E von Schoultz

Karolinska University Hospital, Tukholma, Stockholm, Sweden

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Publications (60)234.12 Total impact

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    ABSTRACT: Abstract Background: In women with breast cancer who were treated with either continuous tamoxifen alone or sequential tamoxifen followed by megestrol acetate (MA), we demonstrated significant positive associations between the breast tumor estrogen receptor (ER) and an increase in serum sex hormone-binding globulin (SHBG) during tamoxifen treatment. We interpreted this as "ER uniformity" in different tissues, e.g., breast, liver. No other associations with ER were found. In the same study, the breast tumor progesterone receptor (PR) was determined. Our aim was to see if there were any associations between PR and endocrine changes during MA treatment. The breast tumor PR before treatment and serum insulin-like growth factor I (∂IGF-1), steroids, steroid-binding proteins, and insulin before and during treatment were measured in 17 postmenopausal women with breast cancer who were treated sequentially with tamoxifen 40 mg/day followed by MA 160 mg/day in alternating 3-month periods. During MA treatment periods, the levels of IGF-1 and insulin increased significantly, whereas the levels of androgens, SHBG, corticosteroid-binding globulin, and cortisol decreased significantly. Significant positive correlations were found between the PR content and increments in ∂IGF-1 but not between PR and any other endocrine change. PR expression in human liver is very weak, but malignant and normal breast tissues secrete considerable amounts of growth hormone and IGF-1 in vitro and in vivo. This activity is stimulated by progestogens. The association between PR and ∂IGF-1 may therefore reflect a direct PR-mediated action of MA on malignant and normal human breast tissues in vivo.
    No preview · Article · Jun 2013 · Hormone molecular biology and clinical investigation
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    ABSTRACT: Background: The management of hormonal deficiency symptoms in breast cancer survivors is an unsolved problem. While hormone replacement therapy (HRT) may increase the risk of breast cancer in healthy women, its effects on recurrence is unclear. Observational studies have suggested decreased recurrence rates from HRT. The few clinical trials in this field have all been closed preterm. Methods: The Stockholm trial was started in 1997 and designed to minimise the dose of progestogen in the HRT arm. Disease-free women with a history of breast cancer were randomised to HRT (n=188) or no HRT (n=190). The trial was stopped in 2003 when another Swedish study (HABITS, the Hormonal Replacement After Breast Cancer - Is it Safe?) reported increased recurrence. However the Stockholm material showed no excess risk after 4 years of follow-up. A long term follow-up has now been performed. Findings: After 10.8 years of follow-up, there was no difference in new breast cancer events: 60 in the HRT group versus 48 among controls (hazard ratio (HR)=1.3; 95% confidence interval (CI)=0.9-1.9). Among women on HRT, 11 had local recurrence and 12 distant metastases versus 15 and 12 for the controls. There were 14 contra-lateral breast cancers in the HRT group and four in the control group (HR=3.6; 95% CI=1.2-10.9; p=0.013). No differences in mortality or new primary malignancies were found. Interpretation: The number of new events did not differ significantly between groups, in contrast to previous reports. The increased recurrence in HABITS has been attributed to higher progestogen exposure. As both trials were prematurely closed, data do not allow firm conclusions. Both studies found no increased mortality from breast cancer or other causes from HRT. Current guidelines typically consider HRT contraindicated in breast cancer survivors. Findings suggest that, in some women symptom relief may outweigh the potential risks of HRT.
    Full-text · Article · Aug 2012 · European journal of cancer (Oxford, England: 1990)
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    Full-text · Article · Oct 2011 · The Breast
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    ABSTRACT: To study the effects of menopausal hormone therapy (HT) on health-related quality of life in women after breast cancer. In the Stockholm trial, breast cancer survivors were randomized to HT (estradiol and progestogen) or to a control group (no treatment). A subgroup of 75 women was studied (38 with HT, 37 controls). Fifty patients were on concomitant tamoxifen. Patients completed three questionnaires (EORTC QLQ C-30, EORTC QLQ-BR 23 and the Hospital Anxiety and Depression Scale (HADS)) during 1 year of treatment. A significant group-by-time interaction was found for improvement of insomnia in the HT group (p < 0.001). Within the HT group, but not in the control group, there was significant improvement for HADS anxiety, HADS depression, emotional, cognitive, and social functions and global quality of life. When HT was added to tamoxifen, the increase in global quality of life was significant (p < 0.01). The effects of HT on quality of life in breast cancer survivors have not previously been reported. The present data suggest that this controversial treatment may improve quality of life after breast cancer.
