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- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Anselmino, M, et al.
(författare)
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Implications of abnormal glucose metabolism in patients with coronary artery disease
- 2008
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1479-1641 .- 1752-8984. ; 5:4, s. 285-290
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal glucose metabolism and type 2 diabetes mellitus (T2DM) are becoming increasingly common. It has been recently confirmed that the period of time prior to the development of diabetes, when patients have impaired glucose tolerance, may also predispose them to increased cardiovascular risk. Therefore prevention and management of T2DM and its antecedents must have high priority when allocating healthcare resources. The present review summarises some information on detection, management and treatment of abnormal glucose metabolism in patients with established coronary artery disease, highlighting the importance of early detection of abnormal glucose metabolism in order to prevent the progression of prediabetes to T2DM and to delay the occurrence of those macrovascular and microvascular complications that impair quality of life and diminish survival.
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| 8. |
- Dolled-Filhart, Marisa, et al.
(författare)
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Classification of breast cancer using genetic algorithms and tissue microarrays
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6459-6468
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: A multitude of breast cancer mRNA profiling studies has stratified breast cancer and defined gene sets that correlate with outcome. However, the number of genes used to predict patient outcome or define tumor subtypes by RNA expression studies is variable, nonoverlapping, and generally requires specialized technologies that are beyond those used in the routine pathology laboratory. It would be ideal if the familiarity and streamlined nature of immunohistochemistry could be combined with the rigorously quantitative and highly specific properties of nucleic acid-based analysis to predict patient outcome. EXPERIMENTAL DESIGN: We have used AQUA-based objective quantitative analysis of tissue microarrays toward the goal of discovery of a minimal number of markers with maximal prognostic or predictive value that can be applied to the conventional formalin-fixed, paraffin-embedded tissue section. RESULTS: The minimal discovered multiplexed set of tissue biomarkers was GATA3, NAT1, and estrogen receptor. Genetic algorithms were then applied after division of our cohort into a training set of 223 breast cancer patients to discover a prospectively applicable solution that can define a subset of patients with 5-year survival of 96%. This algorithm was then validated on an internal validation set (n=223, 5-year survival=95.8%) and further validated on an independent cohort from Sweden, which showed 5-year survival of 92.7% (n=149). CONCLUSIONS: With further validation, this test has both the familiarity and specificity for widespread use in management of breast cancer. More generally, this work illustrates the potential for multiplexed biomarker discovery on the tissue microarray platform.
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- Hage, C, et al.
(författare)
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Glycaemic control and restenosis after percutaneous coronary interventions in patients with diabetes mellitus: a report from the Insulin Diabetes Angioplasty study
- 2009
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 6:2, s. 71-79
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We investigated the impact of glucose control on target lesion restenosis after PCI in patients with type 2 diabetes. Methods: Ninety-three consecutive patients with type 2 diabetes accepted for PCI were randomised to intensified glucose control based on insulin (I-group; n=44) or to continue ongoing glucose-lowering treatment (C-group; n=49).The treatment target was a FBG of 5—7 mmol/L and HbA1c <6.5%. Information on target lesion restenosis after six months was available in 82 patients. Results: At baseline HbA1c and FBG did not differ between the I- and C-groups, respectively (HbA1c: 6.5 vs. 6.5%; p=1.0 and FBG: 7.0 vs. 7.3 mmol/L; p=0.3). After six months there was no significant change in HbA1c or FBG in either group (change in HbA1c: -0.2 vs.-0.1%; p=0.3 and in FBG: +0.2 vs. -0.3 mmol/L; p=0.3 in the I- and C-groups, respectively). Target lesion restenosis at six months did not differ, I vs. C = 41 and 44% (p=0.8). Independent predictors for restenosis were previous myocardial infarction (OR 8.0, 95% CI 2.5—25.7; p=<0.001) and FBG at baseline (OR for an increase by 1 mmol/L = 1.4, 95% CI 1.1—1.9; p=0.015). Conclusions: Restenosis was predicted by baseline FBG suggesting that it would be of interest to target glucose normalisation in future trials. Intensified insulin treatment did not influence the rate of restenosis indicating that the main focus should be on lowering glucose rather than the tool to normalise glucose.
