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Biomedical subjects

K Holli

Publications and source records attributed to K Holli.

At least 37 records · Page 2Linked to original sources
PubMed2000

Toremifene. where do we stand?

Toremifene is a chlorinated triphenylethylene that is indicated for postmenopausal breast cancer. For advanced disease, toremifene has been found to be as effective and at least as well tolerated as tamoxifen. The same appears to apply for adjuvant setting. After a total cumulative clinical exposure to toremifene of approximately 140000 patient-years, only 9 cases of endometrial carcinoma have been reported. The annual hazard rate (per 1000 patient-years) of developing endometrial carcinoma in breast cancer patients on adjuvant toremifene is 1.14 (versus tamoxifen 2.0 and placebo 0.4). Although toremifene (being a partial agonist) may unmask pre-existing endometrial tumours, there is no clinical data implying that it would per se cause endometrial carcinoma.

Antineoplastic Agents, Hormonal↗
PubMed2000

Serum lipid levels during and after adjuvant toremifene or tamoxifen therapy for breast cancer.

Tamoxifen decreases serum cholesterol (S-cholesterol) level about 10% and low-density lipoprotein cholesterol (S-LDL) 15-20%, but in most studies it has increased serum triglyceride levels and had little effect on serum high-density cholesterol (S-HDL). The effect of another antiestrogen, toremifene, on the serum lipid profile has not been completely studied. We monitored serum lipid levels longitudinally in 141 axillary node-positive postmenopausal breast cancer patients who received randomly either 40 mg toremifene or 20 mg tamoxifen as adjuvant therapy for 36 months, and in 34 postmenopausal women who received no adjuvant systemic therapy after surgery for axillary node-negative breast cancer. No significant differences were found between the drugs in their effects on S-cholesterol, LDL, HDL, or triglyceride levels, or on the cholesterol-to-HDL or LDL-to-HDL ratios. For both drugs the S-cholesterol and S-LDL absolute lowering effect was the greater the higher the pretreatment level. For a patient with a median pretreatment value, toremifene decreased S-cholesterol 6% and tamoxifen 13%, and S-LDL decreased by 13% and 23%, respectively, at 6 months of therapy. Six months after stopping three-year antiestrogen therapy S- cholesterol and S-LDL levels had returned to the pretreatment levels. In conclusion, we found no major differences between 40 mg toremifene and 20 mg of tamoxifen in their effect on the serum lipid levels, which return to the pretreatment levels within 6 months after cessation of therapy.

Age Factors↗
PubMed2000

Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.

In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.

Adult↗
PubMed1999

Quality control in health care: an experiment in radiotherapy planning for breast cancer patients after mastectomy.

PURPOSE: The importance of evaluating and improving quality in clinical practice is now generally acknowledged. In this study we estimated different sources of variation in radiotherapy planning for breast cancer patients after mastectomy and sought to test the applicability of a reproducibility and repeatability (R&R) study in a clinical context. METHODS: Eleven radiation oncologists planned radiotherapy three times for three different kinds of breast cancer patients without knowing they were handling the same patient three times. Variation was divided into different components: physicians as operators, patients as parts, and repeated measurements as trials. Variation due to difference across trials (repeatability), that across the physicians (reproducibility), and that across the patients (variability) were estimated, as well as interactions between physicians and patients. Calculation was based on the sum of squares, and analysis was supported by various graphical presentations such as range charts and box plots. RESULTS: Some parts of the planning process were characterized by higher and different kinds of variation than the others. Interphysician variation (i.e., reproducibility) was not high but there were some clearly outlying physicians. The highest variation was in repeatability (= intraphysician variation). The major part of the variation was, however, that from patient to patient: 33% of the total in Parameter 1 and 85% of the total in Parameter 2. CONCLUSIONS: R&R studies are applicable and are needed to evaluate and improve quality in clinical practice. This kind of analysis provides opportunities to establish which kinds of patients require particularly careful attention, which points in the process are most critical for variation, which are the most difficult aspects for each physician and call for more careful description in documents, and which physicians need further training.

