and are reviewed in the present study. Obesity and central fat distribution are believed to act through endocrine intermediates such as hyperinsulinaemia and steroid hormones. Since obesity is one of the few breast cancer risk factors that can be modified, the influence of weight loss, particularly in women at high risk, deserves to be further investigated.

Body Constitution↗
PubMed1997

Choice of stimulation in polycystic ovarian syndrome: the influence of obesity.

Obesity modifies insulin sensitivity and gonadotrophins dynamics, and is associated with disorders of spontaneous ovulation. High concentrations of leptin are possibly a link between weight and spontaneous ovulation. Weight excess in polycystic ovary syndrome (PCOS) patients increases hyperinsulinaemia, which may result in altered follicular maturation. Obese PCOS women are characterized by a decreased efficiency of the different stimulation treatments. Although clomiphene resistance is not associated with obesity, the dose of clomiphene required to achieve ovulation is positively correlated with body weight. Obese PCOS women also require higher doses of gonadotrophins than their lean counterparts, with ultimately poorer results in pulsatile gonadotrophin releasing hormone-stimulated cycles. The first stage in the optimal management of obese PCOS anovulatory women is a weight loss programme, which helps to correct the clinical and endocrine abnormalities.

Clomiphene↗
PubMed1996

Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer.

We investigate whether the prognosis of patients with differentiated thyroid cancer is improved by maintaining a greater level of TSH suppression. One hundred and forty-one patients who underwent hormone therapy after thyroidectomy were followed up from 1970 to 1993 (mean, 95 months). Patients received levothyroxine (L-T4; mean dose, 2.6 micrograms/kg-day). TSH suppression was evaluated by TRH stimulation test until 1986 and thereafter by a second generation immunoradiometric assay. As TSH underwent fluctuation over time in most patients, we focused on subgroups of patients with relatively constant TSH levels during the follow-up. The relapse-free survival (RFS) was longer in the group with constantly suppressed TSH (all TSH values, < or = 0.05 mU/L; n = 18) than in the group with nonsuppressed TSH (all TSH values, > or = 1 mU/L; n = 15; P < 0.01). Age, sex, tumor node metastasis stage, and initial therapy were not different between the suppressed and nonsuppressed TSH groups. In the overall population, we analyzed the level of TSH suppression by studying the percentage of undetectable TSH values (< or = 0.05 mU/L) during the follow-up. The patients with a greater degree of TSH suppression (> 90% of undetectable TSH values; n = 19) had a trend toward a longer RFS than the remaining population (n = 102; P = 0.14). The patients with a lesser degree of TSH suppression (< 10% of undetectable TSH values; n = 27) had a shorter RFS than the remaining patients (n = 94; P < 0.01). In multivariate analysis that included TSH suppression, age, sex, histology, and tumor node metastasis stage, the degree of TSH suppression predicted RFS independently of other factors (P = 0.02). This study shows that a lesser degree of TSH suppression is associated with an increased incidence of relapse, supporting the hypothesis that a high level of TSH suppression is required for the endocrine management of thyroid cancer.

Adolescent↗
PubMed1995

Metastatic phaeochromocytoma with a long-term response after iodine-131 metaiodobenzylguanidine therapy.

Iodine-131 metaiodobenzylguanidine ([131I]MIBG), a radiopharmaceutical agent, is used for treating malignant phaeochromocytoma. [131I]MIBG therapy results in a hormone response rate of approximately 50%, but generally it yields only a partial or no tumour response. We present a case of a 46-year-old woman with a familial history of von Hippel-Lindau disease, who was treated with [131I]MIBG for a metastatic phaeochromocytoma involving the lungs, liver and bones. The patient received a cumulative dose of 33.3 GBq (900 mCi) and a complete hormone response was observed, as evaluated on the basis of catecholamine and metanephrine levels. Conventional radiography, computerized tomography and [131I]MIBG scintigraphy indicated that a near-complete tumour regression was achieved, with no evidence of relapse during a 4-year follow-up period. This case thus demonstrates that treatment with [131I]MIBG may lead to a dramatic tumour response in malignant phaeochromocytoma presenting both soft tissue and bone metastases.

3-Iodobenzylguanidine↗
PubMed1995

[Long term follow up of medical treatment of differentiated thyroid cancer].

