| 1. |
- Fernö, Mårten, et al.
(författare)
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Urokinase plasminogen activator, a strong independent prognostic factor in breast cancer, analysed in steroid receptor cytosols with a luminometric immunoassay
- 1996
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 32a:5, s. 793-801
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase plasminogen activator (uPA) is involved in the activation of different proteases which participate in the degradation of extracellular matrix, thereby enhancing the invasive capacity of tumour cells. uPA has been shown to be of prognostic importance in breast cancer. We have analysed uPA with a new luminometric immunoassay (LIA), applicable in cytosol samples routinely used for oestrogen-receptor (ER) and progesterone-receptor (PgR) analyses. At a cut-off value of 0.62 ng uPA/mg protein, 33% (230/688) samples were classified as representing high uPA tumours. High uPA content was found to be associated with shorter recurrence-free survival (median observation time: 42 months), ER and PgR negativity, increased p53 expression, DNA non-diploidy and a high S-phase fraction (SPF), but not with lymph node involvement or tumour size (< or = 20 mm versus > 20 mm). In the subgroup of patients not treated with systemic adjuvant therapy, multivariate analysis showed uPA to be an independent prognostic factor together with lymph node status and SPF. If these results can be reproduced, uPA may be a factor suitable for inclusion in a prognostic index.
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| 2. |
- Funegård, Ulrika, et al.
(författare)
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Can alpha-tocopherol and beta-carotene supplementation reduce adverse radiation effects on salivary glands?
- 1995
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 31A:13-14, s. 2347-2353
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we evaluated whether supplementation with antioxidant vitamins can reduce the adverse effects of irradiation on the salivary glands in the rat. Four groups of adult Sprague-Dawley rats were given a basic diet providing 0.6 mg alpha-tocopherol and no beta-carotene per day. In two groups the basic diet was supplemented with 3.4 mg alpha-tocopherol and 6 mg beta-carotene per day from 14 days before irradiation until 12 days after completed irradiation. One group of rats given basic diet and one group given supplemented diet were irradiated with 7 Gy daily for five consecutive days. Isoproterenol and pilocarpine-stimulated whole saliva was collected from all rats 2, 4 and 26 weeks after irradiation. Vitamin-supplemented irradiated rats had higher secretion rates on all three occasions compared with those of irradiated rats given basic diet. The changes in saliva composition seen in irradiated rats were less accentuated in vitamin-supplemented, irradiated rats. The proportions of acinar cells were significantly decreased both in parotid and submandibular glands 26 weeks after irradiation. Supplementation with alpha-tocopherol and beta-carotene did not alter the morphology of the glands.
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| 3. |
- Gentile, Massimiliano, et al.
(författare)
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p53 and survival in early onset breast cancer : analysis of gene mutations, loss of heterozygosity and protein accumulation
- 1999
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 35:8, s. 1202-1207
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Tidskriftsartikel (refereegranskat)abstract
- The p53 protein has proven to be central in tumorigenesis by its cell cycle regulatory properties and both gene mutations and protein accumulation have been associated with poor prognosis in breast cancer. The present study was undertaken to investigate the prognostic significance of gene mutations, p53 protein accumulation and of loss of heterozygosity (LOH) at the TP53 locus in young (age <37 years) breast cancer patients. In total, gene mutations were found in 21 of the 123 patients (17%), LOH in 20 of the 47 informative cases (43%) and protein accumulation in 47 of the 102 available cases (46%). Log rank analysis revealed no significant association between survival and TP53 mutations (in general), p53 protein accumulation or LOH. However, missense mutations localised to the zinc binding domain were significantly (P=0.0007) associated with poorer prognosis. As indicated in this as well as other studies, p53 protein accumulation is frequently found in young breast cancer patients, but this protein overexpression appears to be of minor significance for survival. Nevertheless, the present report also suggests that specific mutations contribute substantially to tumour aggressiveness.
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| 4. |
- Johannsson, Oskar, et al.
(författare)
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Incidence of malignant tumours in relatives of BRCA1 and BRCA2 germline mutation carriers
- 1999
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Ingår i: European Journal of Cancer. - 1879-0852. ; 35:8, s. 1248-1257
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Tidskriftsartikel (refereegranskat)abstract
- We investigated cancer incidence between 1958 and 1995 in 1873 individuals belonging to 29 consecutively identified BRCA1 and 20 BRCA2 associated families from Southern Sweden using data from parish and local tax authorities, as well as the Swedish Cancer Registry, Cause of Death Registry and Census Registry. 150 malignant tumours were analysed from 1145 relatives in the BRCA1 families and 87 tumours were analysed from 728 relatives in the BRCA2 families. After excluding index cases which led to the mutation analysis, the incidence for all malignant tumours was significantly increased for both BRCA1- standardised morbidity rate, SMR, 1.98, 95% confidence interval (CI) 1.59-2.45; P < 0.0001 and BRCA2- (SMR 1.79, 95% CI 1.35-2.31; P < 0.0001) associated family members. For women in BRCA1-associated families, the incidence of breast cancer (SMR 3.76, 95% CI 2.29-5.80, P < 0.0001), ovarian cancer (SMR 15.49, 95% CI 9.46-23.92, P < 0.0001), stomach cancer (SMR 5.86, 95% CI 1.60-15.01, P = 0.005) were significantly increased. Amongst men only invasive squamous cell cancer of the skin was significantly increased (SMR 6.02, 95% CI 1.96-14.05, P = 0.002). In BRCA2 associated families, female breast cancer (SMR 3.03, 95% CI 1.61-5.18, P = 0.0005) was increased after exclusion of index cases. If these were included, ovarian cancer (SMR 5.16, 95% CI 1.89-11.24, P = 0.001), invasive cervical cancer (SMR 4.21, 95% CI 1.15-10.79, P = 0.016), male breast cancer (SMR 290.52, 95% CI 125.42-572.43, P < 0.0001), and prostate cancer (SMR 2.21, 95% CI 0.89-4.56, P = 0.042) were significantly increased. The increased risk for ovarian cancer in BRCA2 related families were limited to the cases leading to mutation analysis. Our data suggest that apart from breast and ovarian cancer, the incidence of other cancer types do not appear to be greatly increased in BRCA1- and BRCA2-associated families and does not warrant specific clinical follow-up in carriers.
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| 5. |
- Johannsson, Oscar Thor, et al.
(författare)
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Tumor Biological Features of BRCA1-Induced Breast Cancer
- 1997
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Ingår i: European Journal of Cancer. - 1879-0852. ; 33:3, s. 362-371
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Tidskriftsartikel (refereegranskat)abstract
- BRCA1 mutations, although implicated in disease predisposition in a major part of the hereditary breast cancer population, do not seem to be crucially involved in tumorigenesis of sporadic breast and ovarian cancers. This suggests that tumours arising in BRCA1 mutation carriers may differ from BRCA1 negative hereditary and sporadic cancer in genetic and biological features, as well as in clinical behaviour. Prior to BRCA1 analysis, 79 breast and 19 ovarian tumours from 57 breast and breast-ovarian cancer families, and 170 tumours from a comparison group of stage II breast cancers were studied with regard to histopathological features; immunohistochemistry [c-erbB-2, p53, oestrogen receptor (ER) and progesterone receptor (PR)], DNA flow cytometry and S-phase fraction. BRCA1 mutations were found in 40 breast and 15 ovarian tumours. The BRCA1 positive breast tumours were significantly more often of ductal type, histological grade III and manifested a heavy lymphocyte infiltration. Additionally, as compared to BRCA1 negative tumours, the BRCA1 positive tumours were significantly more often ER, PgR and c-erbB-2 negative. Furthermore, they were significantly more often DNA non-diploid, as well as being characterised by higher S-phase fraction values. These results suggest that BRCA1-induced breast cancers may manifest distinct tumour biological features of clinical importance.
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| 6. |
- Jonsson, O E, et al.
(författare)
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Perivascular cell protection in vivo and increased cell survival in vitro by the antihypertensive agent carvedilol following radiation
- 1999
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Ingår i: European Journal of Cancer. - 1879-0852. ; 35:8, s. 1268-1273
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Tidskriftsartikel (refereegranskat)abstract
- Carvedilol, an antihypertensive drug with activity on adrenoceptors as well as on calcium channel activity, has recently been introduced. In the present study we investigated whether carvedilol interacts with the cytotoxicity induced by irradiation in vitro as well as in vivo. A daily injection of carvedilol in clinically relevant concentrations (3 mg/kg subcutaneously), 4 days before and 3 days after a single radiation dose of 20 Gy significantly decreased the inflammatory reaction in the rat lung, evaluated as number of inflammatory cells in the perivascular area. The density of mast cells was also slightly reduced. In vitro studies revealed that carvedilol caused different radio-protective effects, dependent on dose (1-7 Gy) used and cell line studied. The effects were especially pronounced in a malignant mesothelioma cell line (P-31), and somewhat less evident in a prostatic carcinoma cell line (PC-3). No significant effect was seen in a highly radiosensitive small cell lung cancer cell line (U-1690). Thus, carvedilol may under some circumstances interact with radiation-induced tissue reactions, most probably by a direct interaction at the cellular level. The specific explanation to the differences in sensitivity to carvedilol remains to be evaluated, but the known antioxidative properties and/or scavenging of free radicals of carvedilol may be a plausible mechanism of action. Secondary induced alterations in inflammatory response may also be considered. It is suggested that a potential interaction between drugs such as carvedilol and irradiation should be considered for clinical practice.
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| 7. |
- Kjellén, Elisabeth, et al.
(författare)
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A Phase I/II Evaluation of Metoclopramide as a Radiosensitiser in Patients with Inoperable Squamous Cell Carcinoma of the Lung
- 1995
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 31:13-14, s. 2196-2202
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Tidskriftsartikel (refereegranskat)abstract
- The feasibility of administering metoclopramide (MCA) as a radiosensitizer has been evaluated in 23 patients with a pathological or cytological diagnosis of a squamous cell carcinoma of the lung, clinically evaluated as inoperable. All patients received 40-60 Gy radiotherapy fractionated into 1.8 Gy fractions 5 times per week (Monday-Friday). Two MCA treatment regimens were used: (i) MCA at 2 mg/kg administered by intravenous infusion 1-2 h prior to radiotherapy 3 times per week (Monday, Wednesday, Friday); and (ii) MCA at 1 mg/kg administered by intravenous infusion 1-2 h prior to radiotherapy 5 times per week (Monday-Friday). 11 of the 23 patients treated with radiotherapy and MCA had none to mild pneumonitis or fibrosis and another 8 of the 23 had moderate levels. No patient had their therapy interrupted due to radiation-related side-effects. The MCA-related side-effects were as expected, i.e. 78% of the patients experienced sedation/tiredness and 48% expressed restlessness/anxiety symptoms. Both the total dose and serum levels of MCA were significantly associated to the MCA side-effect profile. Tumour response, duration of tumour response and survival were significantly positively correlated to the total and weekly doses of MCA administered to the patients during their radiotherapy treatment. These favourable phase II data have justified the initiation of a phase II/III randomised multicentred trial being carried out in Europe to evaluate MCA as a radiosensitiser.
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| 8. |
- Nordén, T, et al.
(författare)
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Mammographic screening for breast cancer : What cancers do we find?
- 1997
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 33:4, s. 624-628
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare lymph node involvement of breast cancer cases detected at mammography screening with clinically-detected cases. During a 3-year period, 273 primary breast cancers were detected in a population-based screening programme, and 149 primary breast cancers were diagnosed clinically. Lymph node involvement was evaluated in univariate and multivariate logistic regression models correcting for tumour size, histological grade, steroid receptor status and DNA-ploidy. Patients with screen-detected cancers had a low relative risk of having lymph node metastases (univariate, OR = 0.31; 95% confidence interval = 0.19-0.52). In the multivariate logistic regression model, the relative risk was halved (OR = 0.47; 0.28-0.78). The reduced risk was more pronounced for women younger than 50 years of age compared to older women. The risk for screen-detected cases of having lymph node metastases at diagnosis was statistically significantly lower than for clinically-detected cases. The marked reduction, even when correcting for tumour size, makes it less likely that factors such as detection of clinically innocent tumours, length bias sampling or clinical symptoms related to axillary metastases can explain the whole difference. The results indicate at least part of the effect may be explained by tumour progression in the late preclinical detectable phase.
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| 9. |
- Norrback, Karl-Fredrik, et al.
(författare)
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Telomeres and telomerase in normal and malignant haematopoietic cells
- 1997
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 33:5, s. 774-780
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Tidskriftsartikel (refereegranskat)abstract
- The normal haematopoietic system harbours telomerase-competent cells with a capacity to upregulate the activity to notable levels in a telomere length-independent manner. Strong telomerase activity is found in progenitor stem cells and activated lymphocytes in vitro as well as in vivo, indicating that cells with high growth requirements can readily upregulate telomerase. Despite detection of telomerase activity, a gradual telomere erosion occurs in stem cells and lymphocytes, with significantly shortened telomeres at higher ages, a phenomenon that might be of importance for developing immunosenescence and exhausted haematopoiesis. In malignant haematopoietic disorders telomerase activity is a general finding with large differences in activity levels. The strongest telomerase expression has been shown in acute leukaemias and non-Hodgkin's lymphomas, especially high grade cases. There are indications that the level of activity might parallel tumour progression and be of prognostic relevance, but studies of larger patient materials are needed. An association between the cell cycle and telomerase activity exists, especially for normal haematopoietic cells, and induction of a differentiation programme in immortalised cell lines downregulates telomerase activity. The expression of telomerase activity seems to be regulated at different levels, since for immature bone marrow cells the level of activity seemed to parallel better the phenotype than the proliferation state. The frequent expression of telomerase in leukaemias and lymphomas makes these disorders interesting targets for future anti-telomerase therapy.
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| 10. |
- Påhlman, S., et al.
(författare)
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Differentiation and survival influences of growth factors in human neuroblastoma
- 1995
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Ingår i: European Journal of Cancer. - : Elsevier. - 0959-8049 .- 1879-0852. ; 31A:4, s. 453-458
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Tidskriftsartikel (refereegranskat)abstract
- Human neuroblastoma cell lines are established from high-stage, highly malignant tumours. Despite this and the fact that these tumours are arrested at an early, immature stage, many cell lines have the capacity to undergo neuronal differentiation under proper growth conditions. One such cell line is the noradrenergic SH-SY5Y cell line. These cells can be induced to mature by a variety of modalities, resulting in different mature phenotypes. The use of this cell system as a model to study the stem cell character of neuroblastoma is reviewed and discussed. In particular, we focus on growth factor dependencies in the SH-SY5Y system, and compare that to the normal situation, i.e. growth factor control of sympathetic neuronal and neuroendocrine differentiation during human and rat embryogenesis.
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