Analysis of Variance↗
PubMed1999

The visibility of cancer on earlier mammograms in a population-based screening programme.

The aim of this study was to examine how frequently the later-round screen-detected and interval breast cancers were visible in earlier screening mammograms by retrospective review and to compare their radiological and clinicopathological features with those diagnosed by primary screening. In a population-based mammography screening programme 63,731 women aged 50-59 years were invited and 56,158 examinations were carried out in the period 1987-1992 in the Tampere area in Finland. A total of 276 breast cancers were detected, of which 131 were diagnosed on later screening rounds or were interval cancers. A retrospective review of previous screening mammograms was carried out in 130 cases by the radiologist who diagnosed the breast cancer and thus knew the exact location of the tumour, no blinded review was carried out. 43 (33%) cancers were visible, 84 (65%) were not visible and 3 (2%) not included on the mammogram in a retrospective review. Later round screen-detected cancers were statistically significantly more often visible in earlier screening mammograms (43%) than interval cancers (19%) (P = 0.002). Tumours missed by screening mammography but which were visible on retrospective review were often histologically well-differentiated and were more often diagnosed in the subsequent screening round than by clinical diagnosis as interval cancers. If all retrospectively visible interval cancers had been diagnosed by screening 19% (10/54) of the interval cancers could have been avoided. If all retrospectively visible cancers had been diagnosed at the time of false-negative screening or assessment 65% (84/130) of all patients would have benefitted from an earlier diagnosis compared with the actual figure of 31% (41/130).

Breast Neoplasms↗
PubMed1999

Smoking and survival from lung cancer.

The role of smoking in the etiology of lung cancer is well known but less is known about whether smoking also affects the pathological process. In the present analysis 290 lung cancer patients were divided into three equal-sized groups according to lifetime cigarette consumption (heavy, moderate, light/none). The age of the patient, histology, TNM and S-phase fraction of the tumor were confirmed as prognostic factors. The association between smoking and these factors was evaluated. There was a significant difference in histological type of tumor; adenocarcinomas were more common than other types among light smokers. Tumor size, nodal status and occurrence of distant metastases did not differ significantly between the smoking groups. Heavy smokers had a greater frequency of aneuploid tumors and the S-phase fraction was higher among these patients but neither of these differences was statistically significant. Survival analysis indicated no statistically significant association between survival and lifetime total cigarette consumption. Apart from histological type, smoking is not materially associated with clinical and biological prognostic factors, nor does smoking materially affect the survival of lung cancer patients. Our study material was relatively small and therefore not of sufficient power to detect small effects.

Aged↗
PubMed1999

Hereditary breast cancer.

Information on genetics is in process of exponential growth, with a corresponding recognition that most medical information, screening and diagnostic tests, and disease processes have a genetic component. Hereditary breast cancer is a good example, showing the complexity of cancer genetics in a clinical context. The contribution of family history to the risk of developing breast cancer has been appreciated for some time. Breast cancer was believed to be a result of multiple genetic and environmental factors. Today it is known that single genes are also responsible for breast cancer and some of these genes (BRCA1 and BRCA2) can be identified by genetic testing. Genetic information on breast cancer is, however, still limited and although the tests that are now available can be beneficial, they also carry some risks and limitations.

BRCA2 Protein↗
PubMed1999

Comparison of pharmacokinetics of clodronate after single and repeated doses.