    Full-text · Article · Mar 2010 · Climacteric
  • B Wallberg · E von Schoultz · C von SE Bolund · J Bergh · N Wilking
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    ABSTRACT: Objectives To investigate the attitudes of breast cancer patients who accepted or declined participation in a randomized trial with hormone replacement therapy that might increase their risk of recurrence (the Stockholm trial). MethodsA total of 115 patients free from breast cancer recurrence were interviewed; 57 were participants and 58 were non-participants in the Stockholm trial. Patients answered five questionnaires regarding information needs (two), attitudes to participation in trials (two) and patient role in treatment decisions (one). ResultsParticipants in the Stockholm trial had a lower risk of breast cancer recurrence (measured by node-positive disease and tumor size) and were older than non-participants. Their information needs were the same. Participants in the trial were more prepared to accept uncertainty, to have an altruistic attitude, to accept risks including an increased risk of recurrence of breast cancer, if their quality of life or general health was improved. Most patients preferred a collaborative role in relation to their physician but participants often wanted more influence than they had in treatment decisions. ConclusionA patient's decision to accept or decline participation in the Stockholm trial was influenced by her objective risk of breast cancer recurrence and reflected her attitude to risk, uncertainty and preference to be active in treatment decisions.
    No preview · Article · Dec 2009 · Climacteric
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    ABSTRACT: To investigate the possible correlation between expression of HER2 and vascular endothelial growth factor (VEGF), and to determine the predictive value of these factors in patients receiving adjuvant endocrine therapy including the group with a breast cancer (BC) positive for both oestrogen receptor (ER) and progesterone receptor (PgR). By enzyme immuno-sorbent assays (ELISA) tumour levels of HER2 and VEGF proteins were determined in 679 consecutive primary BC patients, median age 63 years, median follow-up time 92 months. A total of 404 patients received adjuvant endocrine therapy, mainly tamoxifen, out of them 295 had an ER and PgR positive BC. In 160 patients, HER2 status was also determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Overexpression of HER2 by IHC was found in 15% of the patients. Overexpression of HER2 by ELISA correlated with HER2 by IHC (P < 0.001) and a higher VEGF expression (P = 0.004). Patients receiving adjuvant endocrine therapy with high VEGF (RFS P = 0.0087, BCCS P = 0.0012) or over-expressing HER2 (RFS P = 0.0116, BCCS P = 0.0036) had significantly shorter survival. Factors retaining statistical significance in multivariate analyses for recurrence-free survival (RFS) were nodal status (P < 0.001), tumour size (P = 0.005) and VEGF (P = 0.032) and for breast cancer corrected survival (BCCS) nodal status (P < 0.001), tumour size (P = 0.001), ER status (P = 0.022), and VEGF (P = 0.016). Both factors were significantly correlated with survival in the group with a BC positive for both ER and PgR; VEGF (RFS P = 0.0177, BCCS P = 0.0321) and HER2 (RFS P = 0.0143, BCCS P = 0.0311). In multivariate analyses, nodal status (P < 0.001) and VEGF (P = 0.021) were independent factors for RFS. Nodal status (P < 0.001) and tumour size (P = 0.016) retained independent factors for BCCS. Combined analysis identified a high-risk group (HER2 positive and high VEGF) with significantly reduced survival. The results from this retrospective analysis suggest that overexpression of HER2 and higher VEGF expression may add information on patient's outcome after adjuvant endocrine therapy in ER and PgR positive BC.
    No preview · Article · Feb 2009 · Medical Oncology
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    ABSTRACT: Progestogens and progesterone receptors (PR) may play an important role in increased breast proliferation following combined estrogen/progestogen hormone therapy, while androgens may counteract this effect. In 50 untreated healthy postmenopausal women and 48 untreated postmenopausal breast cancer patients, we measured serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estrone (E(1)) and adrenal androgens; and additionally, in the breast cancer patients, cortisol and corticosteroid-binding globulin and endocrine data related to breast proliferation (assessed using the Ki-67/MIB-1 monoclonal antibody) and PR levels (determined by enzyme immunoassay) in the breast cancer tissue. In the healthy women the percentage of MIB-1(+) cells showed significant negative correlations with serum levels of total T, calculated free T (fT) and the fT/E(1) ratio; while in the breast cancer patients PR content showed significant negative correlations with fT level, the fT/E(1) ratio and the T/SHBG ratio. No other correlations were found in any of the groups. Our findings in healthy women confirm previous reports of an antiproliferative effect of androgens in breast tissue and our finding in breast cancer patients suggests that this antiproliferative effect may be mediated via downregulation of PR.
