Search PubMed⌕ Search

Biomedical subjects

J G Klijn

Publications and source records attributed to J G Klijn.

At least 19 recordsLinked to original sources
PubMed1995

Effects of aminoglutethimide, alone and in combination with surgical castration, on pancreatic carcinogenesis in rats and hamsters.

The present 12-month study was carried out to investigate the effects of the aromatase inhibitor aminoglutethimide, alone and in combination with orchiectomy, on pancreatic carcinogenesis in azaserine-treated rats and N-nitrosobis(2-oxopropyl)-amine-treated hamsters. Treatment of the animals started 4 months after the last injection with the carcinogen. They were surgically castrated and/or treated with aminoglutethimide. Aminoglutethimide-treated rats developed less pancreatic tumours than did untreated controls. Multiplicity of (pre-)-neoplastic acinar lesions was lower in orchiectomized rats than in intact rats. Inhibition of pancreatic carcinogenesis was most pronounced in rats that were both orchiectomized and treated with aminoglutethimide. These effects were statistically significant after 8 months, but not after 4 months, of treatment. In hamsters, aminoglutethimide showed an enhancing rather than an inhibitory effect on the formation of ductular pancreatic tumours. Castration appeared to have no effect on the development of N-nitrosobis(2-oxopropyl)amine-induced ductular lesions in the pancreas, either alone, or in combination with aminoglutethimide. The present findings indicate that aminoglutethimide, alone and in combination with surgical castration, might be of value for the treatment of pancreatic acinar tumours, whereas the usefulness of aminoglutethimide for treatment of ductular adenocarcinomas of the pancreas is somewhat doubtful.

Aminoglutethimide↗
PubMed1995

Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment.

In the present study, we aimed to clarify the potential of oncogene amplifications as markers for the prediction of (i) (relapse-free) survival, (ii) response to first-line endocrine therapy and (iii) subsequent chemotherapy in patients with recurrent breast cancer. To attain this goal, amplification of different oncogenes (HER-2/neu, c-MYC and INT-2) was studied in primary tumors of a series of 259 patients with breast cancer (median follow-up of 72 mo). Of these tumors, 49.8% did not contain an amplification of any of the oncogenes studied, whereas in the amplified subgroup, INT-2 was amplified in 13%, HER-2/neu in 24% and c-MYC in 20% of the tumors. In univariate analysis, INT-2 amplification was associated with an increased risk of relapse (p < 0.03), especially in the subgroups of 85 node-negative (p = 0.05) and 156 ER/PgR-positive patients (p = 0.01). Cox multivariate regression analysis showed that c-MYC was the only oncogene whose amplification was significantly related with the rate of relapse. With respect to amplification in patients developing metastatic disease, who received first-line hormonal therapy (n = 114), HER-2/neu amplification was associated with a less favorable response to endocrine therapy (objective response rate only 17% and a progression-free survival (PFS) of only 4% at 12 mo). Interestingly, distinct INT-2 amplification might predict a better response to endocrine therapy (objective response rate of 56%, and a PFS after relapse of 42% at 12 mo).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer.

BACKGROUND: Urokinase-type plasminogen activator (uPA) is a proteolytic enzyme thought to be involved in processes leading to tumor cell invasion of surrounding tissues. Its activity during metastasis may be regulated by an inhibitor, PAI-1. Previous work has shown that high levels of uPA and PAI-1 are associated with poor prognosis in primary breast cancers. PURPOSE: In this pilot study, we explored possible associations between the expression levels of uPA or PAI-1 and the efficacy of tamoxifen treatment in breast cancer patients with relapsed disease. METHODS: Levels of uPA, PAI-1, estrogen receptor (ER), and progesterone receptor (PgR) were assayed in cytosolic extracts derived from the primary breast tumors of 235 tamoxifennaive patients who had recurrent disease. The extracts were classified as positive or negative for each assayed factor. In some analyses, ER and PgR levels were evaluated together. In these analyses, three ER/PgR subsets were defined: low, intermediate, and high. All patients in the study received tamoxifen therapy upon relapse (median follow-up, 57 months). Association of the tested factors with the response to tamoxifen treatment was studied by logistic regression analysis. Association of the factors with progression-free and overall survival was further evaluated by Cox univariate and multivariate regression analyses. RESULTS: Patients with uPA-negative tumors exhibited a better response (tumor regression or stable disease, maintained for more than 6 months) to tamoxifen treatment than those with uPA-positive tumors (51% versus 26% response; odds ratio [OR] = 0.34; 95% confidence interval [CI] = 0.18-0.65). The response rate was also better for patients with PAI-1-negative tumors than for those with PAI-1-positive tumors (49% versus 35% response; OR = 0.57; 95% CI = 0.32-1.01). In addition, patients with uPA-positive or PAI-1-positive tumors showed shorter progression-free survival (P = .001 and P < .05, respectively) and total survival after relapse (P = .005 and P < .005, respectively). When patients were stratified by ER/PgR status, the only statistically significant association between uPA levels and reduced tamoxifen response was seen in the subset whose tumors possessed intermediate levels of ER/PgR (16% response in uPA-positive versus 60% response in uPA-negative tumors; OR = 0.13; 95% CI = 0.04-0.41). Overall, uPA status appeared independent of association with ER/PgR status in its ability to predict response to tamoxifen treatment. The association of PAI-1 expression and the response to tamoxifen was less pronounced when patients were stratified by ER/PgR status. CONCLUSION: Measurement of primary breast tumor uPA levels may be useful in predicting the overall response of metastatic disease to tamoxifen therapy.

Adult↗
PubMed1995

Transforming growth factor beta secretion from primary breast cancer fibroblasts.

Transforming growth factor beta (TGF-beta) is a hormonally regulated growth inhibitor with autocrine and/or paracrine functions in human breast cancer. In vivo, enhanced immunohistochemical staining of extracellular TGF-beta 1 has been detected around stromal fibroblasts in response to the antiestrogen treatment. We have investigated the effects of tamoxifen on the production of TGF-beta by primary human breast fibroblast cultures in serum-free medium. Highly variable levels of mainly latent TGF-beta 1 were detected in conditioned media from both tumor and normal tissue derived fibroblasts. Hydroxy-tamoxifen was shown to increase latent TGF-beta 1 secretion in three of the eight tumor tissue-derived fibroblast cultures. Such effect of hydroxy-tamoxifen was not observed in fibroblast cultures established from normal adjacent breast tissue.

Animals↗
PubMed1995

Expression of tumor-associated 90K-antigen in human breast cancer: no correlation with prognosis and response to first-line therapy with tamoxifen.

It has been shown that a 90-kDa protein (90K), with an as yet unknown function, is expressed in the majority of human breast-cancer tissues. In addition, the serum level of this 90K antigen is elevated in a certain proportion of breast-cancer patients, and high serum levels are associated with a poor overall survival. It was therefore of interest to determine whether levels of 90K in tumor tissues could be used as a prognostic variable in breast cancer. In the present study, the levels of 90K in primary breast tumor cytosols were studied with respect to the length of relapse-free or overall survival in 547 patients (median follow-up, 81.4 months), and the relationship with response to first-line tamoxifen therapy and the length of progression-free survival in 184 patients with recurrent disease (median follow-up, 59.8 months). 90K levels in tumor cytosols were determined with an immunoradiometric assay. The cytosolic contents of 90K were not significantly correlated with age, menopausal status, tumor size, nodal status or differentiation grade. On the other hand, the levels of 90K were positively correlated with those of cytosolic estrogen receptor, progesterone receptor, urokinase-type plasminogen activator, its inhibitor PAI-I, cathepsin D and PS2. The cytosolic tumor level of 90K was not associated with the rate of relapse or death in primary breast cancer, nor with response to first-line therapy with tamoxifen or the length of progression-free survival in recurrent disease.

Actuarial Analysis↗
PubMed1995

Association between RB-1 gene alterations and factors of favourable prognosis in human breast cancer, without effect on survival.

The retinoblastoma (RB) tumour suppressor gene has been associated not only with retinoblastoma but also with several other tumours like osteosarcoma, small cell lung carcinoma and prostate and breast cancer. We have studied the incidence of RB gene alterations in 96 primary breast tumours using Southern blotting techniques. The outcome has been related with patient and tumour characteristics, oncogene amplifications, p53 mutations and prognosis. RB gene alterations were found to occur more frequently in estrogen receptor (ER)-positive than in ER-negative tumours and less frequently in tumours with oncogene amplification than in tumours without oncogene amplification of HER2/neu, c-myc or 11q13. RB gene alteration was observed in tumours both with and without a p53 gene mutation. Data on 87 patients (mean age, 59.6 years; median follow-up, 108 months) and RB gene alterations revealed a significant association between the frequency of RB gene alterations and node-negative patients (p < 0.01) or smaller (< 2 cm) tumours (p < 0.01), but no relation with age, differentiation grade or (relapse-free) survival. Patients with and without RB gene alterations showed the same relapse-free and overall survival.

Adult↗
PubMed1995

Plasminogen activator inhibitor-2: prognostic relevance in 1012 patients with primary breast cancer.

The antigen levels of urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor (PAI) 1, as detected in tumor extracts by ELISA, have been reported to be correlated with a poor prognosis in primary breast cancer. In the present study we have characterized a novel PAI-2-specific ELISA, designed to measure PAI-2 antigen levels in tumor cytosols. We determined PAI-2 antigen levels along with those of uPA and PAI-1 in 1012 routinely prepared tumor cytosols of patients with primary breast cancer (median follow-up, 71 months). In the overall population there was no significant association between the level of PAI-2 and prognosis, while in tumors with high uPA values, PAI-2 (test for trend) was associated with a prolonged relapse-free survival, metastasis-free survival, and overall survival (for all analyses, P < 0.02). In Cox's multivariate analysis for relapse-free survival, metastasis-free survival, and overall survival in tumors with high uPA values (including patient's age, menopausal status, lymph node status, tumor size, estrogen and progesterone receptor status, uPA, and PAI-1), PAI-2 either dichotomized or, as a continuous variable, was independently associated with a favorable relapse-free survival, metastasis-free survival, and overall survival. We conclude that the PAI-2-specific ELISA described herein is well suited for the measurement of PAI-2 levels in cytosols routinely prepared for analysis of steroid hormone receptors. We speculate that PAI-2 may serve as an inhibitor for uPA in human primary breast cancers.

Adult↗
PubMed1995

[Initial Dutch results with a presymptomatic DNA tests in familial breast/ovarian carcinoma. Rotterdamse Werkgroep voor Erfelijke Tumoren].

Recent discoveries in the field of molecular-genetic research make it possible to detect an increased genetic risk of tumours, because several genes are linked to hereditary forms of breast cancer. The breast cancer gene BRCA1, located on chromosome 17q, is quantitatively the most important gene so far. A BRCA1 gene mutation is estimated to occur in 1-3 per 1000 women in the general population, i.e. in about 10,000 women among the 4 million Dutch women aged 25-55 years. In this study experiences are described concerning oncologic, clinical-genetic and psychologic aspects in the first Dutch family in which a BRCA1-gene defect was detected with the corresponding hereditary breast/ovarian cancer syndrome. Of the relatives 88% participated in the genetic family study and 76% wished to be informed on the individual DNA-test results. From the first-degree relatives of the breast cancer patients 54% appeared to be gene mutation carrier. The detection of a gene mutation in a woman could make her decide to undergo preventive mastectomy and (or) ovariectomy, besides regular breast examination and mammography. Surgeons and radiotherapists, the group of doctors who treat primary breast cancer, have to anticipate more radical operations with regard to breasts in this selected group of (future) patients. Detection of the gene may also have consequences for family planning. Identification of carriers of the gene mutation can lead to a selection of women with increased risk of breast cancer. Primary or secondary preventive measures, early diagnostic management and regular examination may lead to a decrease in death from breast cancer.

Adult↗
PubMed1995

[Good results in periodic screening in women with increased risk of breast cancer; retrospective study].

OBJECTIVE: To determine the efficiency of surveillance among women with a high risk of breast cancer by semiannual breast examination and annual mammography. SETTING: 'Dr. Daniel den Hoed' Cancer Centre, Rotterdam, the Netherlands. DESIGN: Retrospective study. METHOD: In 1994 breast cancer was diagnosed in 92 patients: in 19 patients during surveillance (SU), in 48 referred because of symptoms (SY) and in 25 during the national screening programme (SC). The contributions of physical examination, mammography, ultrasound and fine needle aspiration cytology to the diagnosis were evaluated and the tumour stages in the 3 groups were compared. RESULTS: The mean age was 53 years in the SU group, 51 years in the SY group and 64 years in the SC group. Breast cancer was detected by mammography only in 6%, 40% and 42% in the SY, SC and SU groups, respectively. 42% of patients had a family history of breast cancer in the SU group. Mammography failed to reveal malignancy in 25% of patients in the SU and SY groups combined. In women in the SU group 53% of breast cancers were: carcinoma in situ (Tis) or minimal invasive carcinoma (< 0.5 cm diameter; T1a). In patients with a family history of breast cancer 75% (6/8) were diagnosed in stages Tis or T1a, by surveillance. In the SY group 4% were Tis or T1a and 40% N1 + 2, in the SC group 8% and 20% respectively. 15.7% of the SU group had axillary lymph node metastases (N1) but only one of the 8 patients with a family history of breast cancer. CONCLUSIONS: Surveillance by palpation and mammography in women with a high risk of breast cancer is useful, because it detects this disease frequently at an early stage, when the prognosis is still good.

Adult↗
PubMed1995

Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.

We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.

Adult↗
PubMed1995

Second-line chemotherapy with long-term low-dose oral etoposide in patients with advanced breast cancer.

In a phase II study, 27 patients with metastatic breast cancer were treated with oral etoposide as second-line chemotherapy at a dose of 50 mg/m2/day for 21 days, which courses were repeated every 4 weeks. Twenty-one patients were evaluable for response, and twenty-five for toxicity. In two (10%) patients a partial response was observed with a duration of 60 and 122 weeks respectively, and seven patients (33%) showed stable disease. Gastrointestinal toxicity was usually mild, though relatively frequent. Anemia grade II and III was observed in 20% of all courses (< 10% of all measurements), and leukopenia grade III and IV was observed in 22% of all courses (< 10% of all measurements). There was one toxic death. Reviewing the literature we calculated a response rate of intravenous etoposide treatment of 8% in 276 patients with metastatic breast cancer from 7 studies (response rates ranging between 0-14%), while (chronic) oral treatment caused a response rate of 19% in 145 patients from 8 different studies (response rates ranging between 0-35%).

Administration, Oral↗
PubMed1995

Infrequent CDKN2 (MTS1/p16) gene alterations in human primary breast cancer.

Changes which lead to excessive cyclin production or to loss of cell cycle inhibition by proteins such as p16/MTS1 may release breast tumour cells from the constraints of cell division. In order to establish the frequency of MTS1/p16 gene alteration and its relation with genetic damage to the p53 and cyclin D1 genes, we have studied these gene abnormalities in 164 human primary breast cancers and in six breast cancer cell lines. Two breast cancer cell lines and one primary tumour showed a homozygous deletion of exon 2 of the MTS1 gene. Using single-strand conformation polymorphism and subsequent sequencing analysis, one tumour showed an alteration at codon 67 (CCC-->CTC; Pro to Leu). Another tumour showed a mutation at codon 98 (without amino acid change) with an additional polymorphism at codon 140. This polymorphism was also found in 13 other tumour samples, but has no effect on (disease-free) survival. From these data we conclude that the occurrence of CDKN2 (p16/MTS1) mutation in primary breast cancer is a rare event and is not likely to be involved in human breast tumour carcinogenesis and progression.

Base Sequence↗
PubMed1995

Rapid detection of BRCA1 mutations by the protein truncation test.

More than 75% of the reported mutations in the hereditary breast and ovarian cancer gene, BRCA1, result in truncated proteins. We have used the protein truncation test (PTT) to screen for mutations in exon 11, which encodes 61% of BRCA1. In 45 patients from breast and/or ovarian cancer families we found six novel mutations: two single nucleotide insertions, three small deletions (1-5 bp) and a nonsense mutation identified two unrelated families. Furthermore, we were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with PTT, we detected aberrantly spliced products affecting exons 5 and 6 in one of two BRCA1-linked families examined. The protein truncation test promises to become a valuable technique in detecting BRCA1 mutations.

BRCA1 Protein↗
PubMed1994

Ki-67 staining in benign, borderline, malignant primary and metastatic ovarian tumors: correlation with steroid receptors, epidermal-growth-factor receptor and cathepsin D.

Ki-67 immunoreactivity was studied in relation to immunohistochemically assessed expression of epidermal-growth-factor receptor (EGFR), estrogen receptor (ER) progesterone receptor (PgR) and cytosolic levels of cathepsin D in advanced human ovarian adenocarcinomas, borderline and benign cystadenomas and normal ovaries. A significantly higher number of Ki-67-positive cells were found in metastatic tumors vs. primary adenocarcinomas and in the total group of adenocarcinomas vs. benign/borderline cystadenomas. Cathepsin-D levels were also significantly higher in metastatic tumors than in primary adenocarcinomas, which in turn presented higher levels than were found in normal ovaries. However, no significant difference was observed between cathepsin-D levels in malignant adenocarcinomas and borderline/benign cystadenomas. Immunohistochemically assessed expression of ER and PgR was detected in variable percentages of epithelial tumor cells, and stromal cells were occasionally positive as well. In the group of primary adenocarcinomas, 46% were ER-positive and 34% were PgR-positive, although there was no significant difference between primary and metastatic lesions with respect to ER or PgR expression. Concordance between immunohistochemically assessed ER or PgR data and cytosolic ER and PgR levels measured with enzyme immunoassay was relatively low. EGFR, immunohistochemically assessed with MAb-EGFRI, was positive in 76% of the primary and in 78% of the metastatic adenocarcinomas. A strong positive association was detected between ER and PgR, and EGFR was observed to present a weak positive correlation with Ki-67 and ER. Cathepsin-D levels were not found to be significantly correlated with the expression of ER, PgR, EGFR or Ki-67.

Adenocarcinoma↗
PubMed1994

The prognostic value of epidermal growth factor receptor (EGF-R) in primary breast cancer: results of a 10 year follow-up study.

In a study on 214 patients with primary breast cancer (median follow-up 8.5 yr, maximum follow-up 15 yr), EGF-R was negatively correlated to estrogen receptor and progesterone receptor, whereas no association was found with age, lymph node status, and tumor size. Initially, after a follow-up of 5 yr, there was a tendency to a significant association between EGF-R levels and tumor recurrence rate (p = 0.08). Patients with tumors containing intermediate levels of EGF-R experienced a longer relapse-free survival (RFS) than did patients with tumors possessing lower or higher levels of EGF-R. This effect was most pronounced in the subgroup of patients with positive axillary lymph nodes. However, after 10 yr follow-up, this association appears to be lost (p = 0.28) as shown in this update. A similar phenomenon was observed for the ER. While at 5 yr follow-up ER status had significant prognostic value (p = 0.01), at 10 yr follow-up this significance also appears to be lost (p = 0.40). However, tumor size, lymph node status, grade, and PgR status maintained significant prognostic value by univariate analysis. Based on 40 separate studies comprising 5232 patients, the mean percentage of EGF-R positivity reported in breast cancer is 45% (range 14-91%). Nine out of 15 different studies showed in some way a significant negative association between EGF-R and RFS by univariate analysis, and 2 others showed a tendency to such a relationship. Of 7 studies applying multivariate analysis, two demonstrated an independent prognostic value of EGF-R for RFS and two others a tendency to a significant correlation, whereas three did not. It may be concluded that EGF-R status has more or less prognostic value in patients with primary breast cancer, but the prognostic power decreases with longer follow-up. Of great clinical significance is the association of EGF-R with hormone resistance. Therefore EGF-R status can be used for selection of type of treatment. Finally, EGF-R might be useful as a target for new treatment modalities.

Actuarial Analysis↗
PubMed1994

Effects of progestagens and Org OD14 in in vitro and in vivo tumor models.

Sex steroids, in particular estradiol (E2) and progesterone (P4), play, together with other hormones and growth factors, a role in the development of normal breast tissue. The effect of four progestagens (norethisterone, 3-ketodesogestrel, gestodene and P4) and Org OD14, a steroid with weak estrogenic, progestagenic and androgenic properties were studied on growth of breast tumor cells in vitro using two subclones of MCF-7 (H and A) and T47D (S and A) cells. In addition, we investigated the effects of 3-ketodesogestrel, gestodene and Org OD14 on the growth of 7,12-dimethylbenz(a)anthracene(DMBA)-induced mammary tumors in rats. In the in vitro assays with MCF-7 cells norethisterone, 3-ketodesogestrel and gestodene stimulated growth only at high doses (> or = 10(-7) M), whereas P4 had no effect. Gestodene was more potent than 3-ketodesogestrel and norethisterone. Org OD14, stimulated cell growth at a dose of 10(-8) M, while E2 is active at 10(-10) M. In T47D-A cells similar effects were found, but the subclone S did not respond to the progestagens and Org OD14. The two T47D subclones also reacted differently to progestagens during growth stimulation with E2. In T47D-S the progestagens and Org OD14 inhibited, while in T47D-A these compounds did not modulate the effect of E2. In the DMBA model we found that gestodene and 3-ketodesogestrel were able to inhibit tumor growth to the same extent. Surprisingly, Org OD14 was even more effective in the DMBA model using the therapeutic approach. Using the prophylaxic approach tumor development was delayed and tumor growth was strongly suppressed. The inhibitory effects of Org OD14 on tumor growth in the DMBA model may be attributed to its mixed hormonal profile. From these studies we conclude that different cell lines and even subclones thereof respond quite differently to steroids. Both in vitro and in vivo studies are required to judge whether synthetic steroids might be involved in an increased risk for the development of breast tumors.

9,10-Dimethyl-1,2-benzanthracene↗