106 patients, 114 W, 27 M, were thyroidectomized for differentiated thyroid cancer (follicular 29.3%-papillary 54.3%) with different stages of gravity (NO: 48.2% - N1: 32.8% - N2: 19%). Neck dissection was used in cases of involved nodes. One or several doses of 131 I were given to 126 subjects, 106 patients were treated with LT4 (mean daily dose: 2.5 micrograms/kg BW). 23 patients presenting intolerance to LT4 with non suppressed TSH for 13 of them were treated by an association of TRIAC + LT4. The follow up included a yearly check up involving clinical examination, plasma Tg and TSH assessment, neck ultrasonography and X-ray of the chest. Therapy was stopped for 4 weeks in cases with Tg above its detectable value and a total body scan performed with Tg and TSH controls. The mean duration of follow up was 94.5 +/- 67.7 months and extended to more than 5 years for 61% of the patients. We observed 22 relapses of the tumor with 4 deaths. Age less then 45 years, appears as the best factor of prognosis. 2 groups of patients were compared to evaluate the incidence of TSH suppression on the relapse free survival (group 1 n = 30 with a TSH < or = 0.10 mU/l and group 2 n = 15 with a TSH always > 1 mU/l during the follow up). The relapse free survival was shorter in group 2 (p = 0.01). Association of TRIAC with LT4 leads to a reduction of the daily dose of LT4 (m = 25 micrograms/day) with a significant improvement of TSH suppression and clinical tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Rising levels of estrogen receptor in breast cancer over 2 decades.

BACKGROUND: The incidence of estrogen receptor (ER)-positive breast cancer apparently is increasing. It remains unclear whether this increase is due to an improvement in receptor assay sensitivity, a change in patient characteristics, or a change in tumor biology. METHODS: The distribution of ER, tumor size, and patient age for 11,195 tumor specimens gathered from patients nationwide from 1973 to 1992 were analyzed. All assays were performed in a single laboratory. A single-label, dextran-coated charcoal (DCC) method was used from 1973 to 1984, and a dual-label, DCC method, which allows the determination of both ER and progesterone receptor levels in the same assay, was used from 1985 to 1992. RESULTS: The median level of ER has increased steadily from 14 fmol per milligram of protein in 1973 to 58 fmol per milligram of protein in 1992 (P < 0.0001). The percentage of ER-positive tumors also rose from 73-78% during the same period (P = 0.008). When the assay method was modified from single to dual label, no abrupt or stepwise increase occurred. Tumor size decreased over the same period (P < 0.0001). From 1973 to 1977, 48% of tumors were larger than 2 cm, and 15% were larger than 5 cm, compared to 60% and 9%, respectively, from 1988 to 1992. The percentage of women older than 50 years of age remained relatively constant over time. After adjusting for tumor size, age, number of positive lymph nodes, and change in assay method, a sustained rise in ER level remained. In a multivariate analysis that included age, age group, year of biopsy, tumor size, and number of positive nodes, the year of biopsy still was independently predictive of ER level (P < 0.0001). CONCLUSION: The measured level of ER in primary breast cancers has increased during the last 2 decades. It is unlikely that technical improvements or changes in tumor size, age, or nodal status fully explain this increase. The rising level of ER may reflect a change in breast cancer biology and in hormonal events that influence breast cancer genesis and growth.

Age Factors↗
PubMed1994

[Estrogen receptors and breast cancer].

Activation of oestrogen receptor has a promoting effect in early steps of mammary carcinogenesis. Loss of oestrogen receptor, or of its functionality is associated to more aggressive and hormone unresponsive breast cancers. Anti-oestrogens are antiproliferative agents inhibiting oestrogens and growth factors action by binding to the oestrogen receptor. Assay of oestrogen and progesterone receptors, in the cytosol of primary breast cancer provides information on the differentiation and prognosis of the tumour and on the efficacy of endocrine treatment. Several oestrogen receptor variants have been detected in breast cancer, but their significance remains hypothetical. They could act in a positive constitutive fashion (e.g. anomaly of the hormone binding site with conservation of the DNA binding site) or be nonfunctional (e.g. anomaly of the DNA binding domain and or transactivation). They are often associated in the tumor with normal wild type receptors and could decrease their activity by forming nonfunctional heterodimers.

Breast Neoplasms↗
PubMed1994

In vivo stimulation by tamoxifen of cathepsin D RNA level in breast cancer.