OBJECTIVE: Pharmacokinetics of orally given clodronate disodium, a drug for the treatment of hypercalcemia and bone resorption, were studied after a single dose of 400, 800 and 1600 mg given randomly to 11 healthy volunteers in a crossover manner, in 7-14 hospitalized cancer patients given 400, 800 and 1600 mg twice daily, each dosage for one week, and during the customary therapy in 15 additional cancer patients treated in hospital with 400 mg thrice daily for > or = 2 weeks. METHODS: Clodronate concentrations in serum and urine were measured by capillary gaschromatography with mass-selective detection. Pharmacokinetic parameters were calculated with a three-compartmental model. RESULTS: After a single oral dose to healthy volunteers the absolute clodronate concentrations increased almost dose-dependently. The mean cumulative excretion in urine was 1.72-2.77% of the dose, an interindividual range being from 0.92% to 5.52%. With 800 and 1600 mg twice daily for one week to cancer patients the serum drug concentrations increased almost progressively with increasing the dose. In cancer patients serum drug concentrations were clearly higher and renal drug clearances (mean 25-62 ml/min) lower than in healthy volunteers (mean 123-149 ml/min). The mean urinary excretions were 2.24-3.14% of the dose and interindividual ranges from 0.18% to 19.0%. During the routine cancer therapy with 400 mg thrice daily, the clodronate excretions in urine on two successive days were on an average 3.26% (range 0.0-10.5%). CONCLUSIONS: Absolute concentrations in serum and excretions in urine of orally given clodronate increase dose-dependently, but during the maintenance therapy in hospitalized cancer patients the renal drug clearances seem to be lower than in healthy volunteers. This and the large interindividual variation in kinetics propose therapeutic monitoring of clodronate for optimizing the oral dose of the drug.

Adult↗
PubMed1998

Predictive value of topoisomerase IIalpha and other prognostic factors for epirubicin chemotherapy in advanced breast cancer.

Although cytotoxic chemotherapy is widely used in advanced breast cancer, there are no powerful predictors for the therapy response. Because topoisomerase IIalpha (Topo IIalpha) is the molecular target for the anthracycline class of anti-cancer drugs, we compared the immunocytochemical assay of Topo IIalpha with other biomarkers in the prediction of clinical response to Topo II inhibitor chemotherapy. Fifty-five patients with advanced breast cancer were treated with a single cytotoxic drug, Topo II-inhibitor, epirubicin (30 mg m(-2) weekly up to 1000 mg m(-2)), as first line cytotoxic chemotherapy. Objective response to treatment was analysed according to UICC criteria. The predictive value of Topo IIalpha expression, c-erbB2 oncoprotein, p53 tumour-suppressor protein, oestrogen (ER) and progesterone receptor (PR), S-phase fraction and DNA ploidy were analysed from representative formalin-fixed paraffin-embedded primary tumour samples. The proportion of Topo IIalpha-positive cells (Topo IIalpha index) failed to predict response to epirubicin therapy. Mean Topo IIalpha scores in 29 responding patients were similar when compared with those with no change in disease progression (n = 13) and those with progressive disease (n = 13) (14.9% +/- 11.4% vs 15.5% +/- 7.6% vs 17.3% +/- 13.2%, not significant). Among the other biomarkers tested, overexpression of c-erbB2 oncoprotein and hormone receptor negativity were significantly associated with poor response. Response rate in patients with c-erbB2-overexpressing tumours was 32% compared with 65% in patients with no c-erbB2 overexpression (P = 0.0058). Accordingly, the response rate for ER-positive patients was 67% compared with 26% in ER-negative patients (P = 0.0021). Although both negative ER status and c-erbB2 overexpression are associated with high Topo IIalpha expression in breast cancer, step-wise logistic regression analysis showed that ER and c-erbB2 were associated with therapy response independent of Topo IIalpha expression. Histological grade, p53, DNA-ploidy, tumour proliferation rate (S-phase fraction), stage of the disease at diagnosis, age of the patient, previous anti-oestrogen therapy or site of metastasis did not predict the response to epirubicin therapy. In conclusion, despite extensive in vitro evidence, expression of Topo IIalpha is unlikely to predict the response to Topo II inhibitor chemotherapy in advanced breast cancer. Among the prognostic biomarkers, overexpression of c-erbB2 oncogene and negative ER may have predictive value in epirubicin therapy in patients with advanced breast cancer.

Antibiotics, Antineoplastic↗
PubMed1998

Effect of radiotherapy on the interpretation of routine follow-up mammography after conservative breast surgery: a randomized study.

Radiotherapy after conservative surgery causes fat necrosis, fibrosis, skin thickening and other parenchymal distortion of the breast. The interpretation of a mammogram of the irradiated breast may therefore be difficult. We studied the effect of radiotherapy on the interpretation of the routine mammography used in the follow-up of breast cancer patients. A total of 144 low-risk breast cancer patients were randomized to radiotherapy or to no further treatment after conservative surgery. The first routine follow-up mammography was performed 18 months after surgery and every 18 months after that. The number of mammography examinations was estimated per patient and per follow-up year. The number of extra diagnostic tests and the occurrence of positive findings were assessed per mammography session and per follow-up year. Further diagnostic tests prompted by difficulties in interpreting the mammogram were performed to an extent of 0.19 per mammography examination in the radiotherapy group and of 0.15 in the non-radiotherapy group, i.e. 1.3 times more often. Findings that turned out to be negative at confirmation were 2.0 times (P< 0.05) more common in the radiotherapy group. These false-positive findings were more common in the radiotherapy group than in the surgery group and only shortly after treatment. Mammography is more difficult to interpret after radiotherapy than after conservative surgery alone, especially shortly after treatment, and more often involves extra diagnostic tests and findings that will be negative at confirmation.

Breast Neoplasms↗
PubMed1998

Combination chemotherapy versus single-agent therapy as first- and second-line treatment in metastatic breast cancer: a prospective randomized trial.

PURPOSE: We report results of a randomized prospective study that compared single agents of low toxicity given both as the first-line and second-line chemotherapy with combination chemotherapy in advanced breast cancer with distant metastases. PATIENTS AND METHODS: Patients in the single-agent arm (n = 153) received weekly epirubicin (E) 20 mg/m2 until progression or until the cumulative dose of 1,000 mg/m2, followed by mitomycin (M) 8 mg/m2 every 4 weeks, and those in the combination chemotherapy arm (n = 150) were first given cyclophosphamide 500 mg/m2, E 60 mg/m2, and fluorouracil 500 mg/m2 three times per week (CEF) followed by M 8 mg/m2 plus vinblastine (V) 6 mg/m2 every 4 weeks. Exclusion criteria included age greater than 70 years, World Health Organization (WHO) performance status greater than 2, prior chemotherapy for metastatic disease, and presence of liver metastases in patients younger than 50. RESULTS: An objective response (complete [CR] or partial [PR]) was obtained in 55%, 48%, 16%, and 7% of patients treated with CEF, E, M, and MV, respectively. A response to CEF tended to last longer than a response to E (median, 12 v 10.5 months; P = .07). Treatment-related toxicity was less in the single-agent arm and quality-of-life (QOL) analysis favored the single-agent arm. No significant difference in time to progression or survival was found between the two arms. Similarly, no difference in survival was found when the patients who received both the planned first-and second-line treatments were compared or when survival was calculated from the beginning of the second-line therapy. CONCLUSION: Patients treated with single-agent E followed by single-agent M had similar survival, but less treatment-related toxicity and better QOL as compared with those treated with CEF followed by MV.

Adult↗
PubMed1998

Low biologic aggressiveness in breast cancer in women using hormone replacement therapy.

PURPOSE: Hormone replacement therapy (HRT) has been associated with an increased risk for breast cancer. Cancers in women who use HRT are often less advanced, and lower mortality has been reported in those who use HRT than in nonusers. We sought to explain this by a comparison of indicators of tumor aggressiveness in patients who received HRT with those in patients who did not. PATIENTS AND METHODS: A population-based cohort of 477 postmenopausal women with breast cancer were interviewed for the use, type, and duration of HRT. Clinical variables and indicators of tumor aggressiveness (histologic grade, hormone receptors, DNA ploidy, S-phase fraction, and c-erbB-2 oncoprotein overexpression) were analyzed. RESULTS: Breast tumors from HRT users were smaller (odds ratio, 0.47; P=.005), had better histologic differentiation (P=.04), and had a lower proliferation rate (S-phase fraction, P=.009) than tumors from nonusers. These differences persisted after adjustments for age and method of diagnosis (mammography screening v self-referral) by multiple logistic regression. No significant differences were observed in the estrogen (ER) or progesterone receptor content, c-erbB-2 oncogene overexpression, or axillary node involvement. A subgroup analysis showed that the tumor proliferation rates among HRT users were significantly lower only if HRT had been used at the time of diagnosis (P=.001). The type of HRT (estrogen v combination of estrogen and progesterone) was not associated with any clinical parameter or tumor phenotype. The association of HRT with lower proliferation rate and smaller tumor size was exclusively caused by ER-positive tumors (P=.0001 and P=.0035 v P > .1, respectively). CONCLUSION: The results indicate that breast cancer in women who receive HRT is biologically less aggressive than those without previous HRT. The lower cell-proliferation rate and smaller tumor size found in ER-positive tumors from current HRT users suggest a direct ER-mediated growth inhibitory effect of HRT on established breast tumors. This may at least partly explain why breast cancer in HRT users has a more favorable clinical course.

Aged↗
PubMed1998

Adjuvant trials of toremifene vs tamoxifen: the European experience.

When results from the phase II trials of toremifene (Fareston) and tamoxifen (Nolvadex) in metastatic breast cancer were published, the Finnish Breast Cancer Group began to plan the first trial of toremifene in an adjuvant setting. This multicenter, randomized trial is comparing toremifene (40 mg/d) to tamoxifen (20 mg/d) in postmenopausal lymph node-positive breast cancer patients. Treatment duration is 3 years. About 1,150 of a planned 1,460 patients have been enrolled to date. The International Breast Cancer Study Group is also conducting two adjuvant trials evaluating 5 years of toremifene (60 mg/d) vs tamoxifen (20 mg/d). More than 1,000 patients have been enrolled in these studies to date. The efficacy of toremifene is being explored in all of these trials. In the Finnish trial, additional protocols are evaluating treatment side effects, including the formation of DNA adducts in the endometrium and leukocytes, certain ocular problems, thromboembolic events, and subjective side effects. The effects of toremifene on lipid levels and bone density are also being studied. An interim safety analysis, performed in the Finnish study after 500 patients were enrolled (mean follow-up, 18 months), showed no significant differences between toremifene and tamoxifen in terms of efficacy or side effects. Toremifene seems to be well tolerated and may have additional positive effects. Ongoing trials will soon reveal how beneficial toremifene is in the adjuvant setting and whether it is devoid of the adverse effects observed with tamoxifen.

Antineoplastic Agents, Hormonal↗
PubMed1997

Effect of age on the survival of breast cancer patients.

Despite numerous studies, the effect of patient age on the prognosis of breast cancer is still uncertain. The aim of this study was to assess the influence of age on long-term relative survival, to control the results for the extent of disease at diagnosis and assess the association between biological markers and age of the patients. A population-based survival study was made to assess the 5- and 10-year relative survival. All 17,856 female breast cancer patients diagnosed in Finland and reported to the Finnish Cancer Registry in 1977-1986 were included. The results were controlled for the extent of the disease. The markers of biological aggressiveness of tumours and patients' age were correlated in a prospectively collected subset of 2107 patients from the Tampere University area. The relative 5-year and 10-year survival rates (RSRs) were highest in women 46-50 years of age, whereas there was no significant difference between younger and older age groups. No consistent survival trends were observed among the age groups in local, node-negative disease, whereas in node-positive disease the 10-year relative survival was best for women 41-45 years (49%) and poorest in women over 75 years (35%). The youngest age groups were significantly more often oestrogen receptor-negative, but only small differences were observed for S-phase fraction and progesterone receptor positivity.

Adolescent↗