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Biomedical subjects

L V Beex

Publications and source records attributed to L V Beex.

At least 19 recordsLinked to original sources
PubMed2003

[The treatment of ductal carcinoma in situ (DCIS) of the breast].

Ductal carcinoma in situ (DCIS) of the breast is diagnosed more and more often in the Netherlands as a result of mammographic population screening and improved mammography techniques. Mastectomy and local excision, with or without radiotherapy, are used for the treatment of DCIS, but breast-conserving therapy seems a logical option in view of the favourable prognosis. Radiotherapy following total excision of DCIS reduces the local recurrence rate by half. Incomplete excision of DCIS is associated with a higher rate of local recurrence, which is invasive in about 50% of the cases and can therefore affect the prognosis adversely. There are conflicting opinions in the literature as to which patients with DCIS can be treated with breast-conserving therapy and whether local excision should be followed by radiotherapy, as is the case for breast-conserving treatment of invasive mammary carcinoma. The diagnosis and treatment of DCIS are therefore complex and require a multidisciplinary approach. Patients may be selected for breast-conserving therapy on the basis of diagnostic characteristics and risk factors.

Breast Neoplasms↗
PubMed2003

High prevalence of premalignant lesions in prophylactically removed breasts from women at hereditary risk for breast cancer.

PURPOSE: Women with a hereditary predisposition for breast cancer have an extremely high risk of developing invasive breast carcinoma, and many women consider prophylactic mastectomy to avoid this risk. The use of prophylactic mastectomy is still debated. Identification of frequent premalignant lesions in mastectomy specimens would support the preventive concept of prophylactic mastectomy. PATIENTS AND METHODS: We performed a prospective study of breast specimens from 67 women at extremely high genetic risk of breast cancer, with or without previous breast cancer, who were undergoing prophylactic mastectomy (66% were carriers of a BRCA1 or BRCA2 mutation). Breast specimens were studied by radiographic and macroscopic examination of 5-mm tissue slices, with subsequent histology of suspicious lesions and random samples from each quadrant of the breast and the nipple area. RESULTS: In 57% of the women, one or more different types of high-risk histopathologic lesions were present: 37% atypical lobular hyperplasia, 39% atypical ductal hyperplasia, 25% lobular carcinoma-in-situ, and 15% ductal carcinoma-in-situ. A 4-mm invasive ductal carcinoma was found in one woman with ductal carcinoma-in-situ. None of these lesions was detected at palpation or mammography, which were performed before the mastectomy. The presence of high-risk lesions was independently related to age older than 40 years (odds ratio, 6.6; P =.01) and to bilateral oophorectomy before prophylactic mastectomy (odds ratio, 0.2; P = 0.02). CONCLUSION: Many women at high risk of hereditary breast cancer develop high-risk histopathologic lesions, especially after the age of 40 years. Surveillance does not detect such high-risk histopathologic lesions.

Adult↗
PubMed2001

Diverging breast cancer mortality rates in relation to screening? A comparison of Nijmegen to Arnhem and the Netherlands, 1969-1997.

Age-standardised breast cancer mortality rates have been stable for decades. However, rates have started to decline in several Western countries. In countries where population-based screening programmes for breast cancer were introduced in the late 1980s or early 1990s, the key question now is to what extent screening is responsible for the reported declines in mortality. This study compares breast cancer mortality rates in Nijmegen, where a screening programme for breast cancer was introduced in 1975, to a control city, Arnhem, and to the Netherlands as a whole over a 20-year period. Age-standardised breast cancer mortality rates as well as age-standardised mortality ratios were calculated for successive calendar years from 1969 to 1997. Further, a tailor-made period-cohort-group Poisson regression model was fitted. Figures displaying age-standardised mortality rates and ratios showed inconclusive patterns with regard to the expected impact of screening. Depending on when mortality rates were allowed to deviate between populations, the period-cohort-group analysis indicated a non-significant 6% to 16% reduction in breast cancer mortality after 2 decades in favour of the Nijmegen female population. Possible explanations are discussed as to why the mortality reductions reported by randomised trials might not be observed in a public health screening programme, such as the Nijmegen programme, evaluated by comparisons of geographical trends.

Aged↗
PubMed2001

Micro-metastases in axillary lymph nodes: an increasing classification and treatment dilemma in breast cancer due to the introduction of the sentinel lymph node procedure.

BACKGROUND: Sentinel lymph node (SN) biopsy will increasingly replace axillary lymph node dissection (ALND) for staging in breast cancer. For daily practice, examination of the SN by serial sectioning (SS) and/or immunohistochemistry (IHC) is being promoted. Use of these techniques may result into stage migration due to the increased detection of micro-metastases. The consequence may be overshooting of patients with adjuvant therapy, as the prognostic relevance of (small) micro-metastases and isolated tumor cells is unclear. METHODS: The prognostic impact of micro-metastases is determined by reviewing ALND studies with a follow up of at least 5 years, including more than 100 patients, before the SN era. Furthermore, studies in which conventionally haematoxylin-eosin (H&E) negative SNs are investigated for occult metastases by SS and/or IHC are reviewed. RESULTS: In only one of eight studies, occult metastases were an independent risk factor for reduced survival. The outcome is dependent on the size of the nodal metastasis. IHC and SS as used in the SN procedure indeed induce a shift from pNO to pN1a (according to TNM). CONCLUSION: By the thorough pathologic examination of the SN, isolated tumor cells and micro-metastases are more frequently detected. We propose to classify small micro-metastases (<0.5 mm) in a separate pN1a(min) category (min for minimal) to prevent stage migration. As the prognostic relevance of isolated tumor cells and (small) micrometastases has not been proven, the value of adjuvant therapy can be questioned for patients with otherwise good prognostic factors.

Axilla↗
PubMed2001

Tamoxifen resistance in breast cancer: elucidating mechanisms.

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly three decades. Treatment success is primarily dependent on the presence of the estrogen receptor (ER) in the breast carcinoma. While about half of patients with advanced ER-positive disease immediately fail to respond to tamoxifen, in the responding patients the disease ultimately progresses to a resistant phenotype. The possible causes for intrinsic and acquired resistance have been attributed to the pharmacology of tamoxifen, alterations in the structure and function of the ER, the interactions with the tumour environment and genetic alterations in the tumour cells. So far no prominent mechanism leading to resistance has been identified. The recent results of a functional screen for breast cancer antiestrogen resis- tance (BCAR) genes responsible for development of tamoxifen resistance in human breast cancer cells are reviewed. Individual BCAR genes can transform estrogen-dependent breast cancer cells into estrogen-independent and tamoxifen-resistant cells in vitro. Furthermore, high levels of BCAR1/pl30Cas protein in ER-positive primary breast tumours are associated with intrinsic resistance to tamoxifen treatment. These results indicate a prominent role for alternative growth control pathways independent of ER signalling in intrinsic tamoxifen resistance of ER-positive breast carcinomas. Deciphering the differentiation characteristics of normal and malignant breast epithelial cells with respect to proliferation control and regulation of cell death (apoptosis) is essential for understanding therapy response and development of resistance of breast carcinoma.

Antineoplastic Agents, Hormonal↗
PubMed2000

Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Adult↗
PubMed2000

[Adjuvant systemic therapy for patients with resectable breast cancer: guideline from the Dutch National Breast Cancer Platform and the Dutch Society for Medical Oncology].

There is an abundance of evidence that adjuvant systemic therapy with chemotherapy or endocrine therapy results in better survival for all patients with resectable breast cancer. The absolute 10-year survival advantage however varies for the different patient groups. Therefore, for each individual patient the choice of adjuvant therapy must take into account the potential benefits and the possible side effects. A group of medical oncologists from the Dutch National Breast Cancer Platform (NABON) and the Dutch Society for Medical Oncology (NVMO) prepared a guideline for the treatment of patients with early resectable breast cancer. The criterium for choosing adjuvant systemic therapy for the individual patient is an expected increase in 10-year survival of 5% or more. In the guideline a difference is made between patients with and without axillary lymph node metastasis. In patients with axillary lymph node metastasis the choice for adjuvant systemic therapy depends on the following prognostic factors: menopausal status, age, and the presence of estrogen and progesterone receptors in the tumour. In patients without axillary lymph node metastasis the choice depends also on the following prognostic factors: the size of the tumour, the mitotic activity index, or the histopathologic grade of differentiation.

Adult↗
PubMed1999

Quality of adjuvant chemotherapy in primary breast cancer in a non-trial setting. A comprehensive cancer centre study. The Breast Cancer Group of the Dutch Comprehensive Cancer Centre East (IKO).

The quality of adjuvant chemotherapy with cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and the compliance with guidelines for this treatment were studied in 323 premenopausal patients with node positive breast cancer, who were treated in the Comprehensive Cancer Centre East of The Netherlands (IKO) from 1988 to 1992, outside the setting of a clinical trial. The interval surgery-chemotherapy, the duration of chemotherapy, dose intensity (DI) and relative dose intensity (RDI) of CMF chemotherapy and validations of dose modifications were evaluated. 295 of 323 patients (91%) received adjuvant chemotherapy. CMF chemotherapy was used in 230 patients (78% of the chemotherapy receiving patients). The median time to the start of chemotherapy was 62 (range-35-139) days after surgery. Forty-two per cent of the patients finished their CMF chemotherapy within 168 days. Two per cent of the patients did not finish the six courses of CMF chemotherapy. The mean DI and RDI of the eligible patients in all CMF using hospitals were 80.4 +/- 28.8% and 78.2 +/- 28.4%, respectively. Aberrations of recommended guideline procedures resulted more often in suboptimal treatment than haematological toxicity. Adherence to the guidelines was variable and resulted in suboptimal adjuvant chemotherapy. The median follow-up of the patients treated in hospitals that agreed to the use of CMF was 5 years. The mean RDI of CMF in the eligible patients who relapsed was 72.2 +/- 32.7%, compared with 81.4 +/- 25.2% for the patients who did not relapse (P 0.01), suggesting a possible influence of the RDI on disease free survival. However, when the patients who did not receive chemotherapy were excluded, the mean RDI of the patients who relapsed was 85.0 +/- 12.6% and of the patients who did not relapse 87.4 +/- 12.6%, which was not significantly different (P = 0.20).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Cisplatin (P), vinblastine (V) and bleomycin (B) combination chemotherapy in recurrent or advanced granulosa(-theca) cell tumours of the ovary. An EORTC Gynaecological Cancer Cooperative Group study.

The aim of this study was to investigate the clinical activity and toxicity of a modified PVB regimen (cisplatin, vinblastine and bleomycin) in patients with advanced or recurrent, pure granulosa cell tumours (GCTs) or mixed granulosa-theca cell tumours (GTCTs). The PVB regimen consisted of cisplatin (P) 20 mg/m2 intravenous (i.v.) days 1-5, vinblastine (V) 0.15 mg/kg i.v. days 1-2 and bleomycin (B) 30 mg i.v. on day 2, and 15 mg on day 15, for 28 days. 38 eligible patients were entered in this trial. Prior to PVB all patients underwent surgery and 13 received postoperative radio- or other prior chemotherapy. The median number of PVB cycles was 4 in both groups. In the group of 25 patients who had received prior surgery only, 7 and 6 patients had complete and partial responses, respectively (response rate: 52%, 95% confidence limits: 31.3-72.2%). At a median follow-up of 39 months, 6 patients were alive with no evidence of disease, 6 were alive with disease, 12 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 13.9 months. The median survival was 25.4 months. 3-year survival was 49% (95% confidence limits: 29-69%). In the group of 13 patients who had previously received postoperative radio- or chemotherapy, 5 complete and 5 partial responses were observed on PVB (response rate: 77%, 95% confidence limit: 46.2-95.0%). At a median follow-up of 50 months, 6 patients were still alive, only 1 without evidence of disease, 6 died due to malignant disease and 1 died due to intercurrent disease. The median time to progression was 19.3 months. The median duration of survival was 41.1 months. Accompanying toxicity was distributed in a similar pattern for both groups. Severe toxicity was mainly documented as haematological toxicity, nausea/vomiting and alopecia. Furthermore cisplatin-related peripheral neurotoxicity and mild/moderate signs of bleomycin-related pulmonary toxicity were observed. The present data confirm the therapeutic activity of the PVB regimen in advanced/recurrent GCTs. The response rate was moderately high compared with previous studies, with a median duration of response of 20 months for both groups.

Adult↗
PubMed1998

Increased use of immunohistochemistry for oestrogen receptor measurement in mammary carcinoma: the need for quality assurance.

This paper outlines the changes which have occurred over the last 25 years in the methods employed for the measurement of oestrogen receptors to aid the management of women with breast cancer. Immunohistochemistry is now the method of choice and knowledge of oestrogen receptor status is being used with increasing frequency for the selection of adjuvant treatment as well as for the treatment of metastatic disease. It is essential that good quality assurance procedures are established so that results are reproducible and can be used with confidence in individual centres as well as being comparable with those produced elsewhere. A retrospective study of 170 women with metastatic breast cancer provides the basis for a discussion on the advantages and pitfalls of the immunohistochemical assay. Particular emphasis is paid to the choice of cut-off and how the results may be applied in patient management.

Breast Neoplasms↗
PubMed1998

Vorozole (Rivizor): an active and well tolerated new aromatase inhibitor for the treatment of advanced breast cancer patients with prior tamoxifen exposure. Investigational Drug Branch of the European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer Cooperative Group.

Vorozole (Rivizor) is a potent and stereospecific inhibitor of aromatase having shown promising endocrine effects in phase I studies. In the present trial, 27 postmenopausal patients with advanced breast cancer, measurable lesions, presumably hormone responsive (ER or PR+, or ER? with disease-free survival longer than 1 year, or prior documented response to tamoxifen), were treated with vorozole one tablet 2.5 mg daily. All had been previously treated with tamoxifen as adjuvant (two patients) or for advanced disease (24 patients), or both (one patient). Objective remissions were observed in eight patients (30%) with two complete responses (CR) and six partial responses (PR) lasting for a median of 14.3 months (range 6.8-40.6); nine stabilizations were also recorded (median 7.9 months; range 3.7-40.1). Median time to progression for the 27 patients was 5.9 months. Sites of response were skin (three patients), lymph nodes (two patients), lung (two patients) and chest wall plus lymph nodes (one patient). Treatment was very well tolerated: mild hot flushes (four patients), gastrointestinal complaints (four patients) and no significant toxicity (common toxicity criteria grade above 2) or drug-related severe adverse event. It is concluded that vorozole is an active second-line endocrine treatment, deserving consideration for randomized comparison with other agents such as aminoglutethimide, megestrol acetate or medroxyprogesterone acetate.

Adult↗
PubMed1998

Vorozole (R83842) in the treatment of postmenopausal advanced breast cancer: relationship of serum levels of vorozole and clinical results (a study of the EORTC Breast Cancer Cooperative Group).

The new non-steroidal aromatase inhibitor vorozole (R83842) was administered orally at a single daily dose of 2.5 mg to 27 postmenopausal women with advanced breast cancer in a phase II trial as second-line endocrine treatment. The observed objective response rate of 30% and good tolerability of the drug confirm other recent reports. Endocrine determinations during 6 months of treatment demonstrated reduction of serum estrogens: estrone sulfate by more than 60%, estrone by 30-40%, but estradiol by only 10-20%. The ratios of serum androstenedione/estrone and testosterone/estradiol increased significantly, consistent with the inhibition of peripheral aromatase activity. Levels of progesterone, 17-alpha-hydroxyprogesterone, cortisol, dehydroepiandrosterone sulfate, androstenedione and aldosterone remained normal, indicating no interference with adrenocortical steroid synthesis. A general lack of correlation between the observed serum concentrations of vorozole and its effect on hormone serum levels or clinical response was found. This suggests that the determination of such serum levels gives a poor impression of the unambiguous anti-tumor activity of vorozole which may well have its main effect with the tumor tissue itself. The present results are in support of aromatase inhibition, but the possibility of an additional effect on the sulfation of estrogens merits further investigation.

Adult↗
PubMed1997

Breast-cancer mortality in a non-randomized trial on mammographic screening in women over age 65.

Recent case-referent studies in the Nijmegen breast-screening programme have shown a reduction in breast-cancer mortality of approximately 50% due to screening of women aged 65 years and older. In this type of study, however, the results may be biased because of self-selection. The purpose of our present study was to compare the breast-cancer mortality rate in a population invited for screening with that of a reference population from an area without a screening programme. In 1977-1978, 6773 women aged 68-83 years were enrolled in the mammographic screening programme in Nijmegen, The Netherlands. The women were followed up until 31 December, 1990. The reference population consisted of women from the same birth cohort from Arnhem, a neighbouring city without mass screening, for whom the entry date was 1 January, 1978. The ratios of the Nijmegen and Arnhem breast-cancer mortality rates with 95% confidence intervals (CI) were calculated. In the study period, 173 patients were diagnosed with primary breast cancer in Nijmegen vs. 183 in Arnhem; 40 Nijmegen patients had died of breast cancer vs. 51 Arnhem patients. The cumulative mortality-rate ratio was 0.80 (95% CI = 0.53-1.22). In the periods 1978-1981, 1982-1985 and 1986-1990, the mortality rate ratios were 1.44 (95% CI = 0.67-3.10), 081 (95% CI = 0.37-1.79) and 0.53 (95% CI = 0.27-1.04), respectively. After adjustment for the difference in incidence rate that existed between the Nijmegen and Arnhem populations, mammographic screening of women older than 65 can be expected to yield a 40% reduction in breast-cancer mortality after 10 years.

Aged↗
PubMed1997

Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity.

Dihydropyrimidine dehydrogenase (DPD) is responsible for the breakdown of the widely used antineoplastic agent 5-fluorouracil (5-FU), thereby limiting the efficacy of the therapy. It has been suggested that patients suffering from 5-FU toxicities due to a low activity of DPD are genotypically heterozygous for a mutant allele of the gene encoding DPD. In this study we investigated the cDNA and a genomic region of the DPD gene of a cancer patient experiencing severe toxicity following 5-FU treatment for the presence of mutations. Although normal activity of DPD was observed in fibroblasts, the DPD activity in leucocytes of the cancer patient proved to be in the heterozygous range. Analysis of the DPD cDNA showed heterozygosity for a 165bp deletion that results from exon skipping. Sequence analysis of the genomic region encompassing the skipped exon showed that the tumour patient was heterozygous for a G-->A point mutation in the invariant GT splice donor sequence in the intron downstream of the skipped exon. So far, the G-->A point mutation has also been found in 8 out of 11 patients suffering from a complete deficiency of DPD. Considering the frequent use of 5-FU in the treatment of cancer patients, the severe 5-FU-related toxicities in patients with a low activity of DPD and the high frequency of the G-->A mutation in DPD deficient patients, analysis of the DPD activity and screening for the G-->A mutation should be routinely carried out prior to the start of the treatment with 5-FU.

Antimetabolites, Antineoplastic↗
PubMed1997

Cutaneous infection due to Mycobacterium abscessus. A case report.

Erythematous nodular and ulcerating skin lesions occurred in a 56-year-old woman treated with chemotherapy and glucocorticosteroids for metastatic breast cancer. Subsequent culture yielded Mycobacterium abscessus, a facultative pathogen which exists as a saprophyte in the environment and rarely produces clinical disease in humans. This organism is usually relatively resistant to antituberculous as well as a number of other antimicrobial agents. On the basis of in vitro susceptibility results, treatment with clarithromycin and clofazimine was installed and resolution of the lesions initiated. This report emphasizes once again that one should investigate any new or unusual skin lesions in immunocompromised patients by histology and culture of biopsies, including cultures for acidfast organisms.

Breast Neoplasms↗