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- Andersson, H., et al.
(författare)
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Transcriptional profiling of the peripheral blood response during tularemia
- 2006
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Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 7:6, s. 503-513
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Tidskriftsartikel (refereegranskat)abstract
- Tularemia is a febrile disease caused by the highly contagious bacterium Francisella tularensis. We undertook an analysis of the transcriptional response in peripheral blood during the course of ulceroglandular tularemia by use of Affymetrix microarrays comprising 14,500 genes. Samples were obtained from seven individuals at five occasions during 2 weeks after the first hospital visit and convalescent samples 3 months later. In total, 265 genes were differentially expressed, 95 of which at more than one time point. The differential expression was verified with real-time quantitative polymerase chain reaction for 36 genes (R(2)=0.590). The most prominent changes were noted in samples drawn on days 2-3 and a considerable proportion of the upregulated genes appeared to represent an interferon-gamma-induced response and also a proapoptotic response. Genes involved in the generation of innate and acquired immune responses were found to be downregulated, presumably a pathogen-induced event. A logistic regression analysis revealed that seven genes were good predictors of the early phase of tularemia. This is the first description of the transcriptional host response to ulceroglandular tularemia and the study has identified gene subsets relevant to the pathogenesis of the disease and subsets that may serve as early diagnostic biomarkers.
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| 22. |
- Anselmino, M, et al.
(författare)
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A gluco-metabolic risk index with cardiovascular risk stratification potential in patients with coronary artery disease
- 2009
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 6:2, s. 62-70
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Tidskriftsartikel (refereegranskat)abstract
- The primary objective of this study was to classify patients with CAD as regards their gluco-metabolic state by easily available clinical variables. A secondary objective was to explore if it was possible to identify CAD patients at a high cardiovascular risk due to metabolic perturbations. The 1,867 patients with CAD were gluco-metabolically classified by an OGTT. Among these, 990 patients had complete data regarding all components of the metabolic syndrome, BMI, HbA1c and medical history. Only FPG and HDL-c adjusting for age significantly impacted OGTT classification. Based on these variables, a neural network reached a cross-validated misclassification rate of 37.8% compared with OGTT. By this criterion, 1,283 patients with complete one-year follow-up concerning all-cause mortality, myocardial infarction and stroke (CVE) were divided into low- and high-risk groups within which CVE were, respectively, 5.1 and 9.4% (p=0.016).Adjusting for confounding variables the relative risk for a CVE based on the neural network was 2.06 (95% CI: 1.18—3.58) compared with 1.37 (95% CI: 0.79—2.36) for OGTT. Conclusions:The neural network, based on FPG, HDL-c and age, showed useful risk stratification capacities; it may, therefore, be of help when stratifying further risk of CVE in CAD patients.
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- Bartnik, M, et al.
(författare)
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Hyperglycaemia and cardiovascular disease
- 2007
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Ingår i: Journal of internal medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 262:2, s. 145-156
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Tidskriftsartikel (refereegranskat)
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| 32. |
- Bartnik, M, et al.
(författare)
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Management of patients with type 2 diabetes after acute coronary syndromes
- 2005
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Ingår i: Diabetes & vascular disease research. - : SAGE Publications. - 1479-1641 .- 1752-8984. ; 2:3, s. 144-54
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Tidskriftsartikel (refereegranskat)abstract
- Acute coronary syndromes are associated with a high risk for subsequent major cardiovascular events and with a risk for mortality that remains substantially increased for many months following the acute phase. Patients with type 2 diabetes mellitus are especially vulnerable and encounter excessive long-term mortality. Effective management of patients with type 2 diabetes following acute coronary syndromes requires aggressive multidisciplinary efforts for reduction of several risk factors, including meticulous control of blood glucose. The evidence for different medication and treatment strategies capable of improving the outcomes is reviewed and the currently available recommendations are summarised.
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- Berglund, Pontus, et al.
(författare)
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Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
- 2008
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
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| 37. |
- Brennan, Donal J., et al.
(författare)
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CA IX is an independent prognostic marker in premenopausal breast cancer patients with one to three positive lymph nodes and a putative marker of radiation resistance
- 2006
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 12:21, s. 6421-6431
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Hypoxia in breast cancer is associated with poor prognosis and down-regulation of the estrogen receptor. Carbonic anhydrase IX (CA IX) is a hypoxia-inducible gene that has been associated with poor outcome in many epithelial cancers. Previous studies of CA IX in breast cancer have been carried out on mixed cohorts of premenopausal and postmenopausal patients with locally advanced disease and varying treatment regimens. We examined the potential prognostic and predictive role of CA IX in premenopausal breast cancer patients. Experimental Design: Using tissue microarrays, we analyzed CA IX expression in 400 stage 11 breast cancers from premenopausal women. The patients had previously participated in a randomized control trial comparing 2 years of tamoxifen to no systemic adjuvant treatment. Median follow-up was 13.9 years. Results: CA IX expression correlated positively with tumor size, grade, hypoxia-inducible factor 1 alpha Ki-67, cyclin E, and cyclin A2 expression. CA IX expression correlated negatively with cyclin D1, estrogen receptor, and progesterone receptor. CA IX expression was associated with a reduced relapse-free survival (P = 0.032), overall survival (P = 0.022), and breast cancer specific survival (P = 0.005). Multivariate analysis revealed that CA IX was an independent prognostic marker in untreated patients with one to three positive lymph nodes (hazard ratio, 3.2; 95% confidence interval, 1.15-9.13; P = 0.027). Conclusion: CA IX is marker of poor prognosis in premenopausal breast cancer patients and it is an independent predictor of survival in patients with one to three positive lymph nodes. As all these patients received locoregional radiation therapy, CA IX may be associated with resistance to radiotherapy.
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| 39. |
- Eriksson, MJ, et al.
(författare)
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Left atrial mechanics in Type 2 Diabetics
- 2006
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Ingår i: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. - 0735-1097. ; 47:4, s. 120A-120A
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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- Giltnane, Jennifer M., et al.
(författare)
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Quantitative measurement of epidermal growth factor receptor is a negative predictive factor for tamoxifen response in hormone receptor - Positive premenopausal breast cancer
- 2007
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 25:21, s. 3007-3014
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Although there is evidence for interaction between epidermal growth factor receptor ( EGFR) and estrogen receptor ( ER), it is still not clear how this affects response to endocrine therapies like tamoxifen. Here we assess the relationship between EGFR expression and tamoxifen response, with a new quantitative technology. Patients and Methods A tissue microarray was constructed from breast cancer from a cohort of 564 patients enrolled in a randomized clinical trial for adjuvant tamoxifen treatment in early breast cancer, with a median follow-up of 14 years. EGFR expression was measured using automated quantitative analysis, a fluorescence-based method for quantitative analysis of in situ protein expression. Results In ER-positive patients, tamoxifen-treated patients with low EGFR expression ( n = 113) showed a significant effect by 2 years of adjuvant tamoxifen ( P = .01), in contrast to no treatment effect in the EGFR-high group ( n = 73, P = .69). The untreated group showed 49% v 57% 10-year recurrence-free survival for EGFR low versus high ( P = .466) in the corresponding group of ER-positive patients. A significant beneficial effect of tamoxifen treatment was seen in the EGFR-low group ( hazard ratio [ HR] = 0.43 ( 95% CI, 0.22 to 0.84; P = .013) in contrast to no effect in the EGFR-high group ( HR = 1.14; 95% CI, 0.59 to 2.22; P = .7) by using a Cox model. Conclusion This study provides clinical evidence that confirms the basic work that has shown high EGFR can indicate resistance to tamoxifen. It suggests that careful measurement of EGFR protein expression might define a subset of low-stage patients that could benefit from an alternative therapy.
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| 46. |
- Grubb, Tamara L, et al.
(författare)
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Physiologic responses and plasma endothelin-1 concentrations associated with abrupt cessation of nitric oxide inhalation in isoflurane-anesthetized horses
- 2008
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Ingår i: American Journal of Veterinary Research. - : American Veterinary Medical Association (AVMA). - 0002-9645 .- 1943-5681. ; 69:3, s. 423-430
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess physiologic responses and plasma endothelin (ET)-1 concentrations associated with abrupt cessation of nitric oxide (NO) inhalation in isoflurane-anesthetized horses. ANIMALS: 6 healthy adult Standardbreds. PROCEDURES: Horses were anesthetized with isoflurane in oxygen and placed in dorsal recumbency. Nitric oxide was pulsed into the respiratory tract for 2.5 hours, and then administration was abruptly discontinued. Just prior to commencement and at cessation of NO administration, and at intervals during a 30-minute period following cessation of NO inhalation, several variables including PaO(2), mean pulmonary artery pressure, venous admixture or pulmonary shunt fraction (Qs/Qt), and plasma ET-1 concentration were recorded or calculated. RESULTS: After cessation of NO inhalation, PaO(2) decreased slowly but significantly (172.7 +/- 29.8 mm Hg to 84.6 +/- 10.9 mm Hg) and Qs/Qt increased slowly but significantly (25 +/- 2% to 40 +/- 3%) over a 30-minute period. Mean pulmonary artery pressure increased slightly (14.0 +/- 1.3 mm Hg to 16.8 +/- 1 mm Hg) over the same time period. No change in serum ET-1 concentration was detected, and other variables did not change or underwent minor changes. CONCLUSIONS AND CLINICAL RELEVANCE: The improvement in arterial oxygenation during pulsed inhalation of NO to healthy isoflurane-anesthetized horses decreased only gradually during a 30-minute period following cessation of NO inhalation, and serum ET-1 concentration was not affected. Because a rapid rebound response did not develop, inhalation of NO might be clinically useful in the treatment of hypoxemia in healthy isoflurane-anesthetized horses.
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| 47. |
- Gustafsson, I., et al.
(författare)
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[Metabolic control by means of insulin in patients with type 2 diabetes and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity--secondary publication]
- 2006
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Ingår i: Ugeskr Laeger. - : Almindelige danske Lægeforening. - 1603-6824 .- 0041-5782. ; 168:6, s. 581-4
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Tidskriftsartikel (refereegranskat)abstract
- Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. The DIGAMI 2 study investigated the effect of various metabolic treatment strategies in type 2 diabetic patients with acute myocardial infarction: acutely introduced, long-term insulin treatment did not improve survival when compared with conventional management at similar levels of glucose control. However, good glucose control seems important since the glucose level was found to be a strong predictor of long-term mortality in this patient category.
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| 48. |
- Jarnert, C., et al.
(författare)
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Left atrial velocity vector imaging for the detection and quantification of left ventricular diastolic function in type 2 diabetes
- 2008
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Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842. ; 10:11, s. 1080-7
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Left ventricular (LV) diastolic dysfunction (DD) is diagnosed by Doppler echocardiography (DE) and Tissue Doppler imaging (TDI). Velocity vector imaging (VVI) evaluates myocardial deformation (strain). We studied left atrial (LA) deformation and volumes by VVI in relation to established Doppler-derived indices of LV diastolic function in diabetic patients. MATERIAL: Using DE and TDI , 87 patients (males 49%; age 60+/-7 years) with type 2 diabetes mellitus were classified as having no (n=60), mild (n=13) or moderate (n=14) DD. RESULTS: LA volume was larger in moderate (72.3+/-22.4 ml) than in mild DD (58.8+/-16.1 ml; p=0.01) and no DD (57.9+/-16.0 ml; p=0.01). LA roof strain distinguished no DD from mild and moderate DD (p=0.0073). Systolic LA strain correlated to total emptying fraction (r=0.70, p<0.0001), and inversely to LA volume (r=-0.35, p=0.0009). A cross-validated analysis of no versus mild or moderate DD expressed by LA strain revealed a positive predictive value of 48% and negative of 84%. CONCLUSION: LA strain by VVI is impaired in patients with type 2 diabetes mellitus and mild or moderate LV DD. LA strain seems of value in distinguishing normal from abnormal diastolic function. VVI offers new information on regional LA function and LA volumes but has too limited discriminative power to detect early LV DD.
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| 49. |
- Jirström, Karin, et al.
(författare)
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Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial
- 2005
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:11, s. 1135-1142
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Tidskriftsartikel (refereegranskat)abstract
- Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
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