    No preview · Article · Jul 2008 · Gynecological Endocrinology
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    L Lofgren · L Sahlin · S Jiang · B Von Schoultz · R Fernstad · L Skoog · E Von Schoultz
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    ABSTRACT: The mammary stroma is important for modulating epithelial breast cell response to sex steroid hormones. Proteoglycans, such as syndecan-1, promote the integration of cellular signals. The immunohistochemical expression of syndecan-1 and of the androgen receptor (AR) was analyzed in paired samples of cancer and adjacent normal tissue from postmenopausal women. Normal and cancer tissue showed dramatic differences in the expression of syndecan-1. In malignant breast stroma, mean values were more than 10-fold higher than in normal tissue (p<0.001). There was also a marked redistribution from the epithelium to the stroma. The expression of AR was on average 2-fold higher in cancerous than in normal tissue (p<0.01). Breast cancer patients have very different prognoses. Syndecan-1 and the AR may be new molecular markers relevant to clinical outcome. The redistribution from the epithelium and the dramatic increase of syndecan-1 in cancerous stroma may be related to the natural history of the disease.
    Preview · Article · Sep 2007 · Anticancer research
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    ABSTRACT: Postmenopausal hormone therapy (HT) may increase breast cancer risk and influence tumor characteristics. We investigated 321 postmenopausal women aged 50-65 years, with breast cancer, diagnosed and treated at Radiumhemmet, Karolinska Hospital, during 1993-1997. In women using HT (n =90) estrogen receptor concentration (ER) at diagnosis were lower than in non-users (n =135) (1.17 vs 1.70 fmol/microg; p <0.05). HT users also had a tendency to less multifocal (5 vs 12%) (p <0.05) and metastatic disease (5% vs 2%) however this was not statistically significant. The estrogen receptor expression is always considered in the judgement on hormone dependency and the clinical decision on adjuvant endocrine therapy. A suppression of ER during HT could tentatively influence the treatment decisions in breast cancer patients and maybe disregard patients from endocrine treatment.
    Full-text · Article · Jan 2007 · Acta Oncologica
  • L Löfgren · E von Schoultz · R Fernstad · B von Schoultz · K Carlström
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    ABSTRACT: Individual women differ with respect to their sensitivity to estrogen and serum levels of sex hormone-binding globulin (SHBG) may reflect the individual response. We found a significant correlation between estrogen receptor (ER) concentrations in breast cancer tissue and SHBG levels during tamoxifen treatment. Estrogen sensitivity may be a general characteristic common to various organs and different between individual women.
    No preview · Article · May 2006 · The Journal of Steroid Biochemistry and Molecular Biology
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    ABSTRACT: To perform a pilot study of the effects on the breast by low-dose intrauterine progestogen combined with estrogen. A prospective pilot study. University hospital. Twenty postmenopausal women without any previous breast disorder. Women were treated with a low-dose intrauterine system releasing 20 microg/24 hours of levonorgestrel in continuous combination with 2 mg of oral E2 valerate. The effects on mammographic breast density, breast cell proliferation, and hormonal levels were followed for 18 months. Change in mammographic breast density and breast cell proliferation. Correlations with levels of hormones, growth factors, and binding proteins. Three women showed an apparent increase in density. For the remaining 17 women the changes were only a few percent. Digitized assessment of density showed strong correlations with visual classification scales (rs = 0.96-0.97). There was no increase in proliferation as expressed by the percentage of MIB-1-positive breast cells in fine-needle aspiration biopsies. Increase in breast density displayed a positive correlation with patients age (rs = 0.52) and an inverse relationship with levels of E2 (rs = -0.50) and free T (rs = -0.50). Low-dose intrauterine administration progestogen may develop into an attractive alternative for hormonal therapy in postmenopausal women as endometrial protection may be achieved at very low systemic levels.