We have previously shown that 3 weeks of treatment with tamoxifen, of patients with primary breast carcinomas, increased cytosolic cathepsin D protein in oestrogen receptor (ER) positive tumours [Maudelonde et al., Cancer 1989, 63, 1265-1270]. In order to investigate the mechanism of this increase and to eliminate a transient flare-up effect, we semi-quantified cathepsin D RNA levels by in situ hybridisation in 32 breast carcinomas from patients treated with tamoxifen for 3 weeks prior to surgery and in 35 breast cancer patients receiving no tamoxifen. We found that tamoxifen increased cathepsin D RNA level regardless of the ER status of the tumours. In ER positive tumours, tamoxifen increased the cathepsin D RNA level to the same extent as cytosolic cathepsin D protein but not in ER negative tumours. The induction of cathepsin D RNA by tamoxifen in ER positive tumours was probably due to its agonist activity, also observed in vitro in breast cancer cell lines. These results suggest that the cathepsin D gene is inducible by oestrogens in ER positive breast cancer as it is in breast cancer cell lines.

Aged↗
PubMed1993

A prospective study of the prognostic value of cathepsin D levels in breast cancer cytosol.

BACKGROUND: Cathepsin D is a lysosomal protease overexpressed and abnormally secreted in most breast cancer cells. Several retrospective clinical studies have shown that cathepsin D is an independent prognostic factor in breast cancer that is associated with a higher risk of recurrence and a shorter overall survival. METHODS: To the authors' knowledge, this is the first prospective study in which the prognostic value of cathepsin D was studied in 123 patients with primary breast cancer who were followed for 5 years between March 1985 and December 1990. Cathepsin D concentrations in breast cancer cytosol were measured using a solid-phase sandwich immunoenzymatic assay. The most significant prognostic factors were identified by multivariate analysis using the Cox proportional-hazards method. RESULTS: The median value of cathepsin D was 20.8 pmol/mg of protein, which was approximately half than the median value found in subsequent assays done using a commercially available kit and reported in most retrospective studies. The cathepsin D status or level was correlated only with axillary lymph node involvement. A univariate analysis showed that high levels of cathepsin D (> 20 pmol/mg of protein) were correlated with a higher risk of recurrence and a shorter overall survival (P < 0.01 and P < 0.03, respectively). Using multivariate analysis, a high cathepsin D level, a negative progesterone receptor status, and lymph node involvement were the most important factors for predicting relapse-free survival (P = 0.02, P < 0.01, and P < 0.05, respectively). The cathepsin D level had prognostic value in patients with node-positive disease (P = 0.001) and appeared to be particularly useful in association with the progesterone receptor status by isolating a high-risk subgroup of patients (high cathepsin D level; negative progesterone receptor status). CONCLUSIONS: This first prospective study confirmed the prognostic value of the cathepsin D level in association with other major prognostic factors. The next step will be to determine whether the subset of patients with high cathepsin D levels would benefit from adjuvant therapy.

Adult↗
PubMed1993

Prognostic significance of p53 gene alterations in node-negative breast cancer.

UNLABELLED: Mutations in the p53 gene can play a role in the transformation of normal to malignant cells. Because these mutations are more frequently reported later in the course of transformation, their presence could reflect a greater malignant potential of the tumor and, thus, an increased probability of metastasis and recurrence after local therapy. In a pilot study using single-stranded conformation polymorphism analysis (SSCP), 200 node-negative breast tumors were examined for mutations in the region encompassing exons 5 through 9 of the p53 gene. Exons 5 through 9 were tested because they contain 80-90% of known p53 gene mutations. The tumors ranged in size from 1 to 3 cm. 28 tumors were found to have an abnormal band pattern on both initial and repeat analysis. 4 of these tumors were sequenced; 3 contained a p53 mutation and the 4th had a rare neutral polymorphism. Disease-free survival (DFS) at 5 years for women with tumors having an abnormal SSCP analysis was 57% (+/- 10%), compared to a 79% (+/- 3%) DFS for the group with a normal pattern. By the log rank test, this difference was highly significant, p < or = 0.01. The relative risk of recurrence for the group with an abnormal SSCP pattern was 2.2. In a multivariate analysis including ER, PgR, ploidy, S-phase, age, and tumor size, an abnormal p53 by SSCP analysis and patient age were the only factors that independently predicted DFS at 5 years. CONCLUSION: Women with node-negative breast cancer who have tumors with alterations in the p53 gene, as indicated by SSCP analysis, have a significantly poorer prognosis and a higher rate of relapse at 5 years. The prognostic significance is maintained in a multivariate analysis including many established prognostic factors.

Base Sequence↗