    No preview · Article · May 2006 · Fertility and sterility
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    ABSTRACT: This study was undertaken to evaluate different methods for the detection of small changes in uptake between single-photon emission computed tomography (SPECT) examinations in the same individual. No standard exists for making digital evaluations at single-photon examinations. For this purpose, we employed a patient cohort from a previous study assessing the response to neoadjuvant chemotherapy for breast cancer using Tc-hexakis-2-methoxyisobutylisonitrile (Tc-sestamibi). The tumour uptake in 29 women with locally advanced breast cancer was examined using Tc-sestamibi and SPECT before neoadjuvant chemotherapy and, on average, 19 days after one chemotherapy cycle. The histology of the finally resected tumour confirmed a therapeutic response. Different assessments of the uptake, various levels of background activity subtraction and different reference tissues for relative activity calculations were used. The tumour uptake and activity of the reference tissues were also related to the administered activity. Different definitions of tumour activity had little influence. Relating the tumour uptake to a large portion of the abdomen, as well as visual evaluation, showed a therapeutic response. Comparison with the administered activity showed that the apparent responses were due to an increased activity of the reference tissues. Referring the tumour uptake to the administered activity truly depicted a therapeutic response. A critical attitude is necessary when making digital evaluations at SPECT. Digital data may seem more relevant than they really are. Relative comparisons may be unreliable. It may be necessary to develop standardized methods for this purpose.
    No preview · Article · May 2006 · Nuclear Medicine Communications
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    L Löfgren · L Sahlin · B Von Schoultz · R Fernstad · L Skoog · E Von Schoultz
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    ABSTRACT: Female sex steroids are implied in breast cancer development. The estrogen (ER) and progesterone (PR) receptor subtypes may have different roles to modulate the cellular response. Paired samples of cancer and adjacent normal tissue were collected from postmenopausal women at surgery for ductal breast cancer. The expression of ERa, ERss, PRA and PRB was quantified by immunostaining and digitized image analysis. We found ERss to be significantly reduced in breast cancer tissue (35% vs 50%; p?=?0.001) and there was also a decrease of the ERss/ERa ratio. Among women using hormones at the time of diagnosis tumor tissue showed higher values for both PRB and PRA, as compared to women without such treatment. The results extend previous animal data to be valid also in women. There is evidence that loss of ERss expression may relate to estrogen dependent tumor progression. Increased PR expression could possibly relate to breast cancer risk during combined estrogen/progestogen treatment.
    Full-text · Article · Feb 2006 · Acta Oncologica
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    Eva von Schoultz · Lars E Rutqvist
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    ABSTRACT: In 1997 two independent randomized clinical trials, Hormonal Replacement Therapy After Breast Cancer--Is It Safe? (HABITS; 434 patients) and the Stockholm trial (378 patients), were initiated in Sweden to compare menopausal hormone therapy with no menopausal hormone therapy after diagnosis of early-stage breast cancer. Much of the design of both studies was similar; however, a goal of the Stockholm protocol, not shared with the HABITS trial, was to minimize the use of progestogen combined with estrogen. The HABITS trial was prematurely stopped in December 2003, because, at a median follow-up of 2.1 years, the risk for recurrence of breast cancer among patients receiving menopausal hormone therapy was statistically significantly higher (relative hazard [RH] = 3.3, 95% confidence interval [CI] = 1.5 to 7.4) than among those receiving no treatment. In the Stockholm trial, however, at a median follow-up of 4.1 years, the risk of breast cancer recurrence was not associated with menopausal hormone therapy (RH = 0.82, 95% CI = 0.35 to 1.9). Statistically significant heterogeneity in the rate of recurrence was observed (P = .02; two-sided likelihood-ratio test) between the two studies, indicating that chance may not be the only explanation. Doses of estrogen and progestogen and treatment regimens for menopausal hormone therapy may be associated with the recurrence of breast cancer.
    Full-text · Article · May 2005 · Journal of the National Cancer Institute
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    ABSTRACT: To examine the effects on bone mineral density of 2 years of treatment with a luteinizing hormone-releasing hormone (LHRH) agonist alone or in combination with tamoxifen or tamoxifen alone in premenopausal breast cancer. We recruited 89 women from two centers in Stockholm participating in a randomized multicenter trial of three different endocrine approaches in the adjuvant setting (Zoladex in Premenopausal Patients Trial). The women were assigned to receive the LHRH agonist goserelin with or without tamoxifen, tamoxifen alone, or no endocrine therapy. The treatment was given for 2 years. We measured total-body bone density before start of treatment and at 12, 24, and 36 months. After 2 years of treatment, there was a significant loss of bone mineral density (mean change, -5%; P <.001) in the women receiving goserelin alone. The combined goserelin and tamoxifen treatment, as well as tamoxifen alone, resulted in a lesser but statistically significant decline in bone mineral density (mean change, -1.4%; P =.02; and -1.5%; P <.001). One year after cessation of treatment, the goserelin group alone showed a partial recovery from bone loss (mean change, 1.5%; P =.02). Two years of ovarian ablation from goserelin treatment caused a significant reduction in bone mineral density but there was a partial recovery from the bone loss 1 year after cessation of treatment. The addition of tamoxifen seems to partially counteract the demineralizing effects of goserelin.
    Full-text · Article · Sep 2004 · Journal of Clinical Oncology
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    ABSTRACT: To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer. A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d. We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression. The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.
    No preview · Article · Feb 2004 · Medical Oncology

  • No preview · Article · Sep 2003 · EJC Supplements
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    ABSTRACT: The present study was performed to evaluate the immunocytochemical analysis (ICA) of oestrogen (ER) and progesterone receptor (PR) in fine needle aspiration (FNA) biopsies from primary breast cancers as compared with the established enzyme immunoassays (ER-EIA and PR-EIA) based on cytosol homogenates from the corresponding resected tumour specimens. A total of 967 primary breast cancers were assessed for ER and PR content by both methods. Correlations between EIA and ICA expressed as percentage of tumour cells with a positive staining were highly significant (P < 0.001) for ER and PR. Staining intensity yielded only limited additional information. The concordance between the two techniques was about 80%. Evaluation of biological parameters by FNA may be useful to decide the optimal treatment for breast cancer patients.
    No preview · Article · Jul 2003 · Cytopathology
  • B Wilczek · E von Schoultz · J Bergh · E Eriksson · SA Larsson · H Jacobsson
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    ABSTRACT: Response assessment at neoadjuvant (preoperative) chemotherapy of locally advanced breast cancer using clinical examination and mammography is insensitive. Mammoscintigraphy with 99mTc-MIBI was studied for the prediction of response at such therapy before finishing the chemotherapy cycles. Chemotherapy was given as repeated courses of 5-fluorouracil, epirubicin and cyclophosphamide (FEC). In 1 patient group (n = 23), the tumor uptake relative to surrounding breast tissue and lung tissue at SPECT examination after finishing neoadjuvant chemotherapy was compared with the examination made before chemotherapy. In another group (n = 30), a similar comparison after the first therapy cycle (mean 19 days) with a baseline examination was made. Histologic examination of the resected tumors was made. After finishing chemotherapy, there was a strong reduction of the relative tumor activity, while there was no correlation with therapy effect as assessed by histology. After one therapy course, there was no significant reduction of the relative tumor uptake. Scintigraphy with 99mTc-MIBI demonstrated the response after finished neoadjuvant chemotherapy of breast cancer using FEC-courses. It cannot be used to predict a therapy response after one therapy course.
    No preview · Article · Jun 2003 · Acta Radiologica
  • E Isaksson · H Wang · L Sahlin · B von Schoultz · J M Cline · E von Schoultz
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    ABSTRACT: Estrogen is a well-known mitogen in breast epithelium but the role of progesterone is complex and incompletely understood. In contrast to what is seen in the endometrium, combined estrogen/progestogen treatment for postmenopausal replacement (HRT) may carry a risk for breast cancer beyond that of estrogen alone. The ratio of the two progesterone receptor (PR) isoforms, PRA/PRB may define the response to progesterone in reproductive tissues. In a primate model for long-term HRT, surgically, postmenopausal cynomolgus macaques were treated for 35 months with conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE + MPA and tamoxifen (n = 5 in all groups). The immunohistochemical expression of PRA, PRB and the androgen receptor (AR) in breast tissue was quantified by image analysis. Over all, the total PR immunostaining in glandular epithelium was more abundant during CEE (mean 12%) and tamoxifen ( 1%) treatment as compared to CEE/MPA (5%), MPA (4%) and untreated controls (6%). Differences in PRB expression were observed between treatment groups (p < 0.05). In the CEE group levels of PRA were unchanged while there was a decline in the CEE/MPA group. The mean PRA/PRB ratio in the CEE group was 2.7 and in the CEE/MPA group 0.2. Treatment with tamoxifen had effects similar to those of estrogen. There was in all groups a weak positive nuclear AR immunostaining. This is the first in vivo study on the effects on long-term hormonal treatment on the expression of PR isoforms in normal primate breast tissue. The results suggest that hormonal treatments have a different influence on the PRA/PRB balance in the breast.
    No preview · Article · May 2003 · Breast Cancer Research and Treatment

Publication Stats

1k Citations
234.12 Total Impact Points


  • 1996-2013
    • Karolinska University Hospital
      • • Department of Obstetrics and Gynecology
      • • Department of Oncology
      Tukholma, Stockholm, Sweden
  • 2004-2011
    • Karolinska Institutet
      • Department of Oncology-Pathology
      Solna, Stockholm, Sweden
  • 1988-1994
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1993
    • Akademiska Sjukhuset
      Uppsala, Uppsala